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19 Apr 2021 at 01:33
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Bibliography on: Publications by FHCRC Researchers


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 19 Apr 2021 at 01:33 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®)


RevDate: 2021-04-17

Randles A, Wirsching HG, Dean JA, et al (2021)

Computational modelling of perivascular-niche dynamics for the optimization of treatment schedules for glioblastoma.

Nature biomedical engineering, 5(4):346-359.

Glioblastoma stem-like cells dynamically transition between a chemoradiation-resistant state and a chemoradiation-sensitive state. However, physical barriers in the tumour microenvironment restrict the delivery of chemotherapy to tumour compartments that are distant from blood vessels. Here, we show that a massively parallel computational model of the spatiotemporal dynamics of the perivascular niche that incorporates glioblastoma stem-like cells and differentiated tumour cells as well as relevant tissue-level phenomena can be used to optimize the administration schedules of concurrent radiation and temozolomide-the standard-of-care treatment for glioblastoma. In mice with platelet-derived growth factor (PDGF)-driven glioblastoma, the model-optimized treatment schedule increased the survival of the animals. For standard radiation fractionation in patients, the model predicts that chemotherapy may be optimally administered about one hour before radiation treatment. Computational models of the spatiotemporal dynamics of the tumour microenvironment could be used to predict tumour responses to a broader range of treatments and to optimize treatment regimens.

RevDate: 2021-04-17

Percival ME, Wang HL, Zhang MJ, et al (2021)

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone marrow transplantation [Epub ahead of print].

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.

RevDate: 2021-04-17

Xiao J, Rahbar H, Hippe DS, et al (2021)

Dynamic contrast-enhanced breast MRI features correlate with invasive breast cancer angiogenesis.

NPJ breast cancer, 7(1):42.

Angiogenesis is a critical component of breast cancer development, and identification of imaging-based angiogenesis assays has prognostic and treatment implications. We evaluated the association of semi-quantitative kinetic and radiomic breast cancer features on dynamic contrast-enhanced (DCE)-MRI with microvessel density (MVD), a marker for angiogenesis. Invasive breast cancer kinetic features (initial peak percent enhancement [PE], signal enhancement ratio [SER], functional tumor volume [FTV], and washout fraction [WF]), radiomics features (108 total features reflecting tumor morphology, signal intensity, and texture), and MVD (by histologic CD31 immunostaining) were measured in 27 patients (1/2016-7/2017). Lesions with high MVD levels demonstrated higher peak SER than lesions with low MVD (mean: 1.94 vs. 1.61, area under the receiver operating characteristic curve [AUC] = 0.79, p = 0.009) and higher WF (mean: 50.6% vs. 22.5%, AUC = 0.87, p = 0.001). Several radiomics texture features were also promising for predicting increased MVD (maximum AUC = 0.84, p = 0.002). Our study suggests DCE-MRI can non-invasively assess breast cancer angiogenesis, which could stratify biology and optimize treatments.

RevDate: 2021-04-17

Lahman MC, Paulson KG, Nghiem PT, et al (2021)

Quality Is King: Fundamental Insights into Tumor Antigenicity from Virus-Associated Merkel Cell Carcinoma.

The Journal of investigative dermatology pii:S0022-202X(21)00999-4 [Epub ahead of print].

Merkel cell carcinoma (MCC) is a rare skin malignancy that is a paradigm cancer for solid tumor immunotherapy. MCCs associated with Merkel cell polyomavirus (virus-positive MCC [VP-MCC]) or chronic UV exposure (virus-negative MCC [VN-MCC]) are anti-PD(L)1 responsive, despite VP-MCC's low mutational burden. This suggests that antigen quality, not merely mutation quantity, dictates immunotherapy responsiveness, and cell-based therapies targeting optimal antigens may be effective. Despite VP-MCC's antigenic homogeneity, diverse T-cell infiltration patterns are observed, implying microenvironment plasticity and multifactorial contributions to immune recognition. Moreover, VP-MCC exemplifies how antitumor adaptive immunity can provide tumor burden biomarkers for early detection and disease monitoring.

RevDate: 2021-04-17

Parayath NN, MT Stephan (2021)

In Situ Programming of CAR T Cells.

Annual review of biomedical engineering [Epub ahead of print].

Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2021-04-16

Mendelsohn SC, Fiore-Gartland A, Penn-Nicholson A, et al (2021)

Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study.

The Lancet. Global health pii:S2214-109X(21)00045-0 [Epub ahead of print].

BACKGROUND: A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting.

METHODS: In this prospective diagnostic and prognostic accuracy study, adults (aged 18-59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period.

FINDINGS: Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2-5·0) of 285 RISK11-positive participants and one (0·2%; 0·0-1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1-81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6-96·7), and a sensitivity of 87·5% (58·3-100·0) and specificity of 65·8% (62·5-69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7-4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0-0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0-129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6-86·9), and a sensitivity of 88·6% (43·5-98·7) and a specificity of 68·9% (65·3-72·3) for incident tuberculosis at the 60% threshold.

INTERPRETATION: RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis.

FUNDING: Bill & Melinda Gates Foundation and the South African Medical Research Council.

RevDate: 2021-04-16

Smith SD, AK Gopal (2021)

Umbralisib: Walking the Tightrope of PI3K Inhibition in Indolent NHL.

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

RevDate: 2021-04-16

Willcox AC, Richardson BA, Shafi J, et al (2021)

Derivation of an HIV Risk Score for African Women Who Engage in Sex Work.

AIDS and behavior [Epub ahead of print].

No tool exists to stratify HIV risk in contemporary African female sex worker (FSW) populations. Data from a cohort of HIV-negative FSWs in Mombasa, Kenya from 2010 to 2017 were used to conduct a survival analysis assessing predictors of HIV infection. Stepwise regression was used to construct a multivariable model that formed the basis for the score. Seventeen HIV infections occurred over 1247 person-years of follow-up contributed by 670 women. Using depot medroxyprogesterone acetate (DMPA), having a curable sexually transmitted infection (STI), and being married contributed points to the score. HIV incidence was 0.85/100 person-years in a lower-risk group and 3.10/100 person-years in a higher-risk group. In a cohort with overall HIV incidence < 1.50/100 person-years, this risk score identified a subgroup of FSWs with HIV incidence > 3.00/100 person-years, which is the threshold used by the World Health Organization for initiating pre-exposure prophylaxis (PrEP). If validated in an external population, this tool could be useful for targeted PrEP promotion among higher-risk FSWs.

RevDate: 2021-04-16

Stilp AM, Emery LS, Broome JG, et al (2021)

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

American journal of epidemiology pii:6228144 [Epub ahead of print].

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

RevDate: 2021-04-17

Wegermann K, Garrett ME, Zheng J, et al (2021)

Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD.

Hepatology communications, 5(4):598-607.

The development of fibrosis in nonalcoholic fatty liver disease (NAFLD) is influenced by genetics, sex, and menopausal status, but whether genetic susceptibility to fibrosis is influenced by sex and reproductive status is unclear. Our aim was to identify metabolism-related single nucleotide polymorphisms (SNPs), whose effect on NAFLD fibrosis is significantly modified by sex and menopausal status. We performed a cross-sectional, proof-of-concept study of 616 patients in the Duke NAFLD Clinical Database and Biorepository. The primary outcome was nonalcoholic steatohepatitis-Clinical Research Network (NASH-CRN) fibrosis stage. Menopause status was self-reported; age 51 years was used as a surrogate for menopause in patients with missing menopause data. The Metabochip was used to obtain 98,359 SNP genotypes in known metabolic pathway genes for each patient. We used additive genetic models to characterize sex and menopause-specific effects of SNP genotypes on NAFLD fibrosis stage. In the main effects analysis, none of the SNPs were associated with fibrosis at P < 0.05 after correcting for multiple comparisons. Twenty-five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction P < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes: KCNIP4 (potassium voltage-gated channel interacting protein 4), PSORS1C1 (psoriasis susceptibility 1 candidate 1), KLHL8 (Kelch-like family member 8), GLRA1 (glycine receptor alpha 1), NOTCH2 (notch receptor 2), and PRKCH (protein kinase C eta), and four SNPs were intergenic. In stratified models, four SNPs were significant in premenopausal and postmenopausal women, three only in postmenopausal women, two in men and postmenopausal women, and one only in premenopausal women. Conclusion: We identified 10 loci with a significant sex/menopause interaction with respect to fibrosis. None of these SNPs were significant in all sex/menopause groups, suggesting modulation of genetic susceptibility to fibrosis by sex and menopause status. Future studies of genetic predictors of NAFLD progression should account for sex and menopause.

RevDate: 2021-04-16

Wang H, Noordam R, Cade BE, et al (2021)

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Molecular psychiatry [Epub ahead of print].

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

RevDate: 2021-04-16

Seaton KE, Deal A, Han X, et al (2021)

Meta-analysis of HIV-1 vaccine elicited mucosal antibodies in humans.

NPJ vaccines, 6(1):56.

We studied mucosal immune responses in six HIV-1 vaccine trials investigating different envelope (Env)-containing immunogens. Regimens were classified into four categories: DNA/vector, DNA/vector plus protein, protein alone, and vector alone. We measured HIV-1-specific IgG and IgA in secretions from cervical (n = 111) and rectal swabs (n = 154), saliva (n = 141), and seminal plasma (n = 124) and compared to corresponding blood levels. Protein-containing regimens had up to 100% response rates and the highest Env-specific IgG response rates. DNA/vector groups elicited mucosal Env-specific IgG response rates of up to 67% that varied across specimen types. Little to no mucosal IgA responses were observed. Overall, gp41- and gp140-specific antibodies dominated gp120 mucosal responses. In one trial, prior vaccination with a protein-containing immunogen maintained durability of cervical and rectal IgG for up to 17 years. Mucosal IgG responses were boosted after revaccination. These findings highlight a role for protein immunization in eliciting HIV-1-specific mucosal antibodies and the ability of HIV-1 vaccines to elicit durable HIV-1-specific mucosal IgG.

