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Bibliography on: Publications by FHCRC Researchers

RJR-3x

Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Jun 2022 at 01:43 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2022-06-29

Arber DA, Orazi A, Hasserjian RP, et al (2022)

International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data.

Blood pii:485730 [Epub ahead of print].

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

RevDate: 2022-06-29

Greaney AJ, Eguia RT, Starr TN, et al (2022)

The SARS-CoV-2 Delta variant induces an antibody response largely focused on class 1 and 2 antibody epitopes.

PLoS pathogens, 18(6):e1010592 pii:PPATHOGENS-D-22-00448 [Epub ahead of print].

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.

RevDate: 2022-06-29

Kennedy JJ, Whiteaker JR, Ivey RG, et al (2022)

Internal Standard Triggered-Parallel Reaction Monitoring Mass Spectrometry Enables Multiplexed Quantification of Candidate Biomarkers in Plasma.

Analytical chemistry [Epub ahead of print].

Despite advances in proteomic technologies, clinical translation of plasma biomarkers remains low, partly due to a major bottleneck between the discovery of candidate biomarkers and costly clinical validation studies. Due to a dearth of multiplexable assays, generally only a few candidate biomarkers are tested, and the validation success rate is accordingly low. Previously, mass spectrometry-based approaches have been used to fill this gap but feature poor quantitative performance and were generally limited to hundreds of proteins. Here, we demonstrate the capability of an internal standard triggered-parallel reaction monitoring (IS-PRM) assay to greatly expand the numbers of candidates that can be tested with improved quantitative performance. The assay couples immunodepletion and fractionation with IS-PRM and was developed and implemented in human plasma to quantify 5176 peptides representing 1314 breast cancer biomarker candidates. Characterization of the IS-PRM assay demonstrated the precision (median % CV of 7.7%), linearity (median R2 > 0.999 over 4 orders of magnitude), and sensitivity (median LLOQ < 1 fmol, approximately) to enable rank-ordering of candidate biomarkers for validation studies. Using three plasma pools from breast cancer patients and three control pools, 893 proteins were quantified, of which 162 candidate biomarkers were verified in at least one of the cancer pools and 22 were verified in all three cancer pools. The assay greatly expands capabilities for quantification of large numbers of proteins and is well suited for prioritization of viable candidate biomarkers.

RevDate: 2022-06-29

Ali MW, Chen J, Yan L, et al (2022)

A risk variant for Barrett's esophagus and esophageal adenocarcinoma at chr8p23.1 affects enhancer activity and implicates multiple gene targets.

Human molecular genetics pii:6619442 [Epub ahead of print].

Nineteen genetic susceptibility loci for esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) have been identified through genome-wide association studies (GWAS). Clinical translation of such discoveries, however, has been hindered by the slow pace of discovery of functional/causal variants and gene targets at these loci. We previously developed a systematic informatics pipeline to prioritize candidate functional variants using functional potential scores, applied the pipeline to select high-scoring BE/EAC risk loci, and validated a functional variant at chr19p13.11 (rs10423674). Here, we selected two additional prioritized loci for experimental interrogation: chr3p13/rs1522552 and chr8p23.1/rs55896564. Candidate enhancer regions encompassing these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two regions tested exhibited allele-specific enhancer activity - 8p23.1/rs55896564. CRISPR-mediated deletion of the putative enhancer in EAC cell lines correlated with reduced expression of three candidate gene targets: B lymphocyte kinase (BLK), nei like DNA glycosylase 2 (NEIL2), and cathepsin B (CTSB). Expression quantitative trait locus (eQTL) mapping in normal esophagus and stomach revealed strong associations between the BE/EAC risk allele at rs55896564 (G) and lower expression of CTSB, a protease gene implicated in epithelial wound repair. These results further support the utility of functional potential scores for GWAS variant prioritization, and provide the first experimental evidence of a functional variant and risk enhancer at the 8p23.1 GWAS locus. Identification of CTSB, BLK, and NEIL2 as candidate gene targets suggests that altered expression of these genes may underlie the genetic risk association at 8p23.1 with BE/EAC.

RevDate: 2022-06-29

Lai E, Kennedy EB, Lozach J, et al (2022)

A Method for Variant Agnostic Detection of SARS-CoV-2, Rapid Monitoring of Circulating Variants, and Early Detection of Emergent Variants Such as Omicron.

Journal of clinical microbiology [Epub ahead of print].

The rapid emergence of SARS-CoV-2 variants raised public health questions concerning the capability of diagnostic tests to detect new strains, the efficacy of vaccines, and how to map the geographical distribution of variants to understand transmission patterns and loads on healthcare resources. Next-generation sequencing (NGS) is the primary method for detecting and tracing new variants, but it is expensive, and it can take weeks before sequence data are available in public repositories. This article describes a customizable reverse transcription PCR (RT-PCR)-based genotyping approach which is significantly less expensive, accelerates reporting, and can be implemented in any lab that performs RT-PCR. Specific single-nucleotide polymorphisms (SNPs) and indels were identified which had high positive-percent agreement (PPA) and negative-percent agreement (NPA) compared to NGS for the major genotypes that circulated through September 11, 2021. Using a 48-marker panel, testing on 1,031 retrospective SARS-CoV-2 positive samples yielded a PPA and NPA ranging from 96.3 to 100% and 99.2 to 100%, respectively, for the top 10 most prevalent World Health Organization (WHO) lineages during that time. The effect of reducing the quantity of panel markers was explored, and a 16-marker panel was determined to be nearly as effective as the 48-marker panel at lineage assignment. Responding to the emergence of Omicron, a genotyping panel was developed which distinguishes Delta and Omicron using four highly specific SNPs. The results demonstrate the utility of the condensed panel to rapidly track the growing prevalence of Omicron across the US in December 2021 and January 2022.

RevDate: 2022-06-28

Hill JA, Moon SH, Chandak A, et al (2022)

Clinical and Economic Burden of Multiple dsDNA Viral Infections After Allogeneic Hematopoietic Cell Transplantation.

Transplantation and cellular therapy pii:S2666-6367(22)01407-5 [Epub ahead of print].

BACKGROUND: Conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) are immunosuppressive and increase the risk for reactivation of and infection with double-stranded deoxyribonucleic acid (dsDNA) viruses, which contribute to morbidity and mortality after allo-HCT.

OBJECTIVE: This retrospective observational study evaluated the association of dsDNA viral infections with clinical outcomes, health resource utilization (HRU), and health care reimbursement after allo-HCT.

STUDY DESIGN: Patients who underwent allo-HCT (2012 through 2017) were identified from a US open-source claims database (Decision Resource Group Real-World Evidence Data Repository; N=13,363) and categorized according to presence or absence of dsDNA viral infection, defined as having ≥1 diagnosis code for CMV, AdV, HHV-6, or BKV/EBV/JCV (grouped together given lack of specific diagnoses codes) within 1 year after allo-HCT. Only first allo-HCT data were used in patients who underwent multiple procedures. Study outcomes included clinical outcomes (time to all-cause mortality, new diagnosis of renal impairment), HRU (hospital and intensive care unit length of stay [LOS], readmission rates), and health care reimbursement (total, inpatient, and outpatient costs as reported reimbursements from insurance claims). For all outcomes, patients were stratified by presence/absence of any dsDNA viral infection and number (none, 1, 2, ≥3) and type(s) of infection. The effect of graft-versus-host disease (GVHD) was also assessed.

RESULTS: Twenty-nine percent of patients were diagnosed with CMV; 13% with BKV, EBV, or JCV; 5% with AdV; and 4% with HHV-6 in the year following their first allo-HCT. A single dsDNA viral infection was documented in 30% of individuals, 2 in 8%, and ≥3 in 2%. Patients with no viral infections had an overall hospital LOS (index hospitalization plus readmissions) of 41.3 days and a total health care reimbursement of $266,345. These numbers increased for every additional viral infection, regardless of presence or absence of GVHD: patients with 1 viral infection had an overall hospital LOS of 61.4 days and a total healthcare reimbursement of $431,614; patients with 2 viral infections had 77.0 days and $639,097; patients with ≥3 had 103.3 days and $964,378. An increase in the number of dsDNA viral infections was associated with a significantly higher adjusted hazard of all-cause mortality (1 vs no dsDNA viral infections: hazard ratio [95% confidence interval], 1.5 [1.3-1.6]; 2 vs none: 2.0 [1.7-2.3]; and ≥3 vs none: 2.4 [1.8-3.3]) and a significantly higher incidence of new diagnosis of renal impairment, regardless of the presence of GVHD (35% of patients with ≥3 infections, 31% of patients with 2 infections, 26% of patients with 1 infection, and 19% of patients with no infection).

CONCLUSION: These results indicate that more directed prevention and treatment strategies for dsDNA viral infections could substantially improve clinical outcomes and reduce HRU.

RevDate: 2022-06-28

Nnaji C, Smith JC, Daffin GK, et al (2022)

Engaging in Intersectional Liberation for Every(Black)Body Impacted by Anti-Blackness and HIV-Related Stigma.

American journal of public health, 112(S4):S380-S383.

RevDate: 2022-06-28

Hunidzarira P, Brown ER, Chirenje ZM, et al (2022)

Population-level correlation between incidence of curable sexually transmitted infections and HIV-1 among African women participating in HIV-1 pre-exposure prophylaxis trials.

The Journal of infectious diseases pii:6619245 [Epub ahead of print].

BACKGROUND: Highly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for HIV-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STI) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP.

METHODS: We analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modelling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1.

RESULTS: Across 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe) STI and HIV-1 incidences were high: HIV-1 4.9, N. gonorrhoeae 5.3, C. trachomatis 14.5, and T. vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N. gonorrhoeae (r=0.02, p=0.871), C. trachomatis (r=0.49, p=<0.001), and T. vaginalis (r=0.10, p=0.481). The modest association with C. trachomatis was driven by country-level differences in both C. trachomatis and HIV-1, with no statistically significant association within countries.

CONCLUSIONS: STI incidence did not reliably predict HIV-1 incidence at the population level amongst at-risk African women participating in two large PrEP trials.

RevDate: 2022-06-28

Emerson MA, Olshan AF, Chow EJ, et al (2022)

Hospitalization and Mortality Outcomes Among Childhood Cancer Survivors by Race, Ethnicity, and Time Since Diagnosis.

JAMA network open, 5(6):e2219122 pii:2793635.

Importance: Cancer outcomes are relatively poor in adults who belong to minoritized racial and ethnic groups. Survival and long-term outcomes by race and ethnicity in individuals with childhood cancers are less studied.

Objective: To evaluate survival and hospitalization among American Indian and Alaska Native, Asian, Black, and Hispanic children compared with non-Hispanic White children with cancer.

This cohort study evaluated all individuals born in Washington State who were younger than 20 years (hereafter referred to as children) and had been diagnosed with cancer during 1987 to 2012, with follow-up ranging from 1 to 27 years. The data subset was built in 2019, and statistical analyses were completed in January 2022.

Exposures: Race and ethnicity.

Main Outcomes and Measures: Mortality and hospitalization events for all other racial and ethnic groups relative to non-Hispanic White children estimated by Cox proportional hazards regressions for the first 5 years after diagnosis and among cancer survivors 5 or more years after diagnosis.

Results: A total of 4222 children (mean [SD] age, 8.4 [6.4] years; 2199 [52.1%] male; 113 American Indian and Alaska Native [2.7%], 311 Asian [7.4%], 196 Black [4.6%], 387 Hispanic [9.2%], and 3215 non-Hispanic White [76.1%]) with cancer diagnosed at younger than 20 years during 1987 to 2012 were included. Mortality was similar across all groups. Compared with non-Hispanic White survivors at less than 5 years after diagnosis, there were no greatly increased hazard ratios (HRs) for hospitalization. Among survivors at 5 or more years after diagnosis, hospitalization HRs were 1.7 (95% CI, 1.0-3.0) for American Indian and Alaska Native survivors and 1.5 (95% CI, 0.9-2.4) for Black survivors. Significantly increased HRs among Hispanic children were observed for infection-related (HR, 1.4; 95% CI, 1.2-1.6), endocrine-related (HR, 1.3; 95% CI, 1.1-1.6), hematologic-related (HR, 1.3; 95% CI, 1.1-1.5), respiratory-related (HR, 1.3; 95% CI, 1.0-1.5), and digestive-related (HR, 1.2; 95% CI, 1.0-1.5) conditions. American Indian and Alaskan Native children had increased HRs for infection-related (HR, 2.3; 95% CI, 1.2-4.5), hematologic-related (HR, 3.0; 95% CI, 1.4-6.5), and digestive-related (HR, 2.6; 95% CI, 1.3-5.4) conditions. Both American Indian and Alaska Native (HR, 3.6; 95% CI, 1.4-9.0) and Black (HR, 2.5; 95% CI, 1.2-5.5) children had increased mental health-related hospitalizations and death.

Conclusions and Relevance: In this cohort study, disproportionately increased long-term risks of hospitalization for physical and mental conditions may have contributed to worse outcomes by race. A key component to bridging the morbidity gap by race is improved understanding of reasons for greater cause-specific hospitalizations in some groups, with development of culturally appropriate intervention strategies.

RevDate: 2022-06-28

Starr TN, Greaney AJ, Hannon WW, et al (2022)

Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution.

Science (New York, N.Y.) [Epub ahead of print].

SARS-CoV-2 has evolved variants with substitutions in the spike receptor-binding domain (RBD) that impact its affinity for ACE2 receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites-a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single amino-acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently N501Y, cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change, for example enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

RevDate: 2022-06-28

Renner CS, Sumarsono A, Mathew A, et al (2022)

Scholarly productivity and growth of academic hospital medicine full professors.

Journal of hospital medicine [Epub ahead of print].

BACKGROUND: Scholarship remains the principal currency for faculty promotion in academic medicine. Reference points for scholarly growth and productivity at academic medical centers (AMCs) are lacking.

METHODS: We identified hospital medicine full professors (HMFPs) at AMCs ranked in research by US News & World Report. Scopus was used to identify each HMFP's publications, citations, and Hirsch-index (H-index). Publications; citations; and first, middle, and senior author papers were measured in 3-year intervals postresidency. Scholarly productivity was analyzed by quintile based on publications, AMC research ranking, years postresidency, and grant funding.

RESULTS: Data were extracted for 128 HMFPs from 54 AMCs. HMFPs were a mean of 20.5 (SD: 5.4) years postresidency. The median H-index was 7.0 (interquartile range [IQR]: 2.0-16.0); the median number of publications was 15.0 (IQR: 4.0-51.0). Top quintile HMFPs had a median of 175.5 (IQR: 101.5-248.0) publications, whereas fifth quintile HMFPs had a median of 0.0 (IQR: 0.0-1.0) (p < .001). HMFPs on faculty at the top 20 AMCs had a median of 35.5 (IQR: 11.0-108.0) publications, whereas HMFPs in AMCs ranked 81-122 had a median of 3.0 (IQR: 1.0-9.0) (p < .001). Grant-funded HMFPs had a median of 177.0 (IQR: 71.0-278.0) publications, while nongrant-funded HMFPs had a median of 11.0 (IQR: 3.0-25.0) (p < .001). At 3, 6, and 9 years postresidency, HMFPs had a median of 0.0 (IQR: 0.0-1.0), 1.5 (IQR: 0.0-5.0), and 3.5 (IQR: 0.0-11.0) publications. Fellowship training, additional degrees, and top 25 residency programs correlated with the top half of scholarly productivity.

CONCLUSIONS: Scholarly productivity among HMFPs varies considerably. At 3, 6, and 9 years postresidency, it is minimal to modest. Grant funding and AMC research rank may establish separate frames of reference for scholarly growth.

RevDate: 2022-06-27

Sasamoto N, Wang T, Townsend MK, et al (2022)

Pre-diagnosis and post-diagnosis dietary patterns and survival in women with ovarian cancer.

British journal of cancer [Epub ahead of print].

BACKGROUND: Evidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors.

METHODS: We examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality.

RESULTS: Pre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04-3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99-1.92; high/high HR = 1.58, 95% CI = 1.09-2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06-1.95; high/high HR = 1.55, 95% CI = 1.10-2.19).

CONCLUSION: Consuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship.

RevDate: 2022-06-28
CmpDate: 2022-06-21

Wierda WG, Brown J, Abramson JS, et al (2022)

NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2022.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(6):622-634.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

RevDate: 2022-06-25

Reid LA, Mendoza JA, Merchant AT, et al (2022)

Household Food Insecurity is Associated with Diabetic Ketoacidosis but not Severe Hypoglycemia or Glycemic Control in Youth and Young Adults with Youth-Onset Type 2 Diabetes.

Pediatric diabetes [Epub ahead of print].

OBJECTIVE: To examine the association between household food insecurity (HFI), glycemic control, severe hypoglycemia and diabetic ketoacidosis (DKA) among youth and young adults (YYA) with youth-onset type 2 diabetes.

RESEARCH DESIGN AND METHODS: This cross-sectional study included 395 YYA with type 2 diabetes from the SEARCH for Diabetes in Youth Study (2015-2019). HFI was reported by young adult participants or parents of minor participants via the US Household Food Security Survey Module. Glycemic control was assessed by HbA1c and analyzed as a continuous and categorical variable (optimal: <7.0%, suboptimal: ≥7.0%-9.0%, poor: >9.0%). Acute complications included self-reported severe hypoglycemia or DKA in the last 12 months. Adjusted logistic and linear regression were used for binary and continuous outcomes, respectively.

RESULTS: Approximately 31% reported HFI in the past 12 months. Mean HbA1c among those with HFI was 9.2% compared to 9.5% without HFI. Of those with HFI, 56% had an HbA1c > 9.0% compared to 55% without HFI. Adjusted models showed no associations between HFI and glycemic control. Of those with HFI, 14.4% reported experiencing DKA and 4.7% reported severe hypoglycemia. YYA with HFI had 3.08 times (95% CI: 1.18-8.06) the odds of experiencing DKA as those without HFI. There was no association between HFI and severe hypoglycemia.

CONCLUSIONS: HFI was associated with markedly increased odds of DKA but not with glycemic control or severe hypoglycemia. Future research among YYA with type 2 diabetes should evaluate longitudinally whether alleviating HFI reduces DKA. This article is protected by copyright. All rights reserved.

RevDate: 2022-06-24

Ferjan Ramírez N, Hippe DS, K Lindekugel (2022)

Electronic media and social features of language input in bilingually-raised Latinx infants.

Infant behavior & development, 68:101740 pii:S0163-6383(22)00054-6 [Epub ahead of print].

The present study examines the language environments of bilingually-raised Latinx infants (n = 37) to characterize the relation between exposure to electronic media and infants' language input, with a specific focus on parentese, a near-universal style of infant-directed speech, distinguished by its higher pitch, slower tempo, and exaggerated intonation. Previous research shows that parentese and parent-infant turn-taking are both associated with advances in children's language learning. Here we test the hypothesis that exposure to electronic media is associated with a reduction in these two social features of language input. Using the Language Environment Analysis (LENA) technology, two daylong audio recordings were collected from each family. Exposure to electronic media was measured in three ways: 1) Through LENA's automatic estimate; 2) Through manual annotation of LENA audio recordings; and 3) Through a parental questionnaire. Language of electronic media, parental language input, and child language output were quantified through automatic and manual analyses of LENA recordings. Infants' estimated daily exposure to electronic media varied between the three methods used. There was a significant positive correlation between daily media exposure assessed via the two observational methods, but neither significantly correlated with parental report. Infants experienced electronic media in Spanish and English, and the language of electronic media correlated with the language of paternal and maternal child-directed speech. Linear regression analyses controlling for demographics (infant age, sex, socioeconomic status) demonstrated a negative association between exposure to electronic media and parentese, as well as between exposure to electronic media and turn-taking. Exposure to electronic media was also negatively associated with infants' linguistic vocalizations. The present findings suggest that exposure to electronic media negatively impacts infant vocal activity by reducing parental parentese and parent-infant turn-taking, which are known to positively impact infants' linguistic, socioemotional, and cognitive development. This analysis is an important step forward in understanding Latinx infants' electronic media ecologies and their relation to language input and language development.

RevDate: 2022-06-24

Chow EJ, Casto AM, Roychoudhury P, et al (2022)

The Clinical and Genomic Epidemiology of Rhinovirus in Homeless Shelters-King County, Washington.

The Journal of infectious diseases pii:6617600 [Epub ahead of print].

BACKGROUND: Rhinovirus (RV) is a common cause of respiratory illness in all people, including those experiencing homelessness. RV epidemiology in homeless shelters is unknown.

METHODS: We analyzed data from a cross-sectional homeless shelter study in King County, Washington, October 2019-May 2021. Shelter residents or guardians aged ≥3 months reporting acute respiratory illness completed questionnaires and submitted nasal swabs. After April 1, 2020, enrollment expanded to residents and staff regardless of symptoms. Samples were tested by multiplex RT-PCR for respiratory viruses. A subset of RV-positive samples was sequenced.

RESULTS: There were 1,066 RV-positive samples with RV present every month of the study period. RV was the most common virus before and during the COVID-19 pandemic (43% and 77% of virus-positive samples, respectively). Participants from family shelters had the highest prevalence of RV. Among 131 sequenced samples, 33 RV serotypes were identified with each serotype detected for ≤4 months.

CONCLUSIONS: RV infections persisted through community mitigation measures and was most prevalent in shelters housing families. Sequencing showed a diversity of circulating RV serotypes each detected over short periods of time. Community-based surveillance in congregate settings is important to characterize respiratory viral infections during and after the COVID-19 pandemic.

RevDate: 2022-06-24

Nair VS, Hui AB, Chabon JJ, et al (2022)

Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer.

Cancer research pii:705060 [Epub ahead of print].

Genomic profiling of Bronchoalveolar Lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non-small cell lung cancer (NSCLC) to those detected in matched plasma samples. CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared to those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (p<0.001) and in stage I-II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA (mean VAF=0.5%), suggesting the presence of somatic mutations in non-malignant airway cells. Finally, using a Random Forest model with leave-one-out cross validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility.

RevDate: 2022-06-23

Li Z, Ji BW, Dixit PD, et al (2022)

Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Nature metabolism [Epub ahead of print].

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.

RevDate: 2022-06-23

Holtan SG, Yu J, Paranagama D, et al (2022)

Disease progression, hospital readmissions, and clinical outcomes for patients with steroid-refractory acute graft-versus-host disease: A multicenter, retrospective study.

Bone marrow transplantation [Epub ahead of print].

Acute graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). This analysis of 168 patients (mean age, 54.8 years) from a multicenter, retrospective chart review describes the clinical course, treatment patterns, hospitalizations, and clinical outcomes of patients aged ≥12 years who developed grades II-IV acute GVHD after their first allogeneic HCT (January 1, 2014, to June 30, 2016) and were refractory to or dependent on corticosteroids. Between diagnosis and maximum grade (median, 6.0 days), 53.6% of patients had new organ involvement, particularly lower gastrointestinal tract acute GVHD, or an increase in acute GVHD grade. Eighty-nine patients (53.0%) received additional systemic GVHD therapy (after systemic corticosteroids) within a median of 21.0 days. Hospital readmission(s) was required for 56.5% of patients within 100 days post-HCT (mean inpatient length of readmission stay, 49.5 days); 24.4% had ≥2 readmissions within 100 days post-HCT. From the date of acute GVHD diagnosis, 70.2% of patients died at a median (interquartile range) of 117.5 (49-258) days. In summary, steroid-refractory and steroid-dependent acute GVHD is associated with a rapidly worsening clinical course that leads to high readmission and mortality rates, emphasizing the need for effective and tolerable therapies.

RevDate: 2022-06-23

Banach BB, Tripathi P, Da Silva Pereira L, et al (2022)

Highly protective antimalarial antibodies via precision library generation and yeast display screening.

The Journal of experimental medicine, 219(8):.

The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.

RevDate: 2022-06-22

Khoury JD, Solary E, Abla O, et al (2022)

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

Leukemia [Epub ahead of print].

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

RevDate: 2022-06-22

Chow EJ, Winestone LE, Lupo PJ, et al (2022)

Leveraging clinical trial populations and data from the Children's Oncology Group for cancer survivorship research.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:705069 [Epub ahead of print].

Children and adolescents diagnosed with cancer can now expect an average 85% five-year overall survival, with significant improvements in longer-term morbidity and mortality reported over the past several decades. However, the long-term impact of therapeutic agents and modalities introduced in recent years remains unclear and will require dedicated follow-up in the years ahead. The Children's Oncology Group (COG), a part of the National Cancer Institute's National Clinical Trials Network, with over 200 sites across North America and beyond, enrolls more than 10,000 patients onto research protocols annually, inclusive of front-line clinical trials and non-therapeutic studies. COG provides a platform to conduct survivorship research with several unique strengths: 1) a huge catchment to ascertain relatively rare but important adverse events, 2) study populations that are otherwise too rare to study in smaller consortia, including access to highly diverse patient populations, 3) long-term follow-up of clinical trial populations linked to the original trial data, and 4) a natural platform for intervention research. Enhancements in COG infrastructure facilitate survivorship research, including a COG patient registry (Project:EveryChild), availability of a long-term follow-up tracking resource, and successful deployment of various remote-based study procedures to reduce the burden on participants and participating institutions.

RevDate: 2022-06-22

Baron SW, Yu PC, Imrey PB, et al (2022)

Early treatment with thiamine and mortality among patients with alcohol use disorder who are hospitalized for pneumonia.

Journal of hospital medicine [Epub ahead of print].

BACKGROUND: The paucity of research linking thiamine treatment with improved outcomes may be driving its underutilization among patients at risk for Wernicke encephalopathy.

OBJECTIVE: To assess relationships of thiamine usage to outcomes of patients hospitalized with alcohol use disorder and pneumonia. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective cohort study of adult patients hospitalized with pneumonia who also have alcohol use disorder and were treated with benzodiazepines during the initial two hospital days, between 2010 and 2015 at hospitals participating in the Premier Healthcare Database.

EXPOSURE: Any thiamine treatment, and, among those treated, high-dose thiamine treatment, during the initial two hospital days.

MAIN OUTCOME AND MEASURES: Death on days 3-14 of hospitalization (primary); discharge home; transfer to intensive care unit; length of stay (LOS). We used propensity-weighted models to estimate treatment effects.

RESULTS: Among 36,732 patients from 625 hospitals, 26,520 (72.2%) patients received thiamine, with mortality of 6.5% and 8.1% among recipients and nonrecipients, respectively. With propensity score adjustment, thiamine was associated with reduced mortality (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.75-0.85) and more frequent discharges to home (OR: 1.10, 95% CI: 1.06-1.14). Other outcomes were similar. Relative to low-dose thiamine, high-dose thiamine was not associated with mortality (adjusted OR: 0.99, 95% CI: 0.89-1.10), but LOS was longer (ratio of means: 1.06, 95% CI: 1.04-1.08), and discharges to home were less frequent (OR: 0.92, 95% CI: 0.87-0.97).

CONCLUSION: Thiamine is not reliably given to patients with pneumonia and alcohol use disorder receiving benzodiazepines. Improving thiamine administration may represent an opportunity to save lives in this high-risk group of inpatients.

RevDate: 2022-06-21

Takuva S, Takalani A, Seocharan I, et al (2022)

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

PLoS medicine, 19(6):e1004024 pii:PMEDICINE-D-21-04884.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data.

METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting.

CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

RevDate: 2022-06-21

Watts EL, Perez-Cornago A, Fensom GK, et al (2022)

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.

International journal of epidemiology pii:6609600 [Epub ahead of print].

BACKGROUND: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.

METHODS: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.

RESULTS: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.

CONCLUSIONS: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

RevDate: 2022-06-17

Jiao B, Hankins JS, Devine B, et al (2022)

Application of validated mapping algorithms between generic PedsQL scores and utility values to individuals with sickle cell disease.

Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation [Epub ahead of print].

PURPOSE: There is a paucity of empirically estimated health state utility (HSU) values to estimate health-related quality of life among individuals with sickle cell disease (SCD). This study aims to map the Pediatric Quality of Life Inventory generic core scales (PedsQL GCS) to HSUs for children and adolescents with SCD in the United States, using published algorithms, and to assess the construct validity of these HSUs against SCD-specific PedsQL scores.

METHODS: We used the published mapping algorithms identified in four published articles, in which the PedsQL GCS was mapped to either the EuroQol-5 Dimension 3-Level, Youth Version or the Child Health Utility 9-Dimension to obtain HSUs. We employed the algorithms to calculate HSUs for a sample of children and adolescents from the Sickle Cell Clinical Research and Intervention Program. To assess the construct validity of the mapped HSUs in SCD patients, we computed Spearman's correlation coefficient comparing the HSUs with the PedsQL SCD total score and separately with each PedsQL SCD dimension-specific score.

RESULTS: The mean mapped HSU across published algorithms was 0.792 (95% CI: 0.782-0.801). It was significantly higher among children aged 5-12 years than children aged 13-17 years. The Spearman's correlation coefficient for HSUs versus PedsQL SCD total scores was 0.64 (95% CI: 0.57-0.71). Correlations ranged from 0.40 (95% CI: 0.32-0.48) to 0.60 (95% CI: 0.54-0.66) for HSUs versus PedsQL SCD dimension-specific scores.