RevDate: 2021-04-16

Shitole SG, Lazar JM, Hanna DB, et al (2021)

HIV, HCV and risk of new-onset left ventricular dysfunction: the women's interagency HIV study.

AIDS (London, England) pii:00002030-900000000-96421 [Epub ahead of print].

BACKGROUND: HIV and HCV have each been linked with cardiac dysfunction. Studies of HIV have often lacked appropriate controls and primarily involved men, while data for HCV are sparse.

METHODS: We performed repeat echocardiography over a median interval of 12 years in participants from the Women's Interagency HIV Study in order to evaluate the relationships of HIV and HCV with incident left ventricular (LV) dysfunction (systolic or diastolic).

RESULTS: Of the 311 women included (age 39 ± 9), 70% were HIV and 20% HCV positive. Forty three participants (13.8%) developed LV dysfunction, of which 79.1% was diastolic. Compared to participants with neither infection, the group with HIV-HCV coinfection showed a significantly increased risk of incident LV dysfunction after adjustment for risk factors (RR = 2.96 [95% CI = 1.05-8.31]), but associations for the HCV monoinfected and HIV monoinfected groups were not statistically significant (RR = 2.54 [0.83-7.73] and RR = 1.66 [0.65-4.25], respectively). Comparison of HCV-positive and HCV-negative women showed a significantly increased risk independent of covariates (RR = 1.96 [1.02-3.77]), but this was not the case for HIV-positive vs. HIV-negative women (RR = 1.43 [0.76-2.69]). There was no evidence of HCV-by-HIV interaction. A more restrictive definition of LV diastolic dysfunction led to fewer incident cases, but a similar, though non-significant, risk estimate for HCV.

CONCLUSIONS: Among middle-aged women, HCV but not HIV infection was associated with a pronounced risk of incident LV dysfunction. Although the influence of residual confounding cannot be excluded, these findings bolster the potential benefits that could be realized by adopting recent recommendations for expanding HCV screening and treatment.

RevDate: 2021-04-15

Cardle II, Jensen MC, Pun SH, et al (2021)

Optimized Serum Stability and Specificity of an αvβ6 Integrin-Binding Peptide for Tumor Targeting.

The Journal of biological chemistry pii:S0021-9258(21)00445-2 [Epub ahead of print].

The integrin αvβ6 is an antigen expressed at low levels in healthy tissue but upregulated during tumorigenesis, making it a promising target for cancer imaging and therapy. A20FMDV2 is a 20-mer peptide derived from the foot-and-mouth disease virus that exhibits nanomolar and selective affinity for αvβ6 over other integrins. Despite this selectivity, A20FMDV2 has had limited success in imaging and treating αvβ6+ tumors in vivo due to its poor serum stability. Here, we explore the cyclization and modification of the A20FMDV2 peptide to improve its serum stability without sacrificing its affinity and specificity for αvβ6. Using cysteine amino acid substitutions and cyclization by perfluoroarylation with decafluorobiphenyl, we synthesized six cyclized A20FMDV2 variants, and discovered that two retained binding to αvβ6 with modestly improved serum stability. Further d-amino acid substitutions and C-terminal sequence optimization outside of the cyclized region greatly prolonged peptide serum stability without reducing binding affinity. While the cyclized A20FMDV2 variants exhibited increased nonspecific integrin binding compared to the original peptide, additional modifications with the non-natural amino acids citrulline, hydroxyproline, and d-alanine were found to restore binding specificity, with some modifications leading to greater αvβ6 integrin selectivity than the original A20FMDV2 peptide. The peptide modifications detailed herein greatly improve the potential for utilization of A20FMDV2 to target αvβ6 in vivo, expanding opportunities for cancer targeting and therapy.

RevDate: 2021-04-15

Osinde G, Niyonzima N, Mulema V, et al (2021)

Increasing access to quality anticancer medicines in low- and middle-income countries - the experience of Uganda.

Future oncology (London, England) [Epub ahead of print].

Cancer is one of the leading causes of death with 9.6 million deaths registered in 2018, of which 70% occur in Africa, Asia and Central and South America, the low-and middle-income countries (LMICs). The global annual expenditure on anticancer medicines increased from $96 billion in 2013 to $133 billion in 2017. This growth rate is several folds that of newly diagnosed cancer cases and therefore estimated to reach up to $200 billion by 2022. The Uganda Cancer Institute, Uganda's national referral cancer center, has increased access to cancer medicines through an efficient and cost-saving procurement system. The system has achieved cost savings of more than USD 2,000,000 on a total of 37 of 42 essential cancer medicines. This has resulted in 85.8% availability superseding the WHO's 80% target. All selected products were procured from manufacturers with stringent regulatory authority approval or a proven track record of quality products.

RevDate: 2021-04-14

Tseng YD, Pankuch M, Mohindra P, et al (2021)

Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry: Concordance With the ILROG Guidelines.

American journal of clinical oncology pii:00000421-900000000-98576 [Epub ahead of print].

PURPOSE: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG).

METHODS: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8).

RESULTS: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease.

CONCLUSIONS: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

RevDate: 2021-04-14

Beatty JD, Sun Q, Markowitz D, et al (2021)

Identifying breast cancer recurrence histories via patient-reported outcomes.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: To test accuracy of patient self-report of breast cancer recurrence for enhancing standard population-based cancer registries that do not routinely collect cancer recurrence data despite the importance of this outcome.

METHODS: Potential research subjects were identified in the Breast Cancer Research Database (BCRD) of the Swedish Cancer Institute (SCI). The BCRD has collected data within 45 days of each medical encounter on new primary breast cancer patients receiving all or part of their initial care at SCI. Females diagnosed with a new primary breast cancer 2004-2016, Stages I-III, and alive at the time of study initiation (2018) were identified. Recurrent breast cancer patients were matched 1:1 to surviving non-recurrent patients by patient age, date of diagnosis, and single or multiple primary tumors. Consented research subjects were surveyed about their initial and subsequent diagnostic, therapeutic, and recurrent events. PRO survey responses were compared with BCRD information for each individual participant. Discrepancies were reviewed in medical records.

RESULTS: A matched sample of 88 recurrent and 88 non-recurrent patients were used in analyses. Respondents correctly identified the date of diagnosis of first primary breast cancer within 1 year 94% (165/176). Recurrence was reported by 97% (85/88) of recurrent patients. No recurrence was reported by 100% (88/88) of non-recurrent patients. Recurrence date within 1 year was correctly identified in 79% (67/85). Recurrence site was correctly identified in 82% (70/85). Medical record review of survey-registry discrepancies led to BCRD corrections in 4.5% (8/176) of cases.

Breast cancer patients can accurately report their disease characteristics, treatments, and recurrence history. Patient-reported information would enhance cancer registry data.

RevDate: 2021-04-14

Boehmer U, Potter J, Clark MA, et al (2021)

Follow-up surveillance among colorectal cancer survivors of different sexual orientations.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: The purpose of this study was to examine receipt of follow-up surveillance among sexual minority and heterosexual survivors and identify survivor-, physician-, and practice-level characteristics associated with follow-up surveillance.

METHODS: An average of 3 years after their stage I-III colorectal cancer diagnosis, we recruited survivors from four cancer registries. A questionnaire, which queried about sexual orientation and other eligibility criteria, was mailed to all cancer survivors. Subsequently, 418 eligible survivors without recurrent disease participated in a telephone survey. Colorectal cancer-specific follow-up surveillance was defined as colonoscopy, carcinoembryonic antigen (CEA) test, or imaging test. We used logistic regression with forward selection to obtain models that best explained each follow-up test.

RESULTS: About 10% of survivors received no follow-up surveillance, while 70% had colonoscopies. While survivors irrespective of sexual orientation received follow-up surveillance, sexual minority survivors had 3 times the odds of receiving imaging tests compared to heterosexual survivors. Having a designated provider of any specialty was most salient for the receipt of surveillance.

CONCLUSIONS: Sexual minority survivors' greater receipt of imaging tests may indicate providers perceive them at greater risk for recurrence than heterosexual survivors. Future studies need to examine provider behaviors towards monitoring colorectal cancer survivors of diverse sexual orientations.

Guidelines recommend surveillance of colorectal cancer survivors to improve survival. This study showed that having a designated provider for follow-up is most salient for the receipt of surveillance, most survivors receive surveillance, and sexual minority survivors had more imaging tests compared to heterosexual survivors.

RevDate: 2021-04-14

Gooptu M, Romee R, St Martin A, et al (2021)

HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis.

Blood pii:475738 [Epub ahead of print].

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

RevDate: 2021-04-16

Kim E, Jang SH, Andersen MR, et al (2021)

"I Made All Decisions Myself": Breast Cancer Treatment Decision-Making by Receivers and Decliners.

Asia-Pacific journal of oncology nursing, 8(3):322-329.

Objective: Many women with breast cancer refuse adjuvant treatments. How they arrive at their respective decisions and whether they are passively or actively involved in making decisions is less known. We explored the different decision-making behaviors of women who received treatments (receivers) after being diagnosed with breast cancer and those who refused (decliners).

Methods: Seven women (four receivers and three decliners) were recruited from the Breast Cancer Integrative Oncology Study. We conducted an inductive content analysis based on in-depth semi-structured interviews with open-ended questions.