CONCLUSIONS: The existing mapping algorithms show acceptable construct validity in children and adolescents with SCD. Additional algorithms are needed for adults and for specific SCD comorbidities.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Barfield R, Qu C, Steinfelder RS, et al (2022)

Association between germline variants and somatic mutations in colorectal cancer.

Scientific reports, 12(1):10207.

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.

RevDate: 2022-06-20

Bossarte RM, Kessler RC, Nierenberg AA, et al (2022)

The Appalachia Mind Health Initiative (AMHI): a pragmatic randomized clinical trial of adjunctive internet-based cognitive behavior therapy for treating major depressive disorder among primary care patients.

Trials, 23(1):520.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disease morbidity. Combined treatment with antidepressant medication (ADM) plus psychotherapy yields a much higher MDD remission rate than ADM only. But 77% of US MDD patients are nonetheless treated with ADM only despite strong patient preferences for psychotherapy. This mismatch is due at least in part to a combination of cost considerations and limited availability of psychotherapists, although stigma and reluctance of PCPs to refer patients for psychotherapy are also involved. Internet-based cognitive behaviorial therapy (i-CBT) addresses all of these problems.

METHODS: Enrolled patients (n = 3360) will be those who are beginning ADM-only treatment of MDD in primary care facilities throughout West Virginia, one of the poorest and most rural states in the country. Participating treatment providers and study staff at West Virginia University School of Medicine (WVU) will recruit patients and, after obtaining informed consent, administer a baseline self-report questionnaire (SRQ) and then randomize patients to 1 of 3 treatment arms with equal allocation: ADM only, ADM + self-guided i-CBT, and ADM + guided i-CBT. Follow-up SRQs will be administered 2, 4, 8, 13, 16, 26, 39, and 52 weeks after randomization. The trial has two primary objectives: to evaluate aggregate comparative treatment effects across the 3 arms and to estimate heterogeneity of treatment effects (HTE). The primary outcome will be episode remission based on a modified version of the patient-centered Remission from Depression Questionnaire (RDQ). The sample was powered to detect predictors of HTE that would increase the proportional remission rate by 20% by optimally assigning individuals as opposed to randomly assigning them into three treatment groups of equal size. Aggregate comparative treatment effects will be estimated using intent-to-treat analysis methods. Cumulative inverse probability weights will be used to deal with loss to follow-up. A wide range of self-report predictors of MDD heterogeneity of treatment effects based on previous studies will be included in the baseline SRQ. A state-of-the-art ensemble machine learning method will be used to estimate HTE.

DISCUSSION: The study is innovative in using a rich baseline assessment and in having a sample large enough to carry out a well-powered analysis of heterogeneity of treatment effects. We anticipate finding that self-guided and guided i-CBT will both improve outcomes compared to ADM only. We also anticipate finding that the comparative advantages of adding i-CBT to ADM will vary significantly across patients. We hope to develop a stable individualized treatment rule that will allow patients and treatment providers to improve aggregate treatment outcomes by deciding collaboratively when ADM treatment should be augmented with i-CBT.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04120285 . Registered on October 19, 2019.

RevDate: 2022-06-20

Koh KA, Montgomery AE, O'Brien RW, et al (2022)

Predicting Homelessness Among U.S. Army Soldiers No Longer on Active Duty.

American journal of preventive medicine, 63(1):13-23.

INTRODUCTION: The ability to predict and prevent homelessness has been an elusive goal. The purpose of this study was to develop a prediction model that identified U.S. Army soldiers at high risk of becoming homeless after transitioning to civilian life based on information available before the time of this transition.

METHODS: The prospective cohort study consisted of observations from 16,589 soldiers who were separated or deactivated from service and who had previously participated in 1 of 3 baseline surveys of the Army Study to Assess Risk and Resilience in Servicemembers in 2011-2014. A machine learning model was developed in a 70% training sample and evaluated in the remaining 30% test sample to predict self-reported homelessness in 1 of 2 Longitudinal Study surveys administered in 2016-2018 and 2018-2019. Predictors included survey, administrative, and geospatial variables available before separation/deactivation. Analysis was conducted in November 2020-May 2021.

RESULTS: The 12-month prevalence of homelessness was 2.9% (SE=0.2%) in the total Longitudinal Study sample. The area under the receiver operating characteristic curve in the test sample was 0.78 (SE=0.02) for homelessness. The 4 highest ventiles (top 20%) of predicted risk included 61% of respondents with homelessness. Self-reported lifetime histories of depression, trauma of having a loved one murdered, and post-traumatic stress disorder were the 3 strongest predictors of homelessness.

CONCLUSIONS: A prediction model for homelessness can accurately target soldiers for preventive intervention before transition to civilian life.

RevDate: 2022-06-20

Barbhaiya M, Hart JE, Malspeis S, et al (2022)

Association of Ultraviolet-B Radiation and Risk of SLE among Women in the Nurses' Health Studies.

Arthritis care & research [Epub ahead of print].

OBJECTIVE: Ultraviolet radiation (UV) exposure is associated with photosensitivity, rashes, and flares in systemic lupus erythematosus (SLE). However, it is not known whether UV exposure increases risk of developing SLE. We examined UV exposure and SLE risk in a large prospective cohort.

METHODS: The Nurses' Health Study (NHS) enrolled 121,700 U.S. female nurses in 1976; in 1989, 116,429 were enrolled in NHSII. Biennial questionnaires collected lifestyle and medical data. Self-reported incident SLE by American College of Rheumatology classification criteria was confirmed by medical record review. Ambient UV exposure was estimated by linking geocoded residential addresses with a spatiotemporal UV exposure model. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) across tertiles of time-varying cumulative average UV. We examined SLE risk overall and stratified by anti-Ro/La antibodies and by cutaneous manifestations from 1976 through 2014 (NHS)/2015 (NHSII), adjusting for confounders.

RESULTS: With 6,054,665 person-years of exposure, we identified 297 incident SLE cases; mean age at diagnosis was 49.8 (10.6) years. At diagnosis, 16.8% of women had +anti-Ro/La, and 80% had either +anti-Ro/La or ≥1 cutaneous manifestation. Compared to the lowest UV exposure tertile, risk of overall SLE was increased, but not significantly (HR 1.28 [95%CI 0.96-1.70]). Women in the highest tertile had increased risk of malar rash (HR 1.62 [95% CI 1.04-2.52]).

CONCLUSION: Cumulative UV exposure was not associated with SLE risk. Higher UV exposure, however, was associated with increased risk of malar rash at presentation. UV exposure may trigger SLE onset with malar rash among susceptible women.

RevDate: 2022-06-20

Yoon HJ, Peluso A, Durbin EB, et al (2022)

Automatic information extraction from childhood cancer pathology reports.

JAMIA open, 5(2):ooac049 pii:ooac049.

Objectives: The International Classification of Childhood Cancer (ICCC) facilitates the effective classification of a heterogeneous group of cancers in the important pediatric population. However, there has been no development of machine learning models for the ICCC classification. We developed deep learning-based information extraction models from cancer pathology reports based on the ICD-O-3 coding standard. In this article, we describe extending the models to perform ICCC classification.

Materials and Methods: We developed 2 models, ICD-O-3 classification and ICCC recoding (Model 1) and direct ICCC classification (Model 2), and 4 scenarios subject to the training sample size. We evaluated these models with a corpus consisting of 29 206 reports with age at diagnosis between 0 and 19 from 6 state cancer registries.

Results: Our findings suggest that the direct ICCC classification (Model 2) is substantially better than reusing the ICD-O-3 classification model (Model 1). Applying the uncertainty quantification mechanism to assess the confidence of the algorithm in assigning a code demonstrated that the model achieved a micro-F1 score of 0.987 while abstaining (not sufficiently confident to assign a code) on only 14.8% of ambiguous pathology reports.

Conclusions: Our experimental results suggest that the machine learning-based automatic information extraction from childhood cancer pathology reports in the ICCC is a reliable means of supplementing human annotators at state cancer registries by reading and abstracting the majority of the childhood cancer pathology reports accurately and reliably.

RevDate: 2022-06-20

Basourakos SP, Gulati R, Vince RA, et al (2022)

Harm-to-Benefit of Three Decades of Prostate Cancer Screening in Black Men.

NEJM evidence, 1(6):.

BACKGROUND: Prostate-specific antigen screening has profoundly affected the epidemiology of prostate cancer in the United States. Persistent racial disparities in outcomes for Black men warrant re-examination of the harms of screening relative to its cancer-specific mortality benefits in this population.

METHODS: We estimated overdiagnoses and overtreatment of prostate cancer for men of all races and for Black men 50 to 84 years of age until 2016, the most recent year with treatment data available, using excess incidence relative to 1986 based on the Surveillance, Epidemiology, and End Results registry and U.S. Census data as well as an established microsimulation model of prostate cancer natural history. Combining estimates with plausible mortality benefit, we calculated numbers needed to diagnose (NND) and treat (NNT) to prevent one prostate cancer death.

RESULTS: For men of all races, we estimated 1.5 to 1.9 million (range between estimation approaches) overdiagnosed and 0.9 to 1.5 million overtreated prostate cancers by 2016. Assuming that half of the 270,000 prostate cancer deaths avoided by 2016 were attributable to screening, the NND and the NNT would be 11 to 14 and 7 to 11 for men of all races and 8 to 12 and 5 to 9 for Black men, respectively. Alternative estimates incorporating a lag between incidence and mortality resulted in a NND and a NNT for Black men that reached well into the low single digits.

CONCLUSIONS: Complementary approaches to quantifying overdiagnosis indicate a harm-benefit tradeoff of prostate-specific antigen screening that is more favorable for Black men than for men of all races considered together. Our findings highlight the need to account for the increased value of screening in Black men in clinical guidelines. (Funded by the Patient-Centered Outcomes Research Institute, the National Cancer Institute, the Bristol Myers Squibb Foundation, and the Damon Runyon Cancer Research Foundation.).

RevDate: 2022-06-20

Potter GE, Carnegie NB, Sugimoto JD, et al (2022)

Using social contact data to improve the overall effect estimate of a cluster-randomized influenza vaccination program in Senegal.

Journal of the Royal Statistical Society. Series C, Applied statistics, 71(1):70-90.

This study estimates the overall effect of two influenza vaccination programs consecutively administered in a cluster-randomized trial in western Senegal over the course of two influenza seasons from 2009-2011. We apply cutting-edge methodology combining social contact data with infection data to reduce bias in estimation arising from contamination between clusters. Our time-varying estimates reveal a reduction in seasonal influenza from the intervention and a nonsignificant increase in H1N1 pandemic influenza. We estimate an additive change in overall cumulative incidence (which was 6.13% in the control arm) of -0.68 percentage points during Year 1 of the study (95% CI: -2.53, 1.18). When H1N1 pandemic infections were excluded from analysis, the estimated change was -1.45 percentage points and was significant (95% CI, -2.81, -0.08). Because cross-cluster contamination was low (0-3% of contacts for most villages), an estimator assuming no contamination was only slightly attenuated (-0.65 percentage points). These findings are encouraging for studies carefully designed to minimize spillover. Further work is needed to estimate contamination - and its effect on estimation - in a variety of settings.

RevDate: 2022-06-20

Winn M, Karra P, Haaland B, et al (2022)

Metabolic dysfunction and obesity-related cancer: Results from the cross-sectional National Health and Nutrition Examination Survey.

Cancer medicine [Epub ahead of print].

BACKGROUND: Metabolic syndrome (MetS), a group of risk factors that define metabolic dysfunction in adults, is strongly associated with obesity and is an emerging risk factor for cancer. However, the association of MetS and degree of metabolic dysfunction with obesity-related cancer is unknown.

METHODS: Using National Health and Nutrition Examination Survey data from 1999 to 2018, we identified 528 obesity-related cancer cases and 18,972 cancer-free participants. MetS was defined as the presence of or treatment for ≥3 of hyperglycemia, hypertension, hypertriglyceridemia, low HDL-cholesterol, and abdominal obesity. A metabolic syndrome score (MSS) was computed as the total number of abnormal MetS parameters to determine the severity of metabolic dysfunction. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models, adjusting for sociodemographic and lifestyle factors.

RESULTS: About 45.7% of obesity-related cancer cases were classified as having MetS compared with only 33.0% of cancer-free participants. Overall, MetS and MSS were not associated with obesity-related cancer. However, MSS was associated with higher obesity-related cancer risk among participants under 50 years of age (OR [95% CI] = 1.28 [1.08-1.52]). When evaluating MSS categorically, compared with healthy participants with no abnormal MetS parameters (MSS = 0), participants with one or two abnormal parameters had a statistically significant higher risk of obesity-related cancer (OR [95% CI] = 1.73 [1.06-2.83]).

CONCLUSIONS: Metabolic dysfunction is associated with a higher risk of obesity-related cancer, particularly in young adults under 50 years of age, and among participants with one or two abnormal metabolic parameters. A more accurate indicator of metabolic dysfunction, beyond metabolic syndrome, is needed to better assist in stratifying individuals for obesity-related cancer risk.

RevDate: 2022-06-19

Bischof JJ, Elsaid MI, Bridges JFP, et al (2022)

Characterization of older adults with cancer seeking acute emergency department care: A prospective observational study.

Journal of geriatric oncology pii:S1879-4068(22)00138-2 [Epub ahead of print].

INTRODUCTION: Disparities in care of older adults in cancer treatment trials and emergency department (ED) use exist. This report provides a baseline description of older adults ≥65 years old who present to the ED with active cancer.

MATERIALS AND METHODS: Planned secondary analysis of the Comprehensive Oncologic Emergencies Research Network observational ED cohort study sponsored by the National Cancer Institute. Of 1564 eligible adults with active cancer, 1075 patients were prospectively enrolled, of which 505 were ≥ 65 years old. We recruited this convenience sample from eighteen participating sites across the United States between February 1, 2016 and January 30, 2017.

RESULTS: Compared to cancer patients younger than 65 years of age, older adults were more likely to be transported to the ED by emergency medical services, have a higher Charlson Comorbidity Index score, and be admitted despite no significant difference in acuity as measured by the Emergency Severity Index. Despite the higher admission rate, no significant difference was noted in hospitalization length of stay, 30-day mortality, ED revisit or hospital admission within 30 days after the index visit. Three of the top five ED diagnoses for older adults were symptom-related (fever of other and unknown origin, abdominal and pelvic pain, and pain in throat and chest). Despite this, older adults were less likely to report symptoms and less likely to receive symptomatic treatment for pain and nausea than the younger comparison group. Both younger and older adults reported a higher symptom burden on the patient reported Condensed Memorial Symptom Assessment Scale than to ED providers. When treating suspected infection, no differences were noted in regard to administration of antibiotics in the ED, admissions, or length of stay ≤2 days for those receiving ED antibiotics.