Results: Receivers reported that doctors and family members influenced their decision-making. Decliners perceived their doctors as supportive of their decisions and reported that the experience of adjuvant therapy of family and friends, the results of Oncotest, and concerns about side effects influenced their decision-making. Receivers expressed discomfort about their decisions, relied on books, whereas decliners used various sources to find information. Both receivers and decliners believed that they had made the decisions themselves. However, receivers were somewhat negative about doctors' advice. Receivers also reported that, sometimes, the decision-making process was lacking and reported discomfort with the treatment process.

Conclusions: Women with breast cancer need support in understanding the care they are prescribed and getting essential care.

RevDate: 2021-04-14

Tuttle LM, Pacheco D, Warfield L, et al (2021)

Mediator subunit Med15 dictates the conserved "fuzzy" binding mechanism of yeast transcription activators Gal4 and Gcn4.

Nature communications, 12(1):2220.

The acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a "fuzzy" protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein-protein interaction.

RevDate: 2021-04-15

Addetia A, Lieberman NAP, Phung Q, et al (2021)

SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98.

mBio, 12(2):.

RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 has previously been shown to be a major inhibitor of interferon production in both severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show SARS-CoV-2-infected cells display an elevated level of nuclear mRNA accumulation compared to mock-infected cells. We demonstrate that ORF6 is responsible for this nuclear imprisonment of host mRNA, and using a cotransfected reporter assay, we show this nuclear retention of mRNA blocks expression of newly transcribed mRNAs. ORF6's nuclear entrapment of host mRNA is associated with its ability to copurify with the mRNA export factors, Rae1 and Nup98. These protein-protein interactions map to the C terminus of ORF6 and can be abolished by a single amino acid mutation in Met58. Overexpression of Rae1 restores reporter expression in the presence of SARS-CoV-2 ORF6. SARS-CoV ORF6 also interacts with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly copurifies with Rae1 and Nup98 and results in significantly reduced expression of reporter proteins compared to SARS-CoV ORF6, a potential mechanism for the delayed symptom onset and presymptomatic transmission uniquely associated with the SARS-CoV-2 pandemic. We also show that both SARS-CoV and SARS-CoV-2 ORF6 block nuclear import of a broad range of host proteins. Together, these data support a model in which ORF6 clogs the nuclear pore through its interactions with Rae1 and Nup98 to prevent both nuclear import and export, rendering host cells incapable of responding to SARS-CoV-2 infection.IMPORTANCE SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is an RNA virus with a large genome that encodes multiple accessory proteins. While these accessory proteins are not required for growth in vitro, they can contribute to the pathogenicity of the virus. We demonstrate that SARS-CoV-2-infected cells accumulate poly(A) mRNA in the nucleus, which is attributed to the accessory protein ORF6. Nuclear entrapment of mRNA and reduced expression of newly transcribed reporter proteins are associated with ORF6's interactions with the mRNA export proteins Rae1 and Nup98. SARS-CoV ORF6 also shows the same interactions with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly represses reporter expression and copurifies with Rae1 and Nup98 compared to SARS-CoV ORF6. Both SARS-CoV ORF6 and SARS-CoV-2 ORF6 block nuclear import of a wide range of host factors through interactions with Rae1 and Nup98. Together, our results suggest ORF6's disruption of nucleocytoplasmic transport prevents infected cells from responding to the invading virus.

RevDate: 2021-04-14

Biltaji E, Walker B, Au TH, et al (2021)

Can Cost-effectiveness Analysis Inform Genotype-Guided Aspirin Use for Primary Colorectal Cancer Prevention?.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-1580 [Epub ahead of print].

BACKGROUND: Inherited genetic variants can modify the cancer-chemopreventive effect of aspirin. We evaluated the clinical and economic value of genotype-guided aspirin use for colorectal cancer (CRC) chemoprevention in average-risk individuals.

METHODS: A decision analytical model compared genotype-guided aspirin use vs. no genetic testing, no aspirin. The model simulated 100,000 adults {greater than or equal to}50 years of age with average CRC and cardiovascular disease risk. Low-dose aspirin daily starting at age 50 years was recommended only for those with a genetic test result indicating a greater reduction in CRC risk with aspirin use. The primary outcomes were quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER).

RESULTS: The mean cost of using genotype-guided aspirin was $187,109 with 19.922 mean QALYs compared to $186,464 with 19.912 QALYs for no genetic testing, no aspirin. Genotype-guided aspirin yielded an ICER of $66,243 per QALY gained, and was cost-effective in 58% of simulations at $100,000 willingness-to-pay threshold. Genotype-guided aspirin was associated with 1,461 fewer polyps developed, 510 fewer CRC cases, and 181 fewer CRC-related deaths. This strategy prevented 1,078 myocardial infarctions with 1,430 gastrointestinal bleeding events, and 323 intracranial hemorrhage cases compared to no genetic testing, no aspirin.

CONCLUSIONS: Genotype-guided aspirin use for CRC chemoprevention may offer a cost-effective approach for the future management of average-risk individuals.

IMPACT: A genotype-guided aspirin strategy may prevent CRC, CRC-related deaths, and myocardial infarctions, while minimizing bleeding adverse events. This model establishes a framework for genetically-guided aspirin use for targeted chemoprevention of CRC with application towards commercial testing in this population.

RevDate: 2021-04-14

McKay RR, Kwak L, Crowdis J, et al (2021)

Phase 2 multicenter study of enzalutamide in metastatic castration resistant prostate cancer to identify mechanisms driving resistance.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-4616 [Epub ahead of print].

PURPOSE: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.

EXPERIMENTAL DESIGN: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.

RESULTS: 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression.

CONCLUSIONS: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC.

RevDate: 2021-04-16

Wu SJ, Furlan SN, Mihalas AB, et al (2021)

Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression.

Nature biotechnology [Epub ahead of print].

Methods for quantifying gene expression1 and chromatin accessibility2 in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been technically challenging. In this study, we adapted the CUT&Tag method3 to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment.

RevDate: 2021-04-13

Inoue D, Polaski JT, Taylor J, et al (2021)

Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition.

Nature genetics [Epub ahead of print].

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

RevDate: 2021-04-16

Kinganda-Lusamaki E, Black A, Mukadi DB, et al (2021)

Integration of genomic sequencing into the response to the Ebola virus outbreak in Nord Kivu, Democratic Republic of the Congo.

Nature medicine, 27(4):710-716.

On 1 August 2018, the Democratic Republic of the Congo (DRC) declared its tenth Ebola virus disease (EVD) outbreak. To aid the epidemiologic response, the Institut National de Recherche Biomédicale (INRB) implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis and dissemination of genomic epidemiologic results to frontline public health workers. We report 744 new genomes sampled between 27 July 2018 and 27 April 2020 generated by this surveillance effort. Together with previously available sequence data (n = 48 genomes), these data represent almost 24% of all laboratory-confirmed Ebola virus (EBOV) infections in DRC in the period analyzed. We inferred spatiotemporal transmission dynamics from the genomic data as new sequences were generated, and disseminated the results to support epidemiologic response efforts. Here we provide an overview of how this genomic surveillance system functioned, present a full phylodynamic analysis of 792 Ebola genomes from the Nord Kivu outbreak and discuss how the genomic surveillance data informed response efforts and public health decision making.

RevDate: 2021-04-13

Natarajan P, Pampana A, Graham SE, et al (2021)

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nature communications, 12(1):2182.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

RevDate: 2021-04-13

Kpokiri EE, Wu D, Srinivas ML, et al (2021)

Development of an international sexual and reproductive health survey instrument: results from a pilot WHO/HRP consultative Delphi process.

Sexually transmitted infections pii:sextrans-2020-054822 [Epub ahead of print].

Population health surveys are rarely comprehensive in addressing sexual health, and population-representative surveys often lack standardised measures for collecting comparable data across countries. We present a sexual health survey instrument and implementation considerations for population-level sexual health research. The brief, comprehensive sexual health survey and consensus statement was developed via a multi-step process (an open call, a hackathon, and a modified Delphi process). The survey items, domains, entire instruments, and implementation considerations to develop a sexual health survey were solicited via a global crowdsourcing open call. The open call received 175 contributions from 49 countries. Following review of submissions from the open call, 18 finalists and eight facilitators with expertise in sexual health research, especially in low- and middle-income countries (LMICs), were invited to a 3-day hackathon to harmonise a survey instrument. Consensus was achieved through an iterative, modified Delphi process that included three rounds of online surveys. The entire process resulted in a 19-item consensus statement and a brief sexual health survey instrument. This is the first global consensus on a sexual and reproductive health survey instrument that can be used to generate cross-national comparative data in both high-income and LMICs. The inclusive process identified priority domains for improvement and can inform the design of sexual and reproductive health programs and contextually relevant data for comparable research across countries.

RevDate: 2021-04-15

Follmann D, Fintzi J, Fay MP, et al (2021)

A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated.

Annals of internal medicine [Epub ahead of print].

Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.

RevDate: 2021-04-13

Taylor JA, Santiago CC, Gray J, et al (2021)

Localizing Peptidoglycan Synthesis in Helicobacter pylori using Clickable Metabolic Probes.

Current protocols, 1(4):e80.

The bacterial cell wall, composed of peptidoglycan (PG), provides structural integrity for the cell and is responsible for cell shape in most bacteria. Here we present tools to study the cell wall using a clickable PG-specific sugar, 2-alkyne muramic acid (MurNAc-alk), as a metabolic probe. Here we present a new reaction pathway for generating MurNAc-alk. We also include protocols for labeling PG synthesis in Helicobacter pylori, determining the identity of the labeled muropeptides using LC-MS/MS, sample preparation of cells labeled for a short fraction of the doubling time, and visualization using 3D structured illumination microscopy. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Alternative synthesis of MurNAc-alk (direct coupling) Support Protocol 1: Growing Helicobacter pylori in liquid culture Support Protocol 2: Fosfomycin rescue assay Basic Protocol 2: Mass spectrometry (MS) analysis to determine incorporation of MurNAc-alk within the peptidoglycan of H. pylori Support Protocol 3: Hayashi test to determine if SDS is present in the supernatant of peptidoglycan preparations Support Protocol 4: Creating custom cytocentrifuge units for use in a swinging-bucket tabletop centrifuge Basic Protocol 3: Labeling H. pylori with MurNAc-alk or D-Ala-alk Basic Protocol 4: Structured illumination microscopy (SIM) imaging on the DeltaVision OMX.

RevDate: 2021-04-12

Asdahl PH, Oeffinger KC, Albieri V, et al (2021)

Esophageal disease among childhood cancer survivors-A report from the Childhood Cancer Survivors Study.

Pediatric blood & cancer [Epub ahead of print].

There is limited information addressing the occurrence of esophageal strictures among the growing population of survivors of childhood cancer. Using the Childhood Cancer Survivor Study, we analyzed data from 17,121 5-year survivors and 3400 siblings to determine the prevalence and risk factors for esophageal strictures. Prevalence among survivors was 2.0% (95% confidence interval [CI]: 1.8-2.2%), representing a 7.6-fold increased risk compared to siblings. Factors significantly associated with risk of esophageal stricture included diagnosis of Hodgkin lymphoma, greater chest radiation dose, younger age at cancer diagnosis, platinum chemotherapy, and hematopoietic stem cell transplantation. While uncommon, survivors are at risk for therapy-related esophageal strictures.

RevDate: 2021-04-14

Issaka RB, Taylor P, Baxi A, et al (2021)

Model-Based Estimation of Colorectal Cancer Screening and Outcomes During the COVID-19 Pandemic.

JAMA network open, 4(4):e216454 pii:2778450.

Importance: COVID-19 has decreased colorectal cancer screenings.

Objective: To estimate the degree to which expanding fecal immunochemical test-based colorectal cancer screening participation during the COVID-19 pandemic is associated with clinical outcomes.

A previously developed simulation model was adopted to estimate how much COVID-19 may have contributed to colorectal cancer outcomes. The model included the US population estimated to have completed colorectal cancer screening pre-COVID-19 according the American Cancer Society. The model was designed to estimate colorectal cancer outcomes between 2020 and 2023. This analysis was completed between July and December 2020.

Exposures: Adults screened for colorectal cancer and colorectal cancer cases detected by stage.

Main Outcomes and Measures: Estimates of colorectal cancer outcomes across 4 scenarios: (1) 9 months of 50% colorectal cancer screenings followed by 21 months of 75% colorectal cancer screenings; (2) 18 months of 50% screening followed by 12 months of 75% screening; (3) scenario 1 with increased use of fecal immunochemical tests; and (4) scenario 2 with increased use of fecal immunochemical tests.

Results: In our simulation model, COVID-19-related reductions in care utilization resulted in an estimated 1 176 942 to 2 014 164 fewer colorectal cancer screenings, 8346 to 12 894 fewer colorectal cancer diagnoses, and 6113 to 9301 fewer early-stage colorectal cancer diagnoses between 2020 and 2023. With an abbreviated period of reduced colorectal cancer screenings, increasing fecal immunochemical test use was associated with an estimated additional 588 844 colorectal cancer screenings and 2836 colorectal cancer diagnoses, of which 1953 (68.9%) were early stage. In the event of a prolonged period of reduced colorectal cancer screenings, increasing fecal immunochemical test use was associated with an estimated additional 655 825 colorectal cancer screenings and 2715 colorectal cancer diagnoses, of which 1944 (71.6%) were early stage.

Conclusions and Relevance: These results suggest that the increased use of fecal immunochemical tests during the COVID-19 pandemic was associated with increased colorectal cancer screening participation and more colorectal cancer diagnoses at earlier stages. If our estimates are borne out in real-world clinical practice, increasing fecal immunochemical test-based colorectal cancer screening participation during the COVID-19 pandemic could mitigate the consequences of reduced screening rates during the pandemic for colorectal cancer outcomes.

RevDate: 2021-04-15

Starr TN, Greaney AJ, Dingens AS, et al (2021)

Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016.

Cell reports. Medicine [Epub ahead of print].

Monoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for coronavirus disease 2019 (COVID-19). However, ongoing evolution of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can render monoclonal antibodies ineffective. Here, we completely map all of the mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escapes LY-CoV016). In addition, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to the antigenic evolution of SARS-CoV-2.

RevDate: 2021-04-13

Ljungman P, Bermudez A, Logan AC, et al (2021)

A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients.

EClinicalMedicine, 33:100787.

Background: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients.

Methods: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting).

Findings: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (n = 246) or placebo (n = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (n = 87) with ASP0113 and 30•2% (n = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85; p = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (p = 0.027).

Interpretation: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups.

Funding: Astellas Pharma Global Development, Inc .

RevDate: 2021-04-14

Miller MS, Allen PJ, Brown PH, et al (2021)

Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting.

Journal of cancer prevention, 26(1):71-82.

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented.

RevDate: 2021-04-14

Huang Y, Cho J, Y Fong (2021)

Threshold-based subgroup testing in logistic regression models in two-phase sampling designs.

Journal of the Royal Statistical Society. Series C, Applied statistics, 70(2):291-311.

The effect of treatment on binary disease outcome can differ across subgroups characterized by other covariates. Testing for the existence of subgroups that are associated with heterogeneous treatment effects can provide valuable insight regarding the optimal treatment recommendation in practice. Our research in this paper is motivated by the question of whether host genetics could modify a vaccine's effect on HIV acquisition risk. To answer this question, we used data from an HIV vaccine trial with a two-phase sampling design and developed a general threshold-based model framework to test for the existence of subgroups associated with the heterogeneity in disease risks, allowing for subgroups based on multivariate covariates. We developed a testing procedure based on maximum of likelihood-ratio statistics over change planes and demonstrated its advantage over alternative methods. We further developed the testing procedure to account for bias sampling of expensive (i.e. resource-intensive to measure) covariates through the incorporation of inverse probability weighting techniques. We used the proposed method to analyze the motivating HIV vaccine trial data. Our proposed testing procedure also has broad applications in epidemiological studies for assessing heterogeneity in disease risk with respect to univariate or multivariate predictors.

RevDate: 2021-04-11

Kirchhoff A, S Jones (2021)

Financial Toxicity in Adolescent and Young Adult Cancer Survivors: Proposed Directions for Future Research.

Journal of the National Cancer Institute pii:6220202 [Epub ahead of print].

RevDate: 2021-04-15

Grivas P, Agarwal N, Pal S, et al (2021)

Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.

Cancer treatment reviews, 97:102187 pii:S0305-7372(21)00035-9 [Epub ahead of print].

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56-0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin- or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1- tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.

RevDate: 2021-04-11

Kitko CL, Pidala J, Schoemans HM, et al (2021)

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report: NIH cGVHD WG2a.

Transplantation and cellular therapy pii:S2666-6367(21)00824-1 [Epub ahead of print].

Recognition of the earliest signs and symptoms of chronic graft versus host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects have helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are two fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.

RevDate: 2021-04-11

Mammel AE, EM Hatch (2021)

Genome instability from nuclear catastrophe and DNA damage.

Seminars in cell & developmental biology pii:S1084-9521(21)00068-9 [Epub ahead of print].

The nuclear envelope compartmentalizes the eukaryotic genome, provides mechanical resistance, and regulates access to the chromatin. However, recent studies have identified several conditions where the nuclear membrane ruptures during interphase, breaking down this compartmentalization leading to DNA damage, chromothripsis, and kataegis. This review discusses three major circumstances that promote nuclear membrane rupture, nuclear deformation, chromatin bridges, and micronucleation, and how each of these nuclear catastrophes results in DNA damage. In addition, we highlight recent studies that demonstrate a single chromosome missegregation can initiate a cascade of events that lead to accumulating damage and even multiple rounds of chromothripsis.

RevDate: 2021-04-13

Seftel MD, Chitphakdithai P, Miller JP, et al (2021)

Serious Adverse Events in Related Donors: A Report from the Related Donor Safe Study.

Transplantation and cellular therapy, 27(4):352.e1-352.e5.

The incidence and risk factors for severe adverse events (SAEs) in related donors (RD) of hematopoietic cell transplants is unknown. The Related Donor Safe study is a prospective observational cohort of 1680 RDs and represents an opportunity to examine characteristics of SAEs in RDs. In this cohort, we found that SAEs were reported in a total 12 (0.71%) RDs. Of these, 5 SAEs occurred in bone marrow donors (5/404, 1.24%), and 7 (7/1276, 0.55%) were in donors of peripheral blood stem cells. All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. There were no donor fatalities. Of the 12 RDs who experienced an SAE, 10 were either overweight or obese. Five of the 12 RDs had predonation medical conditions that would have resulted in either possible or definite ineligibility for donation were they being assessed as unrelated donors. These SAE data will be useful in the counseling of prospective RDs before planned donation and may be helpful in identifying donors who should be considered medically unsuitable for donation.

RevDate: 2021-04-13

Alsaggaf R, Katta S, Wang T, et al (2021)

Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia.

Transplantation and cellular therapy, 27(4):313.e1-313.e8.

Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.

RevDate: 2021-04-12

Li A, Bhatraju PK, Chen J, et al (2021)

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study.