DISCUSSION: We identified several differences between older (≥65 years old) and younger adults with active cancer seeking emergency care. Older adults frequently presented for symptom-related diagnoses but received fewer symptomatic interventions in the ED suggesting that important opportunities to improve the care of older adults with cancer in the ED exist.

RevDate: 2022-06-19

Kwon DM, Santiago-Torres M, Mull KE, et al (2022)

Older adults who smoke: Do they engage with and benefit from web-based smoking cessation interventions?.

Preventive medicine pii:S0091-7435(22)00167-0 [Epub ahead of print].

Quitting smoking at any age increases life expectancy, but older adults face barriers to receiving cessation services. Despite the promise of web-based smoking cessation interventions to help address access barriers, whether older adults who participate in smoking cessation programs engage with and benefit from these tools at the same rate as younger adults remains unknown. In this secondary analysis, we compared engagement and satisfaction with two web-based smoking cessation interventions and quit rates between older, middle-aged, and young adults in the United States enrolled in the WebQuit trial between March 2014 and August 2015. Participants were divided into age groups: older (60 years and older, n = 439/2637), middle-aged (40-59 years, n = 1308/2637), and young adults (18-39 years, n = 890/2637). Treatment engagement and satisfaction, and 12-month quit rates (self-reported complete-case 30-day PPA and missing-as-smoking) were compared between groups. Older adults engaged more with the websites than young adults through multiple indicators of intervention engagement (i.e., number of sessions, unique days of use, and time spent on the site), and older adults spent more time on the site per session than their counterparts. Satisfaction with websites was high (81%) and non-differential between groups. Older and middle-aged adults quit smoking at a similar rate as younger adults (24%, 24%, 27%, respectively, p = 0.905). Older and middle-aged adults who participated in a web-delivered smoking cessation intervention engaged more with the intervention than their younger counterparts and they quit smoking at a similar rate, thereby demonstrating high acceptability and potential of digital interventions to help older adults quit smoking. Trial registration:ClinicalTrials.gov Identifier: NCT1166334.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Kamdar M, Solomon SR, Arnason J, et al (2022)

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial.

Lancet (London, England), 399(10343):2294-2308.

BACKGROUND: Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL.

METHODS: TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing.

FINDINGS: Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4-11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1-not reached]) compared with the standard-of-care group (2·3 months [2·2-4·3]; stratified hazard ratio 0·35; 95% CI 0·23-0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group.

INTERPRETATION: These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL.

FUNDING: Celgene, a Bristol-Myers Squibb Company.

RevDate: 2022-06-18

Tarlock K, Sulis ML, Chewning JH, et al (2022)

Hematopoietic Cell Transplantation in the Treatment of Pediatric Acute Myeloid Leukemia and Myelodysplastic Syndromes: Guidelines from the American Society of Transplantation and Cellular Therapy.

The role of allogeneic hematopoietic stem cell transplantation (HCT) in the therapy of acute myeloid leukemia (AML) in children is reviewed and critically evaluated in this evidence-based review. Specific criteria were used for searching the published literature, for grading the quality and strength of evidence, and for assigning a strength of treatment recommendation. Genomic characterization and response to therapy have been critical in the risk stratification of pediatric AML. Although some children are cured with chemotherapy alone, allogeneic HCT offers survival benefit in selected patients with certain unfavorable-risk features and is the standard of care for children who relapse following initial treatment with chemotherapy. Important aspects of HCT include recipient characteristics, donor source, and preparative regimen. The goals of HCT are to (1) reduce incidence of relapse, (2) enhance graft versus leukemia (GVL) effects, and (3) minimize graft-versus-host disease. Relapse following HCT remains a significant cause of treatment failure, and interventions pre- and post-HCT, especially those that may augment GVL are an important focus of ongoing investigations.

RevDate: 2022-06-17

Zhao F, Shi Y, Chen X, et al (2022)

Higher Dose of CD34+ cells Promotes Early Reconstitution of Natural Killer Cells and Is Associated with Better Outcomes After Unmanipulated Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.

Transplantation and cellular therapy pii:S2666-6367(22)01368-9 [Epub ahead of print].

BACKGROUND: Natural killer (NK) cells are the first lymphocyte population to recover after allogenic hematopoietic stem cell transplantation (allo-HSCT) and mediate potent graft versus leukemia (GVL) effect particularly in the settings of T-cell depletion. However, the significance of NK cells after unmanipulated transplantation is less clear and factors affecting early NK reconstitution remain elusive.

OBJECTIVES AND STUDY DESIGN: We retrospectively analyze 180 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received unmanipulated allografts. We focus on the early NK reconstitution and its association with disease relapse, overall survival and cytomegalovirus (CMV) reactivation. We also analyze factors that affect NK recovery for example dose of CD34+ cells in the graft and T cell recovery after transplantation.

RESULTS: Penalized splines and receiver operator characteristic (ROC) curves demonstrate a strong association between blood NK counts at 30 days after allo-HSCT (NK30) and all-cause mortality with the cut-off value being close to the median value which divides patients dichotomously. Subsequent analysis shows that rapid NK recovery (higher NK30 and/or higher NK60) is associated with reduced disease relapse and better survival. Robust NK recovery (NK30 and NK60) also correlates with lower incidence of CMV reactivation. We find that NK30 is associated with the numbers of CD34+ cells (r = 0.739, P < 0.001) but not mature NK cells contained in the graft. In a small subset (N = 12) of the cohort, patients in continuous complete remission (N = 6) demonstrate higher frequencies of CD34+CD7+ progenitor cells and CD56bright NK cells in the day +30 bone marrow as compared to patients with disease relapse within 1 year (N = 6). Furthermore, neither T cell recovery after transplantation nor application of anti-thymocyte globulins (ATG) in the conditioning regimen demonstrate suppressive effect on NK recovery.

CONCLUSION: Rapid NK cell recovery is associated with improved prognosis of unmanipulated transplantation for myeloid malignancies. Manipulation of NK cell recovery represents a feasible approach to improve transplant outcomes for example by optimizing CD34+ cells in the graft.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Hansen SG, Hancock MH, Malouli D, et al (2022)

Myeloid cell tropism enables MHC-E-restricted CD8+ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine.

Science immunology, 7(72):eabn9301.

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8+ T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8+ T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component. Using host microRNA (miR)-mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope-targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142-mediated tropism restriction eliminated MHC-E epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-II epitope-targeted response. Inhibition with the endothelial cell-selective miR-126 eliminated MHC-II epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-E epitope-targeted response. Dual miR-142 + miR-126-mediated tropism restriction reverted CD8+ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8+ T cell responses were generally similar, only the vectors programmed to elicit MHC-E-restricted CD8+ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

RevDate: 2022-06-17

Mack PC, Miao J, Redman MW, et al (2022)

Circulating tumor DNA (ctDNA) kinetics predict progression-free and overall survival in EGFR TKI-treated patients with EGFR-mutant NSCLC (SWOG S1403).

Clinical cancer research : an official journal of the American Association for Cancer Research pii:704944 [Epub ahead of print].

PURPOSE: Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome.

EXPERIMENTAL DESIGN: Serial plasma ctDNA (baseline, 8 weeks and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib +/- cetuximab in TKI-naive, EGFR-mutation tissue-positive NSCLC.

RESULTS: EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR-mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared to those with persistent ctDNA at C3D1 (HR (95% CI): 0.23 (0.12-0.45), p<0.0001); with a median PFS of 15.1 (95% CI: 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR (95% CI): 0.44 (0.21-0.90), p=0.02; mOS: 32.6 versus 15.6 (4.9-28.3) months.

CONCLUSIONS: Plasma clearance of mutant EGFR ctDNA at 8-weeks was highly and significantly predictive of progression-free and overall survival, outperforming RECIST response for predicting long-term benefit.

RevDate: 2022-06-17

Li J, Glenn AJ, Yang Q, et al (2022)

Dietary Protein Sources, Mediating Biomarkers, and Incidence of Type 2 Diabetes: Findings From the Women's Health Initiative and the U.K. Biobank.

Diabetes care pii:147100 [Epub ahead of print].

OBJECTIVE: Whether and how dietary protein intake is linked to type 2 diabetes (T2D) remains unclear. The aim of this study was to investigate the associations of protein intake with development of T2D and the potential mediating roles of T2D biomarkers.

RESEARCH DESIGN AND METHODS: We included 108,681 postmenopausal women without T2D at baseline from the Women's Health Initiative (WHI) (primary cohort) and 34,616 adults without T2D from the U.K. Biobank (UKB) (replication cohort). Cox proportional hazard models were used for estimation of protein-T2D associations. Mediation analysis was performed to assess the mediating roles of biomarkers in case-control studies nested in the WHI.

RESULTS: In the WHI, 15,842 incident T2D cases were identified during a median follow-up of 15.8 years. Intake of animal protein was associated with increased T2D risk (hazard ratio in comparing the highest to the lowest quintile = 1.31 [95% CI 1.24-1.37]) and plant protein with decreased risk (0.82 [0.78-0.86]). Intakes of red meat, processed meat, poultry, and eggs were associated with increased T2D risk and whole grains with decreased risk. Findings from the UKB were similar. These findings were materially attenuated after additional adjustment for BMI. Substituting 5% energy from plant protein for animal protein was associated with 21% decreased T2D risk (0.79 [0.74-0.84]), which was mediated by levels of hs-CRP, interleukin-6, leptin, and SHBG.

CONCLUSIONS: Findings from these two large prospective cohorts support the notion that substituting plant protein for animal protein may decrease T2D risk mainly by reducing obesity-related inflammation.

RevDate: 2022-06-17

Gartlan KH, Jaiswal JK, Bull MR, et al (2022)

Preclinical Activity and Pharmacokinetic/Pharmacodynamic Relationship for a Series of Novel Benzenesulfonamide Perforin Inhibitors.

ACS pharmacology & translational science, 5(6):429-439.

Perforin is a key effector of lymphocyte-mediated cell death pathways and contributes to transplant rejection of immunologically mismatched grafts. We have developed a novel series of benzenesulfonamide (BZS) inhibitors of perforin that can mitigate graft rejection during allogeneic bone marrow/stem cell transplantation. Eight such perforin inhibitors were tested for their murine pharmacokinetics, plasma protein binding, and their ability to block perforin-mediated lysis in vitro and to block the rejection of major histocompatibility complex (MHC)-mismatched mouse bone marrow cells. All compounds showed >99% binding to plasma proteins and demonstrated perforin inhibitory activity in vitro and in vivo. A lead compound, compound 1, that showed significant increases in allogeneic bone marrow preservation was evaluated for its plasma pharmacokinetics and in vivo efficacy at multiple dosing regimens to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The strongest PK/PD correlation was observed between perforin inhibition in vivo and time that total plasma concentrations remained above 900 μM, which correlates to unbound concentrations similar to 3× the unbound in vitro IC90 of compound 1. This PK/PD relationship will inform future dosing strategies of BZS perforin inhibitors to maintain concentrations above 3× the unbound IC90 for as long as possible to maximize efficacy and enhance progression toward clinical evaluation.

RevDate: 2022-06-17

Braun TP, Okhovat M, Coblentz C, et al (2022)

Author Correction: Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia.

Nature communications, 13(1):3471 pii:10.1038/s41467-022-30987-0.

RevDate: 2022-06-16

Zhao Y, Yan H, Holte S, et al (2022)

Rapid detection of hot-spots via tensor decomposition with applications to crime rate data.

Journal of applied statistics, 49(7):1636-1662 pii:1874892.

In many real-world applications of monitoring multivariate spatio-temporal data that are non-stationary over time, one is often interested in detecting hot-spots with spatial sparsity and temporal consistency, instead of detecting system-wise changes as in traditional statistical process control (SPC) literature. In this paper, we propose an efficient method to detect hot-spots through tensor decomposition, and our method has three steps. First, we fit the observed data into a Smooth Sparse Decomposition Tensor (SSD-Tensor) model that serves as a dimension reduction and de-noising technique: it is an additive model decomposing the original data into: smooth but non-stationary global mean, sparse local anomalies, and random noises. Next, we estimate model parameters by the penalized framework that includes Least Absolute Shrinkage and Selection Operator (LASSO) and fused LASSO penalty. An efficient recursive optimization algorithm is developed based on Fast Iterative Shrinkage Thresholding Algorithm (FISTA). Finally, we apply a Cumulative Sum (CUSUM) Control Chart to monitor model residuals after removing global means, which helps to detect when and where hot-spots occur. To demonstrate the usefulness of our proposed SSD-Tensor method, we compare it with several other methods including scan statistics, LASSO-based, PCA-based, T2-based control chart in extensive numerical simulation studies and a real crime rate dataset.

RevDate: 2022-06-15

Yu M, Moinova HR, Willbanks A, et al (2022)

Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-grade Dysplasia.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:704906 [Epub ahead of print].

PURPOSE: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high grade dysplasia (HGD) from normal squamous epithelium (SQ) or non-dysplastic BE (NDBE).

EXPERIMENTAL DESIGN: DNA methylation profiling of samples from SQ, NDBE, HGD and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfite-sequencing. Ultra-sensitive methylation-specific droplet digital PCR and NGS-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples.

RESULTS: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared to SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a 4-marker panel (Model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples.

CONCLUSIONS: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation based molecular assays holds promise for the detection of HGD/EAC using esophageal brushing samples.

RevDate: 2022-06-15

Sullivan KM, Jiang X, Guha P, et al (2022)

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

Gut pii:gutjnl-2021-325808 [Epub ahead of print].

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.

DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy.

RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function.

CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

RevDate: 2022-06-16

Wang X, Gharahkhani P, Levine DM, et al (2022)

eQTL set-based association analysis identifies novel susceptibility loci for Barrett's esophagus and esophageal adenocarcinoma.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:704926 [Epub ahead of print].

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNPs) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), explaining a small portion of heritability.

METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTLs), and set-based SKAT association using selected eQTLs that predict the gene expression.

RESULTS: While the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641 and HSP90AA1).

CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set based genetic association approach.

IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set based genetic association approach as an alternative method for TWAS analysis.

RevDate: 2022-06-16

Isacchini G, Spisak N, Nourmohammad A, et al (2022)

Mutual information maximization for amortized likelihood inference from sampled trajectories: MINIMALIST.

Physical review. E, 105(5-2):055309.

Simulation-based inference enables learning the parameters of a model even when its likelihood cannot be computed in practice. One class of methods uses data simulated with different parameters to infer models of the likelihood-to-evidence ratio, or equivalently the posterior function. Here we frame the inference task as an estimation of an energy function parametrized with an artificial neural network. We present an intuitive approach, named MINIMALIST, in which the optimal model of the likelihood-to-evidence ratio is found by maximizing the likelihood of simulated data. Within this framework, the connection between the task of simulation-based inference and mutual information maximization is clear, and we show how several known methods of posterior estimation relate to alternative lower bounds to mutual information. These distinct objective functions aim at the same optimal energy form and therefore can be directly benchmarked. We compare their accuracy in the inference of model parameters, focusing on four dynamical systems that encompass common challenges in time series analysis: dynamics driven by multiplicative noise, nonlinear interactions, chaotic behavior, and high-dimensional parameter space.