Transplantation and cellular therapy, 27(4):308.e1-308.e8.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

RevDate: 2021-04-12

Metheny L, Politikos I, Ballen KK, et al (2021)

Guidelines for Adult Patient Selection and Conditioning Regimens in Cord Blood Transplant Recipients with Hematologic Malignancies and Aplastic Anemia.

Transplantation and cellular therapy, 27(4):286-291.

For cord blood transplantation (CBT), appropriate patient and conditioning regimen selection is necessary to achieve long-term disease-free survival. This review aims to provide comprehensive guidelines on these issues using evidence from the literature and experience at dedicated CBT centers. Topics include patient and disease characteristics that make CBT a good or poor choice and a review of outcomes in commonly used conditioning regimens in CBT. This is accompanied with recommendations on regimen intensity based on disease, organ function, and patient performance status and age. In addition, the use of antithymocyte globulin in CBT is discussed, as is the choice of conditioning in aplastic anemia patients who have access to acceptable CB units.

RevDate: 2021-04-12

Carpenter PA, JA Englund (2021)

Commentary: Is Immune Recovery-Based Post-Transplantation Vaccination in Children Better Than Time-Based Revaccination?.

Transplantation and cellular therapy, 27(4):281-283.

RevDate: 2021-04-13
CmpDate: 2021-04-13

Jackson ML, Hart GR, McCulloch DJ, et al (2021)

Effects of weather-related social distancing on city-scale transmission of respiratory viruses: a retrospective cohort study.

BMC infectious diseases, 21(1):335.

BACKGROUND: Unusually high snowfall in western Washington State in February 2019 led to widespread school and workplace closures. We assessed the impact of social distancing caused by this extreme weather event on the transmission of respiratory viruses.

METHODS: Residual specimens from patients evaluated for acute respiratory illness at hospitals in the Seattle metropolitan area were screened for a panel of respiratory viruses. Transmission models were fit to each virus to estimate the magnitude reduction in transmission due to weather-related disruptions. Changes in contact rates and care-seeking were informed by data on local traffic volumes and hospital visits.

RESULTS: Disruption in contact patterns reduced effective contact rates during the intervention period by 16 to 95%, and cumulative disease incidence through the remainder of the season by 3 to 9%. Incidence reductions were greatest for viruses that were peaking when the disruption occurred and least for viruses in an early epidemic phase.

CONCLUSION: High-intensity, short-duration social distancing measures may substantially reduce total incidence in a respiratory virus epidemic if implemented near the epidemic peak. For SARS-CoV-2, this suggests that, even when SARS-CoV-2 spread is out of control, implementing short-term disruptions can prevent COVID-19 deaths.

RevDate: 2021-04-09

Pidala J, Kitko C, Lee SJ, et al (2021)

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report.

Transplantation and cellular therapy pii:S2666-6367(21)00820-4 [Epub ahead of print].

BACKGROUND: Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible over-treatment and may interfere with the graft-vs-malignancy immune response.

OBJECTIVES: We summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet NIH diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist.

STUDY DESIGN AND RESULTS: The goals of this report are to (1) review current knowledge regarding clinical risk factors for chronic GVHD; (2) review what is known about chronic GVHD risk assignment biomarkers; (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents; and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development including trial design and statistical considerations.

CONCLUSIONS: We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early phase preemptive therapy trials represent the most urgent priorities to advance this novel area of research.

RevDate: 2021-04-09

Mishra A, Preussler JM, Bhatt VR, et al (2021)

Breaking the Age Barrier: Physicians' Perceptions on Candidacy for Allogeneic Hematopoietic Cell Transplantation in Older Adults.

Transplantation and cellular therapy pii:S2666-6367(21)00819-8 [Epub ahead of print].

BACKGROUND: Despite continued increases in use of allogeneic hematopoietic cell transplantation (alloHCT) among older adults, no standardized geriatric assessment (GA) has been established to risk-stratify for transplant-related morbidity. We conducted a survey of transplant physicians to determine perceptions of the impact of older age (≥60 years) on alloHCT candidacy, and utilization of tools to gauge candidacy.

METHODS: We conducted a 23-item, online cross-sectional survey of HCT physicians caring for adults in the United States between May and July 2019.

RESULTS: Of the 770 invited HCT physicians, 175 (22.7%) completed the survey. The majority of respondents were 41-60 years old, male, and practiced in a higher volume teaching hospital. When considering regimen intensity, 29 physicians (17%) stated they would consider a myeloablative regimen for patients ≥70 years, and 141 (82%) would consider reduced intensity/non-myeloablative conditioning for patients ≥70 years. Almost all (90%) endorsed the need for a specialized assessment of pre-HCT vulnerabilities to guide candidacy decisions for older adults. Most physicians reported their centers rarely (33%) or never (46%) utilize a dedicated geriatrician/geriatric-oncologist to assess alloHCT candidates ≥60 years. Common barriers to performing a GA included uncertainty about which tools to use, lack of knowledge and training, and lack of appropriate clinical support staff.

CONCLUSIONS: Many alloHCT physicians will consider alloHCT in patients up to age 75 years and not uncommonly, in patients older than that. However, application of tools and domains varies widely to assess candidacy in older adults. Incorporation of a standardized pre-transplant health assessment tool for risk stratification is a significant unmet need.

RevDate: 2021-04-09

Mayor NP, Wang T, Lee SJ, et al (2021)

Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation.

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

PURPOSE: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study.

METHODS: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017.

RESULTS: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003).

CONCLUSION: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.

RevDate: 2021-04-09

Steineck A, Chow EJ, Doody DR, et al (2021)

Hospitalization and mortality outcomes in the first 5 years after a childhood cancer diagnosis: a population-based study.

Cancer causes & control : CCC [Epub ahead of print].

PURPOSE: Children with cancer are frequently hospitalized. However, hospitalization and death by disease category are not well defined < 5 years from diagnosis.

METHODS: We conducted a retrospective cohort study using linked cancer registry-hospital discharge-vital records to identify cancer cases < 20 years at diagnosis during 1987-2012 (n = 4,567) and comparison children without cancer, matched on birth year and sex (n = 45,582). Data linkage identified serious morbidities resulting in cancer- and non-cancer-related hospitalizations or deaths < 5 years from diagnosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare relative hospitalization and mortality by disease category and after excluding cancer-related outcomes. Among cancer cases, relative risks of these outcomes for children with solid tumors compared with children with leukemia/lymphoma were also estimated.

RESULTS: Greater rates of all-cause hospitalization (281.5/1,000 vs. 6.2/1,000 person years) and death (40.7/1,000 vs. 0.15/1,000 person years) were observed in childhood cancer cases than comparators and across all diagnosis categories. Increased hospitalization (31.0/1,000 vs. 6.2/1,000 person years; HR 5.0, 95% CI 4.5-5.5) and death (1.0/1,000 vs. 0.15/1,000 person years; HR 10.4, 95% CI 5.6-19.1) rates remained when cancer-related outcomes were excluded. Although HRs for hospitalization and death did not differ greatly by treatment era, absolute rates of hospitalization were greater (1987-1999: 233.3/1,000; 2000-2012: 320.0/1,000 person years) and death were lesser (1987-1999: 46.3/1,000; 2000-2012: 36.8/1,000 person years) in the later treatment era among cases. Children with solid tumors were less likely to have a cancer-related hospitalization than were those with leukemia/lymphoma (RR 0.91, 95% CI 0.84-0.98).

CONCLUSION: Even after excluding cancer-related diagnoses, children with cancer experience greater rates of hospitalization and death in all disease categories. Results may guide future toxicity mitigation initiatives and inform anticipatory guidance for families of children with cancer.

RevDate: 2021-04-09

Talbert PB, S Henikoff (2021)

Remodeller-variant tag team slams transposons.

Nature cell biology, 23(4):297-298.

RevDate: 2021-04-11

Unger JM, H Xiao (2021)

The COVID-19 pandemic and new clinical trial activations.

Trials, 22(1):260.

BACKGROUND: The COVID-19 pandemic has caused severe disruptions in care for many patients. A key question is whether the landscape of clinical research has also changed.

METHODS: In a retrospective cohort study, we examined the association of the COVID-19 outbreak with new clinical trial activations. Trial data for all interventional and observational oncology, cardiovascular, and mental health studies from January 2015 through September 2020 were obtained from ClinicalTrials.gov . An interrupted time-series analysis with Poisson regression was used.

RESULTS: We examined 62,252 trial activations. During the initial COVID-19 outbreak (February 2020 through May 2020), model-estimated monthly trial activations for US-based studies were only 57% of the expected estimate had the pandemic not occurred (relative risk = 0.57, 95% CI 0.52 to 0.61, p < .001). For non-US-based studies, the impact of the pandemic was less dramatic (relative risk = 0.77, 95% CI 0.73 to 0.82, p < .001), resulting in an overall 27% reduction in the relative risk of new trial activations for US-based trials compared to non-US-based trials (relative risk ratio = 0.73, 95% CI 0.67 to 0.81, p < .001). Although a rebound occurred in the initial reopening phase (June 2020 through September 2020), the rebound was weaker for US-based studies compared to non-US-based studies (relative risk ratio = 0.87, 95% CI 0.80 to 0.95, p < .001).

CONCLUSIONS: These findings are consistent with the disproportionate burden of COVID-19 diagnoses and deaths during the initial phase of the pandemic in the USA. Reduced activation of cancer clinical trials will likely slow the pace of clinical research and new drug discovery, with long-term negative consequences for cancer patients. An important question is whether the renewed outbreak period of winter 2020/2021 will have a similarly negative impact on the initiation of new clinical research studies for non-COVID-19 diseases.