RevDate: 2022-06-15

Malhi H, Homad LJ, Wan YH, et al (2022)

Immunization with a self-assembling nanoparticle vaccine displaying EBV gH/gL protects humanized mice against lethal viral challenge.

Cell reports. Medicine pii:S2666-3791(22)00190-2 [Epub ahead of print].

Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 165,000 deaths annually. EBV is also the etiological agent of infectious mononucleosis and is linked to multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine would have a significant global health impact. EBV is orally transmitted and has tropism for epithelial and B cells. Therefore, a vaccine would need to prevent infection of both in the oral cavity. Passive transfer of monoclonal antibodies against the gH/gL glycoprotein complex prevent experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Here, we evaluate the immunogenicity of several gH/gL nanoparticle vaccines. All display superior immunogenicity relative to monomeric gH/gL. A nanoparticle displaying 60 copies of gH/gL elicits antibodies that protect against lethal EBV challenge in humanized mice, whereas antibodies elicited by monomeric gH/gL do not. These data motivate further development of gH/gL nanoparticle vaccines for EBV.

RevDate: 2022-06-14

Tortorici MA, Walls AC, Joshi A, et al (2022)

Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein.

Cell pii:S0092-8674(22)00650-X [Epub ahead of print].

The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.

RevDate: 2022-06-14

Hwang JP, Artz AS, Shah P, et al (2022)

Practical Implementation of Universal Hepatitis B Virus Screening for Patients With Cancer.

JCO oncology practice [Epub ahead of print].

RevDate: 2022-06-14

Robbins HA, Ferreiro-Iglesias A, Waterboer T, et al (2022)

Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown.

METHODS: We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality.

RESULTS: The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status.

CONCLUSION: We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.

RevDate: 2022-06-14

Grasso C, Popovic M, Isaevska E, et al (2022)

Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:704891 [Epub ahead of print].

BACKGROUND: Testicular germ cell tumors (TGCTs), histologically classified as seminomas and non-seminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when are subjected to DNA methylation reprogramming. Single-nucleotide polymorphisms (SNPs) in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

METHODS: In this pathway-focused investigation we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls.

RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q-value ≤.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q-value=8.4x10-4), MECP2 (q-value=2x10-3) and ZBTB4 (q-value=0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q-value=2.8x10-4), but not with non-seminomatous tumors (q-value=0.22).

CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk.

IMPACT: This finding suggests that TGCT pathogenesis could be associated to the folate cycle status, and this relation could be partly due to hereditary factors.

RevDate: 2022-06-14

Sapkota Y, Ehrhardt MJ, Qin N, et al (2022)

A novel locus on 6p21.2 for cancer treatment-induced cardiac dysfunction among childhood cancer survivors.

Journal of the National Cancer Institute pii:6605856 [Epub ahead of print].

BACKGROUND: Adult survivors of childhood cancer are at increased risk of cardiac late effects.

METHODS: Using whole-genome sequencing data from 1,870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Significant findings were validated in 301 SJLIFE survivors of African ancestry and 4,020 survivors of European ancestry from the Childhood Cancer Survivor Study (CCSS). All statistical tests were 2-sided.

RESULTS: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction: 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe/disabling or life-threatening CCD and replicated in 4,020 CCSS survivors of European ancestry (OR = 1.40; P = .039). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1,651 SJLIFE survivors of European ancestry showed significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA-sequencing of 75 survivors.

CONCLUSIONS: Leveraging the two largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.

RevDate: 2022-06-13

Aleta A, Martín-Corral D, Bakker MA, et al (2022)

Quantifying the importance and location of SARS-CoV-2 transmission events in large metropolitan areas.

Proceedings of the National Academy of Sciences of the United States of America, 119(26):e2112182119.

Detailed characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission across different settings can help design less disruptive interventions. We used real-time, privacy-enhanced mobility data in the New York City, NY and Seattle, WA metropolitan areas to build a detailed agent-based model of SARS-CoV-2 infection to estimate the where, when, and magnitude of transmission events during the pandemic's first wave. We estimate that only 18% of individuals produce most infections (80%), with about 10% of events that can be considered superspreading events (SSEs). Although mass gatherings present an important risk for SSEs, we estimate that the bulk of transmission occurred in smaller events in settings like workplaces, grocery stores, or food venues. The places most important for transmission change during the pandemic and are different across cities, signaling the large underlying behavioral component underneath them. Our modeling complements case studies and epidemiological data and indicates that real-time tracking of transmission events could help evaluate and define targeted mitigation policies.

RevDate: 2022-06-13

LeBlanc TW, Russell NH, Hernandez-Aldama L, et al (2022)

Patient, Family Member and Physician Perspectives and Experiences with AML Treatment Decision-Making.

Oncology and therapy [Epub ahead of print].

INTRODUCTION: Treatment decisions in older adults with acute myeloid leukemia (AML) are challenging, particularly for those who are not candidates for intensive chemotherapy (IC), and the trade-offs patients, their families and physicians consider when choosing a treatment option are not well understood. This qualitative research explored the value of extending survival and the treatment decision-making process from a multi-stakeholder perspective.

METHODS: Overall, 28 patients with AML (≥ 65 years old, unsuitable for IC), 25 of their relatives and 10 independent physicians from the US, UK and Canada took part in one-on-one, 60-minute qualitative interviews.

RESULTS: Across all stakeholders, improved health-related quality of life (HRQoL), extended survival and relief of AML symptoms were recognized as most important in AML treatment decision-making. However, extending survival in 'good health' was more important than extending survival alone, particularly because of the extra time it gives patients and their relatives together, and allows patients to achieve important goals. Patients' limited understanding of available treatment options, paired with incorrect perceptions of treatment side effects, impacted their involvement in the treatment decision-making process. Patients and physicians perceived physicians to have the most influence in the decision-making process despite their priorities not always aligning.

CONCLUSION: These findings illustrate the importance of having structured discussions which explicitly assess patients' goals and their understanding and expectations of treatments and also the need for patient friendly resources about the lived experience of AML and available treatment options. These measures will help to ensure that patients are fully involved in the shared decision-making process.

RevDate: 2022-06-13

Sowalsky AG, Figueiredo I, Lis RT, et al (2022)

Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:704873 [Epub ahead of print].

PURPOSE: Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied.

EXPERIMENTAL DESIGN: We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome.

RESULTS: In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay associated neither with time to development of castration-resistance nor overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor post-treatment AR-V7 levels associated with volumes of residual disease after therapy.

CONCLUSION: This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

RevDate: 2022-06-13

Simmons JD, Dill-McFarland KA, Stein CM, et al (2022)

Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion.

mSphere [Epub ahead of print].

Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection. IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.

RevDate: 2022-06-13

Barnabas RV, Brown ER, Onono MA, et al (2022)

Efficacy of single-dose HPV vaccination among young African women.

NEJM evidence, 1(5):EVIDoa2100056.

Background: Single-dose HPV vaccination, if efficacious, would be tremendously advantageous; simplifying implementation and decreasing costs.

Methods: We performed a randomized, multi-center, double-blind, controlled trial of single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11) or bivalent (HPV 16/18) HPV vaccination compared to meningococcal vaccination among Kenyan women aged 15-20 years. Enrollment and six monthly cervical swabs and a month three vaginal swab were tested for HPV DNA. Enrollment sera were tested for HPV antibodies. The modified intent-to-treat (mITT) cohort comprised participants who tested HPV antibody negative at enrollment and HPV DNA negative at enrollment and month three. The primary outcome was incident persistent vaccine-type HPV infection by month 18.

Results: Between December 2018 and June 2021, 2,275 women were randomly assigned and followed; 758 received the nonavalent HPV vaccine, 760 the bivalent HPV vaccine, and 757 the meningococcal vaccine; retention was 98%. Thirty-eight incident persistent infections were detected in the HPV 16/18 mITT cohort: one each among participants assigned to the bivalent and nonavalent groups and 36 among those assigned to the meningococcal group; nonavalent Vaccine Efficacy (VE) was 97.5% (95%CI 81.7-99.7%, p=<0.0001), and bivalent VE was 97.5% (95%CI 81.6-99.7%, p=<0.0001). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: four in the nonavalent group and 29 in the meningococcal group; nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95%CI 68.5-96.1%, p<0.0001). The rate of SAEs was 4.5-5.2% by group.

Conclusions: Over the 18 month time-frame we studied, single-dose bivalent and nonavalent HPV vaccines were each highly effective in preventing incident persistent oncogenic HPV infection, similar to multidose regimens.

RevDate: 2022-06-13

Cindy J, Sherri J, Tarana B, et al (2022)

Overcoming COVID-19 disruptions: Innovations in product provision in a multi-national clinical trial among cisgender men, transgender men and transgender women in five countries.

Contemporary clinical trials communications pii:S2451-8654(22)00047-3 [Epub ahead of print].

Clinical trials often depend on participants receiving study product to meet objectives of the protocol. Vitally important are considerations for how sites receive and dispense study product during a study while ensuring appropriate handling, accountability and compliance. The process for provision of study product is detailed in Standard Operating Procedures (SOPs) which are adhered to by the research site throughout the trial. The COVID-19 pandemic unexpectedly affected the ability of study participants to receive study product. We report on the various methods implemented by trial sites to ensure timely provision of study product to participants during this unprecedented pandemic. In MTN-035, participants received 3 potential rectal microbicide formulations in randomized sequences to understand user preferences. Trial sites were permitted to revise dispensing methods to enable participants to continue to receive study product during COVID-19 restrictions. These actions mitigated disruption of study product administration and preserved the integrity of the trial. Out of the 78 participants expecting to receive study products on or after the onset of restrictions due to COVID-19, only four participants (5%) did not receive all three products. Adopting alternative methods to provide product to study participants in extraordinary circumstances was key to successful study completion and maintaining study integrity.

RevDate: 2022-06-12

Thompson MJ, Drain PK, Gregor CE, et al (2022)

A pragmatic randomized trial of home-based testing for COVID-19 in rural native American and Latino communities: Protocol for the "Protecting our Communities" study.

Contemporary clinical trials pii:S1551-7144(22)00146-X [Epub ahead of print].

BACKGROUND: Home-based testing for COVID-19 has potential to reduce existing health care disparities among underserved populations in the United States. However, implementation of home-based tests in these communities may face significant barriers. This study evaluates the acceptability, feasibility, and success of home-based testing and the potential added benefit of active support from trusted community health workers for Native Americans and Hispanic/Latino adults living in rural Montana and Washington states.

METHODS/DESIGN: The academic-community research team designed the trial to be responsive to community needs for understanding barriers and supports to home-based COVID-19 testing. The "Protecting Our Community" study is a two-arm pragmatic randomized controlled trial in which a total of 400 participants are randomized to active or passive arms. Participants of both study arms receive a commercially available home collection COVID-19 test kit, which is completed by mailing a self-collected nasal swab to a central laboratory. The primary study outcome is return of the kit to the central lab within 14 days. The cultural, social, behavioral, and economic barriers to home-based COVID-19 testing are also assessed by qualitative research methods. A survey and semi-structured interviews are conducted after the trial to evaluate perceptions and experience of home-based testing.

DISCUSSION: Implementing home-based testing in underserved populations, including among Native American and Hispanic/Latino communities, may require additional support to be successful. The Protecting Our Community trial examines the effect of trusted community health workers on use of home-based testing, which may be adaptable for community-driven models of home-based testing in other underserved populations.

RevDate: 2022-06-11

Scott SR, O'Donnell M, Manczak EM, et al (2022)

Resilience and Diabetes Distress at 3 Months Following Diagnosis Predict A1C Trajectories in Youth With Type 1 Diabetes: An Argument for Early Intervention.

Journal of pediatric psychology pii:6605911 [Epub ahead of print].

OBJECTIVE: Youth and adolescents with type 1 diabetes (T1D) are at risk for poor health outcomes. Understanding if psychological factors shortly following diagnosis, such as diabetes distress and resilience, predict glycated hemoglobin (A1C) trajectories may help inform both optimal timing and content of psychosocial interventions for youth with T1D.

METHODS: Youth and adolescents (N = 34) with newly diagnosed T1D completed distress and resilience measures at baseline and 3 months following diagnosis. Using multilevel modeling, we predicted A1C trajectories up to 3 years following diagnosis.

RESULTS: We found that in separate models, higher 3-month diabetes distress and lower 3-month resilience predicted larger increases in A1C years 1-3 following diagnosis.

CONCLUSIONS: Our findings suggest that targeting resilience and diabetes distress within 3 months following diagnosis has implications for the yearly rate of A1C increase up to 3 years later.

RevDate: 2022-06-10

Gbadamosi MO, Shastri VM, Elsayed AH, et al (2022)

A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials.

Leukemia [Epub ahead of print].

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.

RevDate: 2022-06-10

Wrotniak BH, Garrett M, Baron S, et al (2022)

Antibody dependent cell cytotoxicity is maintained by the unmutated common ancestor of 6F5, a Gp41 conformational epitope targeting antibody that utilizes heavy chain VH1-2.

Vaccine pii:S0264-410X(22)00719-8 [Epub ahead of print].

In studies on monoclonal IgG antibodies (mAbs) from long-term non-progressors (LTNPs), our laboratory has previously described highly mutated Abs against a complex conformational epitope with contributions from both gp41 the N terminal and C terminal heptad repeat helices. Despite using the VH1-2 gene segment, known to contribute to some of the broadest neutralizing Abs against HIV, members of these Abs, termed group 76C Abs, did not exhibit broad neutralization. Because of the high number of mutations and use of VH1-2, our goal was to characterize the non-neutralizing functions of Abs of group 76C, to assess if targeting of the epitope correlates with LTNP, and to assess the maturation of these Abs by comparison to their predicted common ancestor. Serum competition assays showed group 76C Abs were enriched in LTNPs, in comparison to VRC-01. Specific group 76C clones 6F5 and 6F11, expressed as recombinant Abs, both have robust ADCC activity, despite their sequence disparity. Sequence analysis predicted the common ancestor of this clonal group would utilize the germline non-mutated variable gene. We produced a recombinant ancestor Ab (76Canc) with a heavy chain utilizing the germline variable gene sequence paired to the 6F5 light chain. Competition with group 76C recombinant Ab 6F5 confirms 76Canc binds HIV envelope constructs near the original group C epitope. 76Canc demonstrates comparable ADCC to 6F5 and 6F11 when using gp41 constructs of both clade B and clade C. The functional capability of Abs utilizing germline VH1-2 has implications for disease control and vaccine development.

RevDate: 2022-06-10

VoPham T, Kim NJ, Berry K, et al (2022)

PM2.5 air pollution exposure and nonalcoholic fatty liver disease in the Nationwide Inpatient Sample.

Environmental research pii:S0013-9351(22)00938-0 [Epub ahead of print].

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Particulate matter air pollution <2.5 μm in diameter (PM2.5) is a ubiquitous exposure primarily produced from fossil fuel combustion. Previous epidemiologic studies have been mixed. The objective of this study was to examine the association between ambient PM2.5 exposure and NAFLD among hospitalized patients in the Nationwide Inpatient Sample (NIS).

METHODS: We conducted a cross-sectional analysis of hospitalizations from 2001 to 2011 using the NIS, the largest nationally representative all-payer inpatient care administrative database in the United States. Average annual PM2.5 exposure was estimated by linking census tracts (based on NIS-provided hospital ZIP Codes) with a spatiotemporal exposure model. Clinical conditions were identified using hospital discharge diagnosis codes. Multivariable logistic regression incorporating discharge weights was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PM2.5 exposure and odds of NAFLD among hospitalized patients adjusting for age, sex, race/ethnicity, year, individual- and area-level socioeconomic status, urbanicity, region, obesity, diabetes, metabolic syndrome, impaired fasting glucose, dyslipidemia, hypertension, obstructive sleep apnea, and smoking.

RESULTS: There were 269,705 hospitalized patients with NAFLD from 2001 to 2011 (total unweighted n = 45,433,392 hospitalizations). Higher ambient PM2.5 exposure was associated with increased odds of NAFLD among hospitalized patients (adjusted OR: 1.24 per 10 μg/m3 increase, 95% CI 1.15-1.33, p < 0.01). There were statistically significant interactions between PM2.5 exposure and age, race/ethnicity, diabetes, smoking, and region, with stronger positive associations among patients who were aged ≥45 years, non-Hispanic White or Asian/Pacific Islander, non-diabetics, non-smokers, or in the Midwest and West regions, respectively.

CONCLUSIONS: In this nationwide cross-sectional analysis of the NIS database, there was a positive association between ambient PM2.5 exposure and odds of NAFLD among hospitalized patients. Future research should examine the effects of long-term historical PM2.5 exposure and incident NAFLD cases.

RevDate: 2022-06-10

Reding KW, Cheng RK, Barac A, et al (2022)

Toward a Better Understanding of the Differential Impact of Heart Failure Phenotypes After Breast Cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

RevDate: 2022-06-10

Mayer KH, Yuhas K, Amico KR, et al (2022)

Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305).

AIDS and behavior [Epub ahead of print].

HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ2 = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ2 = 9.36, p = 0.009 and χ2 = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.

RevDate: 2022-06-10

García-Guerra A, Rivera JA, Neufeld LM, et al (2022)

Consumption of Micronutrient Powder, Syrup or Fortified Food Significantly Improves Zinc and Iron Status in Young Mexican Children: A Cluster Randomized Trial.

Nutrients, 14(11): pii:nu14112231.

The objective of this study was to compare the effect of three micronutrient products on biomarkers of iron and zinc status of Mexican children 6-12 months of age. As part of research to improve the impact of a national program, 54 communities were randomly assigned to receive: (1) fortified food (FF), provided by the program at the time, or (2) micronutrient powders (MNP) or (3) syrup. Each product contained 10 mg each of zinc and iron, plus other micronutrients. Children consumed the product 6 days/week for four months. Primary outcomes were changes in serum zinc, ferritin, soluble transferrin receptor, hemoglobin concentrations, and their deficiencies. Zinc concentration increased significantly from baseline to follow-up in all groups, with the largest change in the syrup group (geometric mean difference: +4.4 µmol/L; 95%CI: 3.2, 5.5), followed by MNP (+2.9 µmol/L; 95%CI: 2.1, 3.6) and FF (+0.9 µmol/L; 95%CI: 0.3, 1.6). There was a significant increase in hemoglobin concentration (+5.5 g/L; 2.5, 8.4) and a significant reduction in anemia prevalence (44.2% to 26.8%, p < 0.01) only in the MNP group. Compliance differed significantly among groups (MNP vs. FF, p = 0.04; MNP vs. syrup, p = 0.04), but may not fully explain the greater improvement in zinc and iron status in the syrup and MNP groups. The food matrix may influence nutrient utilization from supplements.

RevDate: 2022-06-09

Lieber A, Wang H, Germond A, et al (2022)

In vivo HSC transduction in rhesus macaques with an HDAd5/3+ vector targeting desmoglein 2 and transiently over-expressing cxcr4.

Blood advances pii:485519 [Epub ahead of print].

We developed a new in vivo hematopoietic stem cell (HSC) gene therapy approach that involves only intravenous injections and does not require myeloablation/conditioning and HSC transplantation. In this approach, HSCs are mobilized from the bone marrow into the peripheral blood stream and transduced with intravenously injected helper-dependent adenovirus (HDAd) vectors. A fraction of transduced HSCs returns to the bone marrow and persists there long-term. Here, we report desmoglein 2 (DSG2) as a new receptor that can be employed for in in vivo HSC transduction. We developed HDAd5/3+ vectors that use DSG2 as a high-affinity attachment receptor and studied in vivo HSC transduction and safety after intravenous injection of an HDAd5/3+GFP vector in G-CSF/AMD3100(Plerixafor)-mobilized rhesus macaques. Unlike previously used CD46-targeting HDAd5/35++ vectors, HDAd5/3+ virions were not sequestered by rhesus erythrocytes and therefore mediated ~10-fold higher GFP marking rates in primitive HSCs (CD34+/CD45RA-/CD90+ cells) in the bone marrow at day 7 after vector injection. To further increase the return of in vivo transduced, mobilized HSCs to the bone marrow, we transiently expressed CXC motif chemokine receptor 4 (cxcr4) in mobilized HSCs from the HDAd5/3+ vector. In vivo transduction with a HDAd5/3+GFP/cxcr4 vector at a low dose of 0.4x1012vp/kg resulted in up to 7% of GFP-positive CD34+/CD45RA-/CD90+ cells in the bone marrow. This transduction rate is a solid basis for in vivo base or prime editing in combination with natural or drug-induced expansion of edited HSCs. Furthermore, our study provides new insights into HSC biology and trafficking after mobilization in non-human primates.

RevDate: 2022-06-09

Wang Z, Peters BA, Usyk M, et al (2022)

Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection.

Arteriosclerosis, thrombosis, and vascular biology [Epub ahead of print].

BACKGROUND: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection.

METHODS: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up.

RESULTS: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus, were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines.

CONCLUSIONS: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

RevDate: 2022-06-09

Song Q, Nasri U, Nakamura R, et al (2022)

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity.

Frontiers in immunology, 13:907673.

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma) due to the graft-versus-leukemia (GVL) activity mediated by alloreactive T cells that can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells can cause a serious side effect, known as graft-versus-host disease (GVHD). GVHD and GVL occur in distinct organ and tissues, with GVHD occurring in target organs (e.g., the gut, liver, lung, skin, etc.) and GVL in lympho-hematopoietic tissues where hematological cancer cells primarily reside. Currently used immunosuppressive drugs for the treatment of GVHD inhibit donor T cell activation and expansion, resulting in a decrease in both GVHD and GVL activity that is associated with cancer relapse. To prevent GVHD, it is important to allow full activation and expansion of alloreactive T cells in the lympho-hematopoietic tissues, as well as prevent donor T cells from migrating into the GVHD target tissues, and tolerize infiltrating T cells via protective mechanisms, such as PD-L1 interacting with PD-1, in the target tissues. In this review, we will summarize major approaches that prevent donor T cell migration into GVHD target tissues and approaches that augment tolerization of the infiltrating T cells in the GVHD target tissues while preserving strong GVL activity in the lympho-hematopoietic tissues.

RevDate: 2022-06-09

Markowski MC, Wang H, De Marzo AM, et al (2022)

Clinical Efficacy of Bipolar Androgen Therapy in Men with Metastatic Castration-Resistant Prostate Cancer and Combined Tumor-Suppressor Loss.

European urology open science, 41:112-115 pii:S2666-1683(22)00612-7.

Bipolar androgen therapy (BAT) relies on oscillating levels of serum testosterone as a way to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Aggressive-variant prostate cancers typically require combination chemotherapy and are frequently associated with loss-of-function mutations in tumor suppressor genes. Here we report clinical outcomes after BAT among patients with mCRPC harboring pathogenic alterations in at least two of three genes: TP53, PTEN, and RB1. In this setting, BAT induced a meaningful PSA50 response rate, progression-free survival and overall survival, particularly in patients without prior chemotherapy.

Patient summary: Bipolar androgen therapy, in which drugs are used to raise testosterone levels and then allow them to decrease again in a cycle, may be a safe and effective treatment for prostate cancer that is resistant to testosterone suppression and has mutations in tumor suppressor genes. A randomized study comparing this approach to chemotherapy is needed to confirm the findings.

RevDate: 2022-06-08

González Moreno IM, Trejo-Falcón J, Matsumoto MM, et al (2022)

Radiology volunteers to support a breast cancer screening program in Peru: Description of the project, preliminary results, and impressions.

Radiologia, 64(3):256-265.

Breast cancer is the second most common cancer in Peruvian women. Due to limitations in national breast cancer screening programs, especially in rural areas, more than 50% of cases of breast cancer in Peru are diagnosed in advanced stages. In collaboration with a local clinic registered as a nongovernmental organization (CerviCusco), RAD-AID International aims to create a sustainable diagnostic structure to improve breast cancer screening in Cuzco. With the support of local, national, and international partners that have collaborated in analyzing radiological resources, raising awareness in the population, acquiring equipment, training clinical staff, and building referral networks, our teams of radiologists, included in the RAD-AID team, have participated in training CerviCusco staff in breast ultrasound, thus enabling additional training for radiology residents through a regulated international collaboration.

RevDate: 2022-06-08

Sebina I, Rashid RB, Sikder MAA, et al (2022)

IFN-λ Diminishes the Severity of Viral Bronchiolitis in Neonatal Mice by Limiting NADPH Oxidase-Induced PAD4-Independent NETosis.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.2100876 [Epub ahead of print].

Infants with attenuated type III IFN (IFN-λ) responses are at increased risk of severe lower respiratory tract infection (sLRI). The IL-28Rα-chain and IL-10Rβ-chain form a heterodimeric receptor complex, necessary for IFN-λ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-λlo microenvironment predisposes to a sLRI, we inoculated neonatal wild-type and IL-28R-deficient (IL-28R-/-) mice with pneumonia virus of mice, a rodent-specific pneumovirus. Infected IL-28R-/- neonates displayed an early, pronounced, and persistent neutrophilia that was associated with enhanced reactive oxygen species (ROS) production, NETosis, and mucus hypersecretion. Targeted deletion of the IL-28R in neutrophils was sufficient to increase neutrophil activation, ROS production, NET formation, and mucus production in the airways. Inhibition of protein-arginine deiminase type 4 (PAD4), a regulator of NETosis, had no effect on myeloperoxidase expression, citrullinated histones, and the magnitude of the inflammatory response in the lungs of infected IL-28R-/- mice. In contrast, inhibition of ROS production decreased NET formation, cellular inflammation, and mucus hypersecretion. These data suggest that IFN-λ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-λ signaling may confer protection against sLRI.

RevDate: 2022-06-08

Garcia-Basteiro AL, White RG, Tait D, et al (2022)

End-point definition and trial design to advance tuberculosis vaccine development.

European respiratory review : an official journal of the European Respiratory Society, 31(164): pii:31/164/220044.

Tuberculosis (TB) remains a leading infectious cause of death worldwide and the coronavirus disease 2019 pandemic has negatively impacted the global TB burden of disease indicators. If the targets of TB mortality and incidence reduction set by the international community are to be met, new more effective adult and adolescent TB vaccines are urgently needed. There are several new vaccine candidates at different stages of clinical development. Given the limited funding for vaccine development, it is crucial that trial designs are as efficient as possible. Prevention of infection (POI) approaches offer an attractive opportunity to accelerate new candidate vaccines to advance into large and expensive prevention of disease (POD) efficacy trials. However, POI approaches are limited by imperfect current tools to measure Mycobacterium tuberculosis infection end-points. POD trials need to carefully consider the type and number of microbiological tests that define TB disease and, if efficacy against subclinical (asymptomatic) TB disease is to be tested, POD trials need to explore how best to define and measure this form of TB. Prevention of recurrence trials are an alternative approach to generate proof of concept for efficacy, but optimal timing of vaccination relative to treatment must still be explored. Novel and efficient approaches to efficacy trial design, in addition to an increasing number of candidates entering phase 2-3 trials, would accelerate the long-standing quest for a new TB vaccine.

RevDate: 2022-06-08

Peters BA, Lin J, Qi Q, et al (2022)

Menopause Is Associated with an Altered Gut Microbiome and Estrobolome, with Implications for Adverse Cardiometabolic Risk in the Hispanic Community Health Study/Study of Latinos.

mSystems [Epub ahead of print].

Menopause is a pivotal period during which loss of ovarian hormones increases cardiometabolic risk and may also influence the gut microbiome. However, the menopause-microbiome relationship has not been examined in a large study, and its implications for cardiometabolic disease are unknown. In the Hispanic Community Health Study/Study of Latinos, a population with high burden of cardiometabolic risk factors, shotgun metagenomic sequencing was performed on stool from 2,300 participants (295 premenopausal women, 1,027 postmenopausal women, and 978 men), and serum metabolomics was available on a subset. Postmenopausal women trended toward lower gut microbiome diversity and altered overall composition compared to premenopausal women, while differing less from men, in models adjusted for age and other demographic/behavioral covariates. Differentially abundant taxa for post- versus premenopausal women included Bacteroides sp. strain Ga6A1, Prevotella marshii, and Sutterella wadsworthensis (enriched in postmenopause) and Escherichia coli-Shigella spp., Oscillibacter sp. strain KLE1745, Akkermansia muciniphila, Clostridium lactatifermentans, Parabacteroides johnsonii, and Veillonella seminalis (depleted in postmenopause); these taxa similarly differed between men and women. Postmenopausal women had higher abundance of the microbial sulfate transport system and decreased abundance of microbial β-glucuronidase; these functions correlated with serum progestin metabolites, suggesting involvement of postmenopausal gut microbes in sex hormone retention. In postmenopausal women, menopause-related microbiome alterations were associated with adverse cardiometabolic profiles. In summary, in a large U.S. Hispanic/Latino population, menopause is associated with a gut microbiome more similar to that of men, perhaps related to the common condition of a low estrogen/progesterone state. Future work should examine similarity of results in other racial/ethnic groups. IMPORTANCE The menopausal transition, marked by declining ovarian hormones, is recognized as a pivotal period of cardiometabolic risk. Gut microbiota metabolically interact with sex hormones, but large population studies associating menopause with the gut microbiome are lacking. Our results from a large study of Hispanic/Latino women and men suggest that the postmenopausal gut microbiome in women is slightly more similar to the gut microbiome in men and that menopause depletes specific gut pathogens and decreases the hormone-related metabolic potential of the gut microbiome. At the same time, gut microbes may participate in sex hormone reactivation and retention in postmenopausal women. Menopause-related gut microbiome changes were associated with adverse cardiometabolic risk in postmenopausal women, indicating that the gut microbiome contributes to changes in cardiometabolic health during menopause.