RevDate: 2021-04-08

Sekabira R, Mcgowan I, Yuhas K, et al (2021)

Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis.

AIDS (London, England) pii:00002030-900000000-96434 [Epub ahead of print].

OBJECTIVE: The objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.

DESIGN: A substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.

METHODS: Plasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.

RESULTS: Thirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P < 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P < 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P < 0.05).

CONCLUSION: Colorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.

RevDate: 2021-04-16

Eguia RT, Crawford KHD, Stevens-Ayers T, et al (2021)

A human coronavirus evolves antigenically to escape antibody immunity.

PLoS pathogens, 17(4):e1009453.

There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these "future" viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8-17 years later. The decreased neutralization of "future" viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

RevDate: 2021-04-08

Osarogiagbon RU, Sineshaw HM, Unger JM, et al (2021)

Immune-Based Cancer Treatment: Addressing Disparities in Access and Outcomes.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 41:1-13.

Avoidable differences in the care and outcomes of patients with cancer (i.e., cancer care disparities) emerge or worsen with discoveries of new, more effective approaches to cancer diagnosis and treatment. The rapidly expanding use of immunotherapy for many different cancers across the spectrum from late to early stages has, predictably, been followed by emerging evidence of disparities in access to these highly effective but expensive treatments. The danger that these new treatments will further widen preexisting cancer care and outcome disparities requires urgent corrective intervention. Using a multilevel etiologic framework that categorizes the targets of intervention at the individual, provider, health care system, and social policy levels, we discuss options for a comprehensive approach to prevent and, where necessary, eliminate disparities in access to the clinical trials that are defining the optimal use of immunotherapy for cancer, as well as its safe use in routine care among appropriately diverse populations. We make the case that, contrary to the traditional focus on the individual level in descriptive reports of health care disparities, there is sequentially greater leverage at the provider, health care system, and social policy levels to overcome the challenge of cancer care and outcomes disparities, including access to immunotherapy. We also cite examples of effective government-sponsored and policy-level interventions, such as the National Cancer Institute Minority-Underserved Community Oncology Research Program and the Affordable Care Act, that have expanded clinical trial access and access to high-quality cancer care in general.

RevDate: 2021-04-08

Moon J, LeBlanc M, M Othus (2021)

Accounting for All Patients in Waterfall Plots.

JCO clinical cancer informatics, 5:414-420.

RevDate: 2021-04-11

Ueda Oshima M, Storer BE, Qiu H, et al (2021)

Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis.

Transplantation and cellular therapy, 27(2):163.e1-163.e7.

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from HLA-identical related donors using cyclosporine (CSP) and mycophenolate mofetil (MMF) for postgrafting immunosuppression is effective therapy for hematologic cancers. However, graft-versus-host-disease (GVHD) remains a major cause of morbidity and mortality. Pilot data suggested lower acute GVHD incidence with tacrolimus/MMF compared to historical experience using CSP/MMF after nonmyeloablative HCT. In a phase II multicenter trial, we evaluated the effect of tacrolimus/MMF for GVHD prophylaxis after HLA-identical related donor peripheral blood HCT in patients with hematologic malignancies (n = 150) using conditioning with 2 Gy total body irradiation (TBI) for patients with a preceding (within 6 months) planned autologous HCT (n = 50) or combined with 90 mg/m2 fludarabine for those without recent autologous HCT (n = 100). Oral tacrolimus was given from days -3 to 56 (tapered by day +180 if no GVHD). Oral MMF was given from days 0 to 27. Patient median age was 57 (range, 20 to 74) years. The cumulative incidences (CI) of day 100 grade II to IV and III to IV acute GVHD were 27% and 4%, respectively. With median follow-up of 10.3 (range, 3.1 to 14.5) years, the 5-year CI of chronic extensive GVHD was 48%. One-year and 5-year estimates of nonrelapse mortality, relapse/progression, survival, and progression-free survival were 9% and 13%, 35% and 50%, 73% and 53%, and 56% and 37%, respectively. GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute GVHD and compared favorably with results from a concurrent trial using CSP/MMF. A randomized phase III trial to investigate tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT is warranted.

RevDate: 2021-04-09

Carpenter PA, Papanicolaou G, Chemaly RF, et al (2021)

American Society for Transplantation and Cellular Therapy Infectious Disease Guidelines: Preface to the Series.

Transplantation and cellular therapy, 27(2):103-104.

RevDate: 2021-04-08

Greenberg JA, Jiang X, Tinker LF, et al (2021)

Eggs, dietary cholesterol, choline, betaine, and diabetes risk in the Women's Health Initiative: a prospective analysis.

The American journal of clinical nutrition pii:6214584 [Epub ahead of print].

BACKGROUND: Epidemiological studies have been inconsistent regarding the relations between diabetes risk and the consumption of eggs and nutrients in eggs, such as choline, betaine, and cholesterol. There have been few studies among elderly women.

OBJECTIVES: The objective of this study was to examine associations between consumption of eggs, cholesterol, choline, and betaine and the risk of diabetes among elderly US women.

METHODS: Multivariable Cox regression was used with data from the prospective Women's Health Initiative. Population attributable risks were calculated. Consumption of eggs alone (not mixed in foods) and nutrients were assessed with an FFQ. Diabetes incidence was defined as the first incidence of self-reported diabetes treated with oral diabetes medication or insulin injections.

RESULTS: There were 46,263 women at follow-up baseline. During 13.3 y and 592,984 person-years of follow-up, there were 5480 incident diabetes cases. Higher egg, cholesterol, and choline consumption were each significantly associated with increases in diabetes risk. The associations for eggs and choline were not significant after adjustment for cholesterol consumption. The association for eggs was attenuated after adjustment for non-egg cholesterol consumption, with 1 significant HR in the top consumption quintile (≥3 eggs/wk) of 1.15 (95% CI: 1.05, 1.27; P for linear trend = 0.0001). The population attributable risks for obesity, overweight, consumption of ≥3 eggs/wk, inadequate exercise, and poor diet were 25.0 (95% CI: 22.3, 27.6), 12.8 (95% CI: 11.1, 14.5), 4.2 (95% CI: 2.3, 6.1), 3.5 (95% CI: 1.2, 5.8), and 3.1 (95% CI: 0.5, 5.7), respectively.

CONCLUSIONS: As egg consumption increased to ≥3 eggs/wk, there was a steady increase in diabetes risk that may have been due to the cholesterol in the eggs. The population attributable risk for ≥3 eggs/wk was far lower than that for being obese or overweight.

RevDate: 2021-04-08

Knight B, Anderson L, Lerner D, et al (2021)

Case Series: Development of Polyps as a Late Effect After Total Body Irradiation-based Hematopoietic Cell Transplantation in Children With High-risk Leukemia.

Journal of pediatric hematology/oncology pii:00043426-900000000-96928 [Epub ahead of print].

Advancements in hematopoietic cell transplantation (HCT) have led to increased survivorship rates in many childhood diseases. However, this growing group of long-term survivors face a myriad of late effects. There are currently limited guidelines for surveillance of gastrointestinal polyps for pediatric transplant patients. Here we describe 5 patients undergoing HCT with total body irradiation-based conditioning regimens for leukemia who developed symptomatic polyps a median of 4.5 (range: 0.75 to 5.75) years after HCT. Because of limited surveillance guidelines in children, we conclude that the development of new or progressive symptoms related to the gastrointestinal tract deserves prompt recognition and evaluation.

RevDate: 2021-04-08

Jin Q, Hart PA, Shi N, et al (2021)

Dietary Patterns of Insulinemia, Inflammation and Glycemia and Pancreatic Cancer Risk: Findings from the Women's Health Initiative.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1478 [Epub ahead of print].

BACKGROUND: Pancreatic cancer risk is increasing in countries with high consumption of Western dietary patterns and rising obesity rates. We examined the hypothesis that specific dietary patterns reflecting hyperinsulinemia (empirical dietary index for hyperinsulinemia-EDIH), systemic inflammation (empirical dietary inflammatory pattern-EDIP), and postprandial glycemia (glycemic index-GI, glycemic load-GL) are associated with pancreatic cancer risk, including the potential modifying role of type 2 diabetes (T2D) and body mass index (BMI).

METHODS: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 129,241 women, 50-79 years-old in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for pancreatic cancer risk.

RESULTS: During a median 19.9 years of follow-up, 850 pancreatic cancer cases were diagnosed. We observed no association between dietary scores and pancreatic cancer risk overall. However, risk was elevated among participants with longstanding T2D (present >3 years before pancreatic cancer diagnosis) for EDIH. For each 1 standard deviation increment in dietary score, the HRs (95%CIs) were: EDIH, 1.33(1.06-1.66); EDIP, 1.26(0.98-1.63); GI, 1.26(0.96-1.67); and GL, 1.23(0.96-1.57); though interactions were not significant (all Pinteraction >0.05). Separately, we observed inverse associations between GI, 0.86(0.76-0.96), Pinteraction=0.0068; and GL, 0.83 (0.73-0.93), Pinteraction=0.0075, with pancreatic cancer risk among normal-weight women.

CONCLUSION: We observed no overall association between the dietary patterns evaluated and pancreatic cancer risk, although women with T2D appeared to have greater cancer risk.

IMPACT: The elevated risk for hyperinsulinemic diets among women with longstanding T2D and the inverse association among normal-weight women warrant further examination.

RevDate: 2021-04-08

Addetia A, Phung Q, Bradley BT, et al (2021)

In vivo generation of BK and JC polyomavirus defective viral genomes in human urine samples associated with higher viral loads.

Journal of virology pii:JVI.00250-21 [Epub ahead of print].