RevDate: 2022-06-08

Lin DY, Baden LR, El Sahly HM, et al (2022)

Durability of Protection Against Symptomatic COVID-19 Among Participants of the mRNA-1273 SARS-CoV-2 Vaccine Trial.

JAMA network open, 5(6):e2215984 pii:2793157.

RevDate: 2022-06-08

Chow EJ, Chen Y, Armstrong GT, et al (2022)

Underdiagnosis and Undertreatment of Modifiable Cardiovascular Risk Factors Among Survivors of Childhood Cancer.

Journal of the American Heart Association [Epub ahead of print].

Background Determine the prevalence and predictors associated with underdiagnosis and undertreatment of modifiable cardiovascular disease (CVD) risk factors (hypertension, dyslipidemia, glucose intolerance/diabetes) among adult survivors of childhood cancer at high risk of premature CVD. Methods and Results This was a cross-sectional study of adult-aged survivors of childhood cancer treated with anthracyclines or chest radiotherapy, recruited across 9 US metropolitan regions. Survivors completed questionnaires and in-home clinical assessments. The comparator group was a matched sample from the National Health and Nutrition Examination Survey. Multivariable logistic regression estimated the risk (odds ratios) of CVD risk factor underdiagnosis and undertreatment among survivors compared with the National Health and Nutrition Examination Survey. Survivors (n=571; median age, 37.7 years and 28.5 years from cancer diagnosis) were more likely to have a preexisting CVD risk factor than the National Health and Nutrition Examination Survey (n=345; P<0.05 for all factors). While rates of CVD risk factor underdiagnosis were similar (27.1% survivors versus 26.1% National Health and Nutrition Examination Survey; P=0.73), survivors were more likely undertreated (21.0% versus 13.9%, P=0.007; odds ratio, 1.8, 95% CI, 1.2-2.7). Among survivors, the most underdiagnosed and undertreated risk factors were hypertension (18.9%) and dyslipidemia (16.3%), respectively. Men and survivors who were overweight/obese were more likely to be underdiagnosed and undertreated. Those with multiple adverse lifestyle factors were also more likely undertreated (odds ratio, 2.2, 95% CI, 1.1-4.5). Greater health-related self-efficacy was associated with reduced undertreatment (odds ratio, 0.5; 95% CI, 0.3-0.8). Conclusions Greater awareness of among primary care providers and cardiologists, combined with improving self-efficacy among survivors, may mitigate the risk of underdiagnosed and undertreated CVD risk factors among adult-aged survivors of childhood cancer. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03104543.

RevDate: 2022-06-07

Santana-Davila R (2022)

Chemo and Immuno-Therapeutic Options for Nonsmall Cell Lung Cancer Lung Cancer.

The Surgical clinics of North America, 102(3):493-498.

Over the last decade, the use of immune checkpoint inhibitors (ICI) has dramatically changed the treatment paradigm and outcome of patients with nonsmall cell lung cancer (NSCLC) across all stages of the disease. In this review, we provide a concise history of the use of ICIs in the treatment of NSCLC and review discuss the data behind the different indications.

RevDate: 2022-06-07

Cuvelier GDE, Logan BR, Prockop S, et al (2022)

Outcomes Following Treatment for Adenosine Deaminase Deficient Severe Combined Immunodeficiency: A Report from the PIDTC.

Blood pii:485484 [Epub ahead of print].

Adenosine deaminase (ADA) deficiency causes ~13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 ADA-SCID patients diagnosed between 1982-2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies. Baseline clinical, immunologic, genetic characteristics and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT) (p<0.01). Overall survival (OS) at 5-years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT) (p=0.01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs. 68% if ≥3.5 months, p=0.02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs. 68.2%, p<0.01) and OS (64.7% vs. 82.3%, p=0.02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies ADA-SCID patients soon after birth and before the onset of infections.

RevDate: 2022-06-07

Zuo S, Yadala R, Yang F, et al (2022)

Recurrent Plant-Specific Duplications of KNL2 and Its Conserved Function as a Kinetochore Assembly Factor.

Molecular biology and evolution pii:6603878 [Epub ahead of print].

KINETOCHORE NULL2 (KNL2) plays key role in the recognition of centromeres and new CENH3 deposition. To gain insight into the origin and diversification of the KNL2 gene, we reconstructed its evolutionary history in the plant kingdom. Our results indicate that the KNL2 gene in plants underwent three independent ancient duplications in ferns, grasses and eudicots. Additionally, we demonstrated that previously unclassified KNL2 genes could be divided into two clades αKNL2 and βKNL2 in eudicots and γKNL2 and δKNL2 in grasses, respectively. KNL2s of all clades encode the conserved SANTA domain, but only the αKNL2 and γKNL2 groups additionally encode the CENPC-k motif. In the more numerous eudicot sequences, signatures of positive selection were found in both αKNL2 and βKNL2 clades, suggesting recent or ongoing adaptation. The confirmed centromeric localization of βKNL2 and mutant analysis suggests that it participates in loading of new CENH3, similarly to αKNL2. A high rate of seed abortion was found in heterozygous βKNL2 plants and the germinated homozygous mutants did not develop beyond the seedling stage. Taken together, our study provides a new understanding of the evolutionary diversification of the plant kinetochore assembly gene KNL2, and suggests that the plant-specific duplicated KNL2 genes are involved in centromere and/or kinetochore assembly for preserving genome stability.

RevDate: 2022-06-07

Juluri KR, Siu C, RD Cassaday (2022)

Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy.

Blood and lymphatic cancer : targets and therapy, 12:55-79 pii:342052.

Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell subtypes, ALL is more common in children, comprising nearly 30% of pediatric malignancies, but also constitutes 1% of adult cancer diagnoses. Outcomes are age-dependent, with five-year overall survival of greater than 90% in children and less than 20% in older adults. L-asparaginase, an enzyme not found in humans, depletes serum levels of L-asparagine. As leukemic cells are unable to synthesize this amino acid, its deprivation results in cell death. The success of asparaginase-containing regimens in the treatment of pediatric ALL, and poor outcomes with conventional cytotoxic regimens in adults, have led to trials of pediatric or pediatric-inspired regimens incorporating asparaginase in the adolescent and young adult (AYA) and adult populations. Initially purified from Escherichia coli, newer formulations of asparaginase have been developed to address short half-life, high immunogenic potential, and manufacturing difficulties. Unfamiliarity with asparaginase use and management of its unique toxicities may result in treatment-decisions that negatively impact outcomes. In this review, we address the current use of asparaginase in the treatment of ALL, with an emphasis on its role in the treatment of adults, key clinical trials, recognition and management of toxicities, and ongoing directions of study.

RevDate: 2022-06-06

Huang C, Callahan BJ, Wu MC, et al (2022)

Phylogeny-guided microbiome OTU-specific association test (POST).

Microbiome, 10(1):86.

BACKGROUND: The relationship between host conditions and microbiome profiles, typically characterized by operational taxonomic units (OTUs), contains important information about the microbial role in human health. Traditional association testing frameworks are challenged by the high dimensionality and sparsity of typical microbiome profiles. Phylogenetic information is often incorporated to address these challenges with the assumption that evolutionarily similar taxa tend to behave similarly. However, this assumption may not always be valid due to the complex effects of microbes, and phylogenetic information should be incorporated in a data-supervised fashion.

RESULTS: In this work, we propose a local collapsing test called phylogeny-guided microbiome OTU-specific association test (POST). In POST, whether or not to borrow information and how much information to borrow from the neighboring OTUs in the phylogenetic tree are supervised by phylogenetic distance and the outcome-OTU association. POST is constructed under the kernel machine framework to accommodate complex OTU effects and extends kernel machine microbiome tests from community level to OTU level. Using simulation studies, we show that when the phylogenetic tree is informative, POST has better performance than existing OTU-level association tests. When the phylogenetic tree is not informative, POST achieves similar performance as existing methods. Finally, in real data applications on bacterial vaginosis and on preterm birth, we find that POST can identify similar or more outcome-associated OTUs that are of biological relevance compared to existing methods.

CONCLUSIONS: Using POST, we show that adaptively leveraging the phylogenetic information can enhance the selection performance of associated microbiome features by improving the overall true-positive and false-positive detection. We developed a user friendly R package POSTm which is freely available on CRAN (https://CRAN.R-project.org/package=POSTm). Video Abstract.

RevDate: 2022-06-06

Kourtis N, Wang Q, Wang B, et al (2022)

A single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma.

Nature cancer [Epub ahead of print].

A complete chart of the chromatin regulatory elements of immune cells in patients with cancer and their dynamic behavior is necessary to understand the developmental fates and guide therapeutic strategies. Here, we map the single-cell chromatin landscape of immune cells from blood, normal tumor-adjacent kidney tissue and malignant tissue from patients with early-stage clear cell renal cell carcinoma (ccRCC). We catalog the T cell states dictated by tissue-specific and developmental-stage-specific chromatin accessibility patterns, infer key chromatin regulators and observe rewiring of regulatory networks in the progression to dysfunction in CD8+ T cells. Unexpectedly, among the transcription factors orchestrating the path to dysfunction, NF-κB is associated with a pro-apoptotic program in late stages of dysfunction in tumor-infiltrating CD8+ T cells. Importantly, this epigenomic profiling stratified ccRCC patients based on a NF-κB-driven pro-apoptotic signature. This study provides a rich resource for understanding the functional states and regulatory dynamics of immune cells in ccRCC.

RevDate: 2022-06-06

Georgeson P, Harrison TA, Pope BJ, et al (2022)

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.

Nature communications, 13(1):3254.

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

RevDate: 2022-06-06

Ose J, Gigic B, Hardikar S, et al (2022)

Pre-surgery adhesion molecules and angiogenesis biomarkers are differently associated with outcomes in colon and rectal cancer: Results from the ColoCare Study.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:699390 [Epub ahead of print].

BACKGROUND: Cell-to-cell adhesion and angiogenesis are hallmarks of cancer. No studies have examined associations of adhesion-molecules and angiogenesis biomarkers with clinical outcomes in colorectal cancer (CRC).

METHODS: In pre-surgery serum from n=426 CRC patients (stage I-III) we investigated associations of CRP, SAA, adhesion molecules (sICAM-1, sVCAM-1), and angiogenesis markers (VEGF-A, and -D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed hazard ratios (HR) and 95% confidence intervals; adjusted for age, sex, BMI, stage, site, and study site, stratified by tumor site in exploratory analyses.

RESULTS: N=65 (15%) were deceased, 59 patients (14%) had a recurrence after a median follow-up of 31 months. We observed significant associations of biomarkers with OS, DFS, and risk of recurrence on a continuous scale and comparing top to bottom tertile, with HRs ranging between 1.19 - 13.92. CRP was associated with risk of death and recurrence in patients in the top tertile compared to patients in the bottom tertile, e.g., risk of recurrence HRQ3-Q1:13.92 (1.72, 112.56). Significant heterogeneity between biomarkers and clinical outcomes was observed in stratified analysis by tumor site for CRP, SAA, sICAM-1, sVCAM-1, and VEGF-D. VEGF-D was associated with a 3-fold increase in risk of death for rectal cancer (HRlog2: 3.26; 95% CI: 1.58-6.70) compared to no association for colon cancer (HRlog2: 0.78; 95% CI: 0.35-1.73; pheterogenity =0.01).

CONCLUSIONS: Adhesion molecules and angiogenesis biomarkers are independent prognostic markers for CRC, with differences by tumor site.

IMPACT: There is need for tailored treatment for colon and rectal cancer.

RevDate: 2022-06-06

Johnson MG, Puenpatom A, Moncada PA, et al (2022)

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease.

OBJECTIVE: To identify other potential clinical benefits of molnupiravir versus placebo.

DESIGN: Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597).

SETTING: 107 sites globally.

PARTICIPANTS: 1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19.

INTERVENTION: Molnupiravir, 800 mg, or placebo every 12 hours for 5 days.

MEASUREMENTS: Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo 2), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization.

RESULTS: Participants receiving molnupiravir showed faster normalization of CRP and Spo 2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19-related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants.

LIMITATIONS: Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2.

CONCLUSION: The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death.

PRIMARY FUNDING SOURCE: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

RevDate: 2022-06-06

Clark JD, Baden HP, Berkman ER, et al (2022)

Ethical Considerations in Ever-Expanding Utilization of ECLS: A Research Agenda.

Frontiers in pediatrics, 10:896232.

Technological advancements and rapid expansion in the clinical use of extracorporeal life support (ECLS) across all age ranges in the last decade, including during the COVID-19 pandemic, has led to important ethical considerations. As a costly and resource intensive therapy, ECLS is used emergently under high stakes circumstances where there is often prognostic uncertainty and risk for serious complications. To develop a research agenda to further characterize and address these ethical dilemmas, a working group of specialists in ECLS, critical care, cardiothoracic surgery, palliative care, and bioethics convened at a single pediatric academic institution over the course of 18 months. Using an iterative consensus process, research questions were selected based on: (1) frequency, (2) uniqueness to ECLS, (3) urgency, (4) feasibility to study, and (5) potential to improve patient care. Questions were categorized into broad domains of societal decision-making, bedside decision-making, patient and family communication, medical team dynamics, and research design and implementation. A deeper exploration of these ethical dilemmas through formalized research and deliberation may improve equitable access and quality of ECLS-related medical care.

RevDate: 2022-06-07

Shinohara MM, Mahurin HM, Tarabadkar E, et al (2021)

Health-related quality of life in cutaneous T-cell lymphoma: A cross-sectional survey study.

Skin health and disease, 1(3):e45 pii:SKI245.

Background: Patients with cutaneous T-cell lymphoma (CTCL) often have indolent but symptomatic disease.

Objective: Assessment of the health-related quality of life (HRQoL) of patients with CTCL.

Methods: Cross-sectional survey study. HRQoL was measured by Skindex-16 and FACT-G.