Defective viral genomes (DVGs) are parasitic viral sequences containing point mutations, deletions, or duplications that might interfere with replication. DVGs are often associated with viral passage at high multiplicities of infection in culture systems but have been increasingly reported in clinical specimens. To date however, only RNA viruses have been shown to contain DVGs in clinical specimens. Here, using direct deep sequencing with multiple library preparation strategies and confirmatory ddPCR of urine samples taken from immunosuppressed individuals, we show clinical BKPyV and JCPyV strains contain widespread genomic rearrangements across multiple loci that likely interfere with viral replication. BKPyV DVGs were derived from BKPyV genotypes Ia, Ib-1, and Ic. The presence of DVGs was associated with specimens containing higher viral loads but never reached clonality, consistent with a model of parasitized replication. These DVGs persisted during clinical infection as evidenced in two separate pairs of samples containing BK virus collected from the same individual up to 302 days apart. In a separate individual, we observed the generation of DVGs after a 57.5-fold increase in viral load. In summary, by extending the presence of DVGs in clinical specimens to DNA viruses, we demonstrate the ubiquity of DVGs in clinical virology.IMPORTANCEDefective viral genomes (DVGs) can have a significant impact on the production of infectious virus particles. DVGs have only been identified in cultured viruses passaged at high multiplicities of infection and RNA viruses collected from clinical specimens - no DNA virus in the wild has been shown to contain DVGs. Here, we identified BK and JC polyomavirus DVGs in clinical urine specimens and demonstrated that these DVGs are more frequently identified in samples with higher viral loads. The strains containing DVGs had rearrangements throughout their genomes with the majority affecting genes required for viral replication. Longitudinal analysis showed these DVGs can persist during an infection, but do not reach clonality within the chronically infected host. Our identification of polyomavirus DVGs suggests these parasitic sequences exist across the many classes of viruses capable of causing human disease.

RevDate: 2021-04-07

Shen BW, Quispe JD, Luyten Y, et al (2021)

Coordination of phage genome degradation versus host genome protection by a bifunctional restriction-modification enzyme visualized by CryoEM.

Structure (London, England : 1993) pii:S0969-2126(21)00085-X [Epub ahead of print].

Restriction enzymes that combine methylation and cleavage into a single assemblage and modify one DNA strand are capable of efficient adaptation toward novel targets. However, they must reliably cleave invasive DNA and methylate newly replicated unmodified host sites. One possible solution is to enforce a competition between slow methylation at a single unmodified host target, versus faster cleavage that requires multiple unmodified target sites in foreign DNA to be brought together in a reaction synapse. To examine this model, we have determined the catalytic behavior of a bifunctional type IIL restriction-modification enzyme and determined its structure, via cryoelectron microscopy, at several different stages of assembly and coordination with bound DNA targets. The structures demonstrate a mechanism in which an initial dimer is formed between two DNA-bound enzyme molecules, positioning the endonuclease domain from each enzyme against the other's DNA and requiring further additional DNA-bound enzyme molecules to enable cleavage.

RevDate: 2021-04-07

Fiorenza S, CJ Turtle (2021)

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success.

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy [Epub ahead of print].

Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.

RevDate: 2021-04-07

Nørskov KH, Yi JC, Crouch ML, et al (2021)

Correction to: Social support as a moderator of healthcare adherence and distress in long-term hematopoietic cell transplantation survivors.

RevDate: 2021-04-07

Laberge RM, Sun Y, Orjalo AV, et al (2021)

Author Correction: MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.

RevDate: 2021-04-14
CmpDate: 2021-04-14

Khan OM, Almagro J, Nelson JK, et al (2021)

Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12.

Nature communications, 12(1):2043.

The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.

RevDate: 2021-04-12

Bond V, Hoddinott G, Viljoen L, et al (2021)

How 'place' matters for addressing the HIV epidemic: evidence from the HPTN 071 (PopART) cluster-randomised controlled trial in Zambia and South Africa.

Trials, 22(1):251.

BACKGROUND: In a cluster-randomised trial (CRT) of combination HIV prevention (HPTN 071 (PopART)) in 12 Zambian communities and nine South African communities, carried out from 2012 to 2018, the intervention arm A that offered HIV treatment irrespective of CD4 count did not have a significant impact on population level HIV incidence. Intervention arm B, where HIV incidence was reduced by 30%, followed national guidelines that mid trial (2016) changed from starting HIV treatment according to a CD4 threshold of 500 to universal treatment. Using social science data on the 21 communities, we consider how place (community context) might have influenced the primary outcome result.

METHODS: A social science component documented longitudinally the context of trial communities. Data were collected through rapid qualitative assessment, interviews, group discussions and observations. There were a total of 1547 participants and 1127 observations. Using these data, literature and a series of qualitative analysis steps, we identified key community characteristics of relevance to HIV and triangulated these with HIV community level incidence.

RESULTS: Two interdependent social factors were relevant to communities' capability to manage HIV: stability/instability and responsiveness/resistance. Key components of stability were social cohesion; limited social change; a vibrant local economy; better health, education and recreational services; strong institutional presence; established middle-class residents; predictable mobility; and less poverty and crime. Key components of responsiveness were community leadership being open to change, stronger history of HIV initiatives, willingness to take up HIV services, less HIV-related stigma and a supported and enterprising youth population. There was a clear pattern of social factors across arms. Intervention arm A communities were notably more resistant and unstable. Intervention arm B communities were overall more responsive and stable.

CONCLUSIONS: In the specific case of the dissonant primary outcome results from the HPTN 071 (PopART) trial, the chance allocation of less stable, less responsive communities to arm A compared to arm B may explain some of the apparently smaller impact of the intervention in arm A. Stability and responsiveness appear to be two key social factors that may be relevant to secular trends in HIV incidence. We advocate for a systematic approach, using these factors as a framework, to community context in CRTs and monitoring HIV prevention efforts.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01900977 . Registered on July 17, 2013.

RevDate: 2021-04-07

McDermott CL, Curtis JR, Sun Q, et al (2021)

Polypharmacy, chemotherapy receipt, and medication-related out-of-pocket costs at end of life among commercially insured adults with advanced cancer.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

BACKGROUND: Polypharmacy raises the risk of drug-drug interactions and adverse events among patients with cancer. Most polypharmacy research has focused on adults age 65 or older enrolled in Medicare insurance. To better inform pharmacy practice and cancer care delivery, data are needed on polypharmacy among commercially insured patients with cancer and those younger than 65.

METHODS: We performed a retrospective analysis of insurance enrollment and claims files linked to the Puget Sound Cancer Surveillance System for adults age 18 and older who were commercially insured, diagnosed with stage IV cancer, survived 30+ days after diagnosis, and did not enroll in hospice. We describe the prevalence of polypharmacy, chemotherapy use, and medication-related out-of-pocket (OOP) costs in the last month of life.

RESULTS: Of 606 patients, 390 (64%) experienced polypharmacy (i.e. 5+ medications) in the last 30 days of life. Almost half (n = 297, 49%) received chemotherapy or targeted agents; chemotherapy was associated with significantly higher odds of polypharmacy (odds ratio (OR) 2.93, 95% confidence interval (CI) 2.04-4.20). The most commonly prescribed medications at end of life were opioids, benzodiazepines and anti-emetics. Among 484 patients (80%) incurring medication-related costs in the last month of life, median total OOP cost was $82 (interquartile range $30-$200). Seven patients (1%) had total costs above $5,000. The median chemotherapy-related OOP cost was $446 (IQR $150-$1896); 32 patients (7%) had chemotherapy-related OOP costs between $1,000 and $5,000.

CONCLUSION: Most patients with advanced cancer experienced polypharmacy at end of life, although most medications observed herein are commonly used for supportive care. Patients receiving chemotherapy had higher medication-related OOP costs, and chemotherapy was significantly associated with polypharmacy at end of life. Evaluation of polypharmacy at end of life may represent an important opportunity to improve quality of life and reduce costs for patients and families.

RevDate: 2021-04-06

de Kleuver M, Faraj SSA, Haanstra TM, et al (2021)

The Scoliosis Research Society adult spinal deformity standard outcome set.

Spine deformity [Epub ahead of print].

PURPOSE: Symptomatic adult spinal deformity (ASD) with an extremely variable presentation with pain, with and without neurogenic leg pain, and/or disturbed sagittal and coronal balance, causes a significant societal burden of disease. It is an important consequence of the aging adult population, generating a plethora of spine-related interventions with variable treatment efficacy and consistently high costs. Recent years have witnessed more than a threefold increase in the prevalence and treatment of ASD, and further increases over the coming decades are expected with the growing elderly population worldwide. The ability to monitor and assess clinical outcomes has not kept pace with these developments. This paper addresses the pressing need to provide a set of common outcome metrics for this growing group of patients with back pain and other disabilities due to an adult spinal deformity.

METHODS: The standard outcome set was created by a panel with global representation, using a thorough modified Delphi procedure. The three-tiered outcome hierarchy (Porter) was used as a framework to capture full cycle of care. The standardized language of the International Classification of Functioning, Disability and Health (WHO-ICF) was used.

RESULTS: Consensus was reached on a core set of 25 WHO-ICF outcome domains ('What to measure'); on the accompanying globally available clinician and patient reported measurement instruments and definitions ('How to measure'), and on the timing of the measurements ('When to measure'). The current work has brought to light domains not routinely reported in the spinal literature (such as pulmonary function, return to work, social participation), and domains for which no adequate instruments have yet been identified (such as how to clinically quantify in routine practice lumbar spinal stenosis, neurogenic claudication, radicular pain, and loss of lower extremity motor function).

CONCLUSION: A standard outcome set was developed for patients undergoing treatment for adult spinal deformity using globally available outcome metrics. The current framework can be considered a reference for further work, and may provide a starting point for routine methodical and systematic monitoring of outcomes. Post-COVID e-health may accelerate the routine capture of these types of data.

RevDate: 2021-04-06

Forrat R, Dayan GH, DiazGranados CA, et al (2021)

Analysis of hospitalized and severe dengue cases over the six-years of follow-up of the tetravalent dengue vaccine (CYD-TDV) efficacy trials in Asia and Latin America.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6210060 [Epub ahead of print].

BACKGROUND: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post-hoc analysis assessed hospitalized and severe virologically-confirmed dengue (VCD) over the complete 6-year follow-up of three CYD-TDV efficacy studies (CYD14, CYD15 and CYD23/CYD57).

METHODS: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to five years after the last injection.

RESULTS: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over six years compared to placebo (HR [95% confidence interval] Multiple Imputation from Month 0 method, 0.19 [0.12-0.30] and 0.15 [0.06-0.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups.

CONCLUSIONS: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire six-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year olds.

RevDate: 2021-04-09

Meyerhardt JA, Shi Q, Fuchs CS, et al (2021)

Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial.

JAMA, 325(13):1277-1286.

Importance: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.

Objective: To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.

Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.

Interventions: Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization.

Main Outcomes and Measures: The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.

Results: Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.

Conclusions and Relevance: Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.

RevDate: 2021-04-13

Raspin K, FitzGerald LM, Marthick JR, et al (2021)

A rare variant in EZH2 is associated with prostate cancer risk.

International journal of cancer [Epub ahead of print].

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10-5). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.

RevDate: 2021-04-15

Trim A, Hankinson SE, Liu S, et al (2021)

Biomarkers of phthalates and inflammation: Findings from a subgroup of Women's Health Initiative participants.

International journal of hygiene and environmental health, 234:113743 pii:S1438-4639(21)00058-4 [Epub ahead of print].

BACKGROUND: Recent experimental work has shown that phthalates may increase inflammation. Prior research has not examined the role of exposure to phthalates in relation to inflammatory status among postmenopausal women who are at higher risk of developing inflammation-related chronic disorders.

OBJECTIVES: We aimed to examine the associations of urinary phthalate biomarker concentrations with circulating levels of c-reactive protein [CRP] and interleukin-6 [IL-6] among 443 postmenopausal women selected into a breast cancer case-control study nested within the Women's Health Initiative (WHI).

METHODS: A total of 13 phthalate metabolites were measured in urine samples provided at WHI enrollment from 1993 to 1998. We also measured baseline levels of CRP and IL-6 in these women's serum or plasma samples. Multivariable linear models were used to investigate the role of each phthalate biomarker in relation to CRP and IL-6, adjusting for potential confounding factors and specifically evaluating the role of BMI.

RESULTS: In adjusted models we observed positive associations of monocarboxynonyl phthalate (MCNP) with CRP (β = 0.092; 95% CI 0.026, 0.158) and IL-6 (β = 0.108; 95% CI 0.013, 0.204). These positive associations were attenuated and non-significant, however, after further adjustment for body mass index (BMI). In contrast, we observed inverse associations of monoethyl phthalate (MEP) (β = -0.019; 95% CI -0.036, -0.001) and monobenzyl phthalate (MBzP) (β = -0.034; 95% CI -0.058, -0.010) with CRP levels only after adjustment for BMI. Other phthalate biomarkers examined were not significantly associated with either CRP or IL-6 levels.

CONCLUSIONS: Overall, these results do not suggest an important role for phthalates in promoting an inflammatory response. Future prospective studies are warranted to improve understanding of these associations, particularly in clarifying the role of BMI.

RevDate: 2021-04-16

Keibler MA, Dong W, Korthauer KD, et al (2021)

Differential Substrate Use in EGF- and Oncogenic KRAS-Stimulated Human Mammary Epithelial Cells.

The FEBS journal [Epub ahead of print].

Many metabolic phenotypes in cancer cells are also characteristic of proliferating non-transformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate, and provide a model to distinguish the metabolic influences of oncogenic mutations and non-oncogenic growth.

RevDate: 2021-04-13

Schmitt FCF, Schneider M, Mathejczyk W, et al (2021)

Postoperative Complications Are Associated with Long-Term Changes in the Gut Microbiota Following Colorectal Cancer Surgery.

Life (Basel, Switzerland), 11(3):.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups-patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

RevDate: 2021-04-13

McCann SE, Hullar MAJ, Tritchler DL, et al (2021)

Enterolignan Production in a Flaxseed Intervention Study in Postmenopausal US Women of African Ancestry and European Ancestry.

Nutrients, 13(3):.

Lignans are phytochemicals studied extensively as dietary factors in chronic disease etiology. Our goal was to examine associations between the gut microbiota and lignan metabolism and whether these associations differ by ethnicity. We conducted a flaxseed (FS) dietary intervention in 252 healthy, postmenopausal women of African ancestry (AA) and European ancestry (EA). Participants consumed ~10 g/d ground flaxseed for 6 weeks and provided overnight urine collections and fecal samples before and after intervention. The gut microbiota was characterized using 16S rRNA gene sequencing and differences in microbial community composition compared by ethnicity and intervention status. We observed a significant difference in the composition of the microbiota measured as beta diversity (p < 0.05) between AA and EA at baseline that was attenuated with FS consumption. Genera that were significantly associated with ENL production (e.g., Klebsiella, Lactobacillus, Slackia, Senegalimassilia) were unique to each group. Bacteria (e.g., Fusobacteria, Pyramidobacter and Odoribacter) previously associated with colorectal cancer and cardiovascular disease, both diet-related chronic diseases, were unique to either AA or EA and were significantly reduced in the FS intervention. This study suggests that ethnic variation in ENL metabolism may be linked to gut microbiota composition, and its impact on disease risk deserves future investigation.

RevDate: 2021-04-08

Haselbeck AH, Tadesse BT, Park J, et al (2021)

Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) Using a Cluster-Randomized Controlled Phase IV Trial: Trial Design and Population Baseline Characteristics.

Vaccines, 9(3):.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392).

RevDate: 2021-04-13

Yang S, Jerome KR, Greninger AL, et al (2021)

Endogenously Produced SARS-CoV-2 Specific IgG Antibodies May Have a Limited Impact on Clearing Nasal Shedding of Virus during Primary Infection in Humans.

Viruses, 13(3):.

While SARS-CoV-2 specific neutralizing antibodies have been developed for therapeutic purposes, the specific viral triggers that drive the generation of SARS-CoV-2 specific IgG and IgM antibodies remain only partially characterized. Moreover, it is unknown whether endogenously derived antibodies drive viral clearance that might result in mitigation of clinical severity during natural infection. We developed a series of non-linear mathematical models to investigate whether SARS-CoV-2 viral and antibody kinetics are coupled or governed by separate processes. Patients with severe disease had a higher production rate of IgG but not IgM antibodies. Maximal levels of both isotypes were governed by their production rate rather than different saturation levels between people. Our results suggest that an exponential surge in IgG levels occurs approximately 5-10 days after symptom onset with no requirement for continual antigenic stimulation. SARS-CoV-2 specific IgG antibodies appear to have limited to no effect on viral dynamics but may enhance viral clearance late during primary infection resulting from the binding effect of antibody to virus, rather than neutralization. In conclusion, SARS-CoV-2 specific IgG antibodies may play only a limited role in clearing infection from the nasal passages despite providing long-term immunity against infection following vaccination or prior infection.

RevDate: 2021-04-13

Francica JR, Shi W, Chuang GY, et al (2021)

Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria.

Vaccines, 9(3):.

The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the Plasmodium falciparum circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope-CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.

RevDate: 2021-04-13

Finch CL, Dyall J, Xu S, et al (2021)

Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo.

Microorganisms, 9(3):.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

RevDate: 2021-04-08

Textor A, Grunewald L, Anders K, et al (2021)

CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus.

Cancers, 13(5):.

Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors.

RevDate: 2021-04-02

Roth JA, Trivedi MS, Gray SW, et al (2021)

Patient Knowledge and Expectations About Return of Genomic Results in a Biomarker-Driven Master Protocol Trial (SWOG S1400GEN).

JCO oncology practice [Epub ahead of print].

PURPOSE: Biomarker-driven master protocols represent a new paradigm in oncology clinical trials, but their complex designs and wide-ranging genomic results returned can be difficult to communicate to participants. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung Cancer Master Protocol (Lung-MAP).

METHODS: Eligible participants with previously treated advanced non-small-cell lung cancer were recruited from patients enrolled in Lung-MAP. Participants completed a 38-item telephone survey ≤ 30 days from Lung-MAP consent. The survey assessed understanding about the benefits and risks of Lung-MAP participation and knowledge of the potential uses of somatic testing results returned. Descriptive statistics and odds ratios for associations between demographic factors and correct responses to survey items were assessed.

RESULTS: From August 1, 2017, to June 30, 2019, we recruited 207 participants with a median age of 67, 57.3% male, and 94.2% White. Most participants "strongly/somewhat agreed" with statements that they "received enough information to understand" Lung-MAP benefits (82.6%) and risks (69.5%). In items asking about potential uses of Lung-MAP genomic results, 87.0% correctly indicated that the results help to select cancer treatment, but < 20% correctly indicated that the results are not used to confirm cancer diagnosis, would not reveal risk of developing diseases besides cancer, and would not indicate if family members had increased cancer risk. There were no associations between sociodemographic factors and proportions providing correct responses.

CONCLUSION: In a large National Clinical Trials Network biomarker-driven master protocol, most participants