Results: A total of 372 responses were received; 80 incomplete/ineligible responses were excluded. A majority of respondents identified as white (87%; 250/288) and female (67%; 193/286) with a mean age of 57 ± 14 years. Most patients had early-stage (IA-IIA) (74%; 162/203) mycosis fungoides (87%; 241/279). There were 33 (12%; 33/279) patients with Sézary syndrome. Mean itch score (visual analogue scale; VAS) was 3.2 ± 2.8, overall; 2.7 ± 2.6 for early, and 4.2 ± 2.9 for advanced disease (p = 0.008). Thirty-eight percent (108/284) and 24% (69/284) reported head/neck and groin/genital involvement, respectively.Overall HRQoL was 46 ± 27 (Skindex-16) and 71 ± 19 (FACT-G), with worse HRQoL for patients with advanced versus early disease (Skindex-16: 67 vs. 40; p=<0.001, FACT-G: 62 vs. 76; p = 0.001). Predictors of worse HRQoL included head/neck, hand/foot or groin/genital involvement, younger age and spending >15 min daily treating CTCL.

Limitations: Include anonymous survey methodology, underrepresentation of certain CTCL subtypes and non-white respondents.

Conclusions: Patients with CTCL, particularly those with advanced disease or involvement of the head/neck, acral or groin/genital sites, experience significant impact on HRQoL.

RevDate: 2022-06-06

Cuvelier GDE, Schoettler M, Buxbaum NP, et al (2022)

Towards a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.

Transplantation and cellular therapy pii:S2666-6367(22)01334-3 [Epub ahead of print].

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in non-classical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. While still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD, while outlining a research framework for future studies to be undertaken within the next three to seven years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.

RevDate: 2022-06-06

Farhadfar N, Weaver M, Al-Mansour Z, et al (2022)

Self-efficacy for Symptom Management in Long-term Adult Hematopoietic Stem Cell Survivors.

Transplantation and cellular therapy pii:S2666-6367(22)01329-X [Epub ahead of print].

BACKGROUND: Hematopoietic cell transplantation (HCT) survivors have a complex and multiphase recovery period. Health care delivery and psychosocial interventions for HCT survivors are challenging as many HCT recipients live great distances from the facility where they had their HCT. Therefore, identifying factors associated with a patient's capability to self-manage symptoms is a significant focus of survivorship research. A patient's self-efficacy may be important for the successful management of major stressors associated with treatments and recovery. Here, we aimed to evaluate the impact of perceived self-efficacy on distress, quality of life (QoL), depression, and fatigue, and identify the factors associated with lower self-efficacy.

METHODS: This cross-sectional study analyzed baseline data from a randomized controlled trial INSPIRE (NCT01602211) in adult (age 18 and older) survivors 2-10 years post HCT. Patients with recurrence or subsequent malignancy requiring cancer treatment during the two years prior to enrollment, inability to read and understand English and lack of access to email and the Internet were excluded. Data included medical records and patient-reported outcomes (PROs) including Cancer and Treatment Distress (CTXD) with 6 subscales, Patient Health Questionnaire depression scale (PHQ-8), Short Form 12 Health Survey (SF-12) physical function (PCS) and mental function (MCS) scores, Brief Fatigue Inventory (BFI) and Self-Efficacy. Pearson correlations were used to test bivariate associations for self-efficacy of CTXD, SF-12, BFI, and PHQ8. General linear models were used to test the independent associations for CTXD and SF-12 outcomes with self-efficacy, controlling for selected sociodemographic and treatment covariates. Tenability of statistical model assumptions were examined, and no remediation was necessary.

RESULTS: A total of 1078 HCT survivors were included in the analysis. Participants were 19 to 85 years (mean age 58), 53% male, and over 90% white and non-Hispanic. Only 16% reported living in a rural area. A majority received an autologous HCT (55%) and were less than 5 years from their first HCT (54%). Among the allogeneic HCT recipients, more than half (55%) had active chronic Graft-versus-Host (cGVHD) and nearly 40% were on active systemic treatment. The mean self-efficacy score was 3.01 (SD 0.49). Female sex (p=0.014), younger age at HCT, younger age at cGVHD presentation (p = 0.031), moderate to severe currently active cGVHD (p=0.003) and household income less than $40,000 (p < 0.001) were associated with lower self-efficacy. In bivariate analyses, self-efficacy was negatively correlated with mean total distress (CTXD, r -0.5, p <0.001) and each of the CTXD subscales. HCT survivors with higher self-efficacy also reported better physical (r 0.48, p<0.001) and mental function on the SF-12 (r 0.57, p<0.001). Moreover, self-efficacy was negatively correlated with symptoms such as fatigue (r -0.44, p<0.001) and depression (r -0.48, p<0.001). In a regression model investigating the impact of self-efficacy on CTXD controlled for demographics and disease characteristics, lower self-efficacy was independently associated with higher distress (CTXD, β -0.232; 95% CI (-0.294, -0.169), p< 0.001). Moreover, there was a significant positive relationship between self-efficacy and both mental (beta 4.68; 95% CI (3.82, 5.54); p <0.001) and physical (beta 2.69; 95% CI (1.74, 3.64); p<0.001) components of QoL.

CONCLUSION: Our study demonstrates that lower levels of self-efficacy reported by HCT survivors were independently associated with higher levels of symptoms such as fatigue and depression, lower QoL, and more cancer -related distress. Furthermore, self-efficacy was more likely to be impaired in females, younger adults, those with lower incomes, and survivors with active cGVHD. These findings support the value of self-management interventions focused on improving self-efficacy as having the potential to improve multiple symptoms and QoL in HCT survivors.

RevDate: 2022-06-07

Santiago-Torres M, Mull KE, Sullivan BM, et al (2022)

Efficacy of smartphone applications for smoking cessation in heavy-drinking adults: Secondary analysis of the iCanQuit randomized trial.

Addictive behaviors, 132:107377.

INTRODUCTION: Efficacious smoking cessation treatments are needed for heavy-drinking adults who often have difficulty quitting smoking. In a secondary analysis of a parent randomized controlled trial, we explored the efficacy of an Acceptance and Commitment Therapy (ACT)-based smartphone application (iCanQuit) versus a US Clinical Practice Guidelines (USCPG)-based smartphone application (QuitGuide) for smoking cessation among heavy-drinking participants (4 + drinks/day for women; 5 + drinks/day for men).

METHODS: Participants were randomized to receive iCanQuit (n = 188) or QuitGuide (n = 160) for 12-months. Smoking cessation outcomes were measured at 3, 6 and 12-months. The primary outcome was self-reported complete-case 30-day point prevalence abstinence (PPA) at 12-months. Secondary outcomes were 7-day PPA at all timepoints; prolonged abstinence; and cessation of all nicotine-containing products at 12-months. Multiple imputation and missing-as-smoking analyses were also conducted. Exploratory outcomes were cessation of both smoking and heavy drinking and change in alcohol use (drinks/day) at 12-months. Treatment engagement and satisfaction and change in ACT-based processes were compared between arms.

RESULTS: Retention rate was 85% at 12-months and did not differ by arm. At 12-months, iCanQuit participants had nearly double the odds of smoking cessation compared to QuitGuide (complete-case 30-day PPA = 24% vs. 15%; OR = 1.87 95% CI: 1.03, 3.42). Findings were similar for the multiple imputation and missing-as-smoking outcomes at 12-months. Combined cessation of smoking and heavy drinking, and alcohol use at 12-months did not differ by arm. iCanQuit was significantly more engaging and satisfying than QuitGuide. Increased acceptance of thoughts about smoking mediated the effect of treatment on cessation of heavy drinking at 12-months.

CONCLUSIONS: The iCanQuit smartphone application was more efficacious and engaging for smoking cessation among heavy-drinking adults than a USCPG-based smartphone application.

RevDate: 2022-06-06

Xu K, Li S, Muskens IS, et al (2022)

Accelerated epigenetic aging in newborns with Down syndrome.

Aging cell [Epub ahead of print].

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.

RevDate: 2022-06-06

Richardson PG, Jacobus SJ, Weller EA, et al (2022)

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

The New England journal of medicine [Epub ahead of print].

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.

METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.

RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).

CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

RevDate: 2022-06-06

Li S, CM Counter (2022)

An ultra-sensitive method to detect mutations in human RAS templates.

Small GTPases [Epub ahead of print].

The RAS family of small GTPases are mutated in roughly a fifth of human cancers. Hotspot point mutations at codons G12, G13, and Q61 account for 95% of all these mutations, which are well established to render the encoded proteins oncogenic. In humans, this family is comprised of the three genes HRAS, NRAS, and KRAS. Accumulating evidence argues that oncogenic RAS point mutations may be initiating, as they are often truncal in human tumors and capable of inducing tumorigenesis in mice. As such, there is great interest in detecting oncogenic mutation in the RAS genes to understand the origins of cancer, as well as for early detection purposes. To this end, we previously adapted the microbial ultra-sensitive Maximum Depth Sequencing (MDS) assay for the murine Kras gene, which was capable of detecting oncogenic mutations in the tissues of mice days after carcinogen exposure, essentially capturing the very first step in tumor initiation. Given this, we report here the adaption and details of this assay to detect mutations in a human KRAS sequence at an analytic sensitivity of one mutation in a million independently barcoded templates. This humanized version of MDS can thus be exploited to detect oncogenic mutations in KRAS at an incredible sensitivity, and modified for the same purpose for the other RAS genes.

RevDate: 2022-06-07

Henderson V, Strayhorn SM, Bergeron NQ, et al (2022)

Healthcare Predictors of Information Dissemination About Genetic Risks.

Cancer control : journal of the Moffitt Cancer Center, 29:10732748221104666.

OBJECTIVES: Despite the benefits of genetic counseling and testing (GCT), utilization is particularly low among African American (AA) women who exhibit breast cancer features that are common in BRCA-associated cancer. Underutilization is especially problematic for AA women who are more likely to die from breast cancer than women from any other race or ethnicity. Due to medical mistrust, fear, and stigma that can be associated with genetic services among racial/ethnic minorities, reliance on trusted social networks may be an impactful strategy to increase dissemination of knowledge about hereditary cancer risk. Informed by the social cognitive theory, the purpose of this study is to determine: 1) which AA patients diagnosed with breast cancer and with identified hereditary risk are sharing information about hereditary risk with their networks; 2) the nature of the information dissemination; and 3) if personal GCT experiences is associated with dissemination of information about hereditary risk.

METHODS: Among consented participants (n = 100) that completed an interview administered using a 202-item questionnaire consisting of open- and closed-ended questions, 62 patients were identified to be at higher risk for breast cancer. Descriptive statistics, bivariable chi-square, Pearson's exact tests, and regression analyses were conducted to examine differences in characteristics between high-risk participants who disseminated hereditary risk information and participants who did not.

RESULTS: Among high-risk participants, 25 (40%) indicated they had disseminated information about hereditary risk to at least one member in their family/friend network and 37 (60%) had not. Receipt of both provider recommendations and receipt of GCT services was associated with greater odds of disseminating information about hereditary risk with networks, OR = 4.53, 95%CI [1.33, 15.50], p = .02.

CONCLUSION: Interventions that increase self-efficacy gained through additional personalized knowledge and experience gained through provider recommendations and by undergoing GCT may facilitate information dissemination among social/familial networks.

RevDate: 2022-06-07

Goldman JD, Gonzalez MA, Rüthrich MM, et al (2022)

COVID-19 and Cancer: Special Considerations for Patients Receiving Immunotherapy and Immunosuppressive Cancer Therapies.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 42:1-13.

Patients with cancer generally have a higher risk of adverse outcomes from COVID-19, with higher age, male sex, poor performance status, cancer type, and uncontrolled malignant disease as the main risk factors. However, the influence of specific cancer therapies varies and raises concerns during the pandemic. In patients undergoing cancer immunotherapy or other immunosuppressive cancer treatments, we summarize the evidence on outcomes from COVID-19; address the safety, immunogenicity, and efficacy of COVID-19 vaccination; and review COVID-19 antiviral therapeutics for the patient with cancer. Despite higher mortality for patients with cancer, treatment with immune checkpoint inhibitors does not seem to increase mortality risk based on observational evidence. Inhibitory therapies directed toward B-cell lineages, including monoclonal antibodies against CD20 and CAR T-cell therapies, are associated with poor outcomes in COVID-19; however, the data are sparse. Regarding vaccination in patients receiving immune checkpoint inhibitors, clinical efficacy comparable to that in the general population can be expected. In patients undergoing B-cell-depleting therapy, immunogenicity and clinical efficacy are curtailed, but vaccination is not futile, which is thought to be due to the cellular response. Vaccine reactogenicity and toxicity in all groups of patients with cancer are comparable to that of the general population. Preexposure prophylaxis with monoclonal antibodies directed against the viral spike may provide passive immunity for those not likely to mount an adequate vaccine response. If infected, prompt treatment with monoclonal antibodies or oral small molecule antivirals is beneficial, though with oral antiviral therapies, care must be taken to avoid drug interactions in patients with cancer.

RevDate: 2022-06-07

Pettit K, Rezazadeh A, Atallah EL, et al (2022)

Management of Myeloproliferative Neoplasms in the Molecular Era: From Research to Practice.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 42:1-19.

The 1960 discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) marked the beginning of the modern genomic era of oncology. In the following years, the molecular underpinnings of CML were unraveled, culminating in the development of the first molecularly targeted therapy: imatinib. Imatinib revolutionized CML management, inducing deep molecular responses for most patients and aligning survival curves with those of age-matched control participants. Five additional tyrosine kinase inhibitors are now approved for CML: dasatinib, nilotinib, bosutinib, ponatinib, and asciminib (approved October 2021). The 2005 discovery of JAK2 mutations in myelofibrosis (MF) sparked enthusiasm that molecularly targeted therapies could have a similar impact in that disease. Three JAK inhibitors are now available for MF: ruxolitinib, fedratinib, and pacritinib (approved February 2022). JAK inhibitors are helpful for improving symptoms and splenomegaly but still only scratch the surface of MF pathophysiology. Clinical research testing novel agents, next-generation JAK inhibitors, and combinations of JAK inhibitors plus novel agents is moving at a tremendous pace in the hope that outcomes for patients with MF may mirror those with CML one day. This review provides an update on the status of clinical care and research for MF and addresses ongoing issues related to CML management.

RevDate: 2022-06-02

Grivas P, Kopyltsov E, Su PJ, et al (2022)

Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

European urology pii:S0302-2838(22)02264-3 [Epub ahead of print].

BACKGROUND: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy.

OBJECTIVE: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone.

A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint.

INTERVENTION: Avelumab plus BSC (n = 350) or BSC alone (n = 350).

National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses.

RESULTS AND LIMITATIONS: Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points.

CONCLUSIONS: Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life.

PATIENT SUMMARY: In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

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Curriculum Vitae for R J Robbins

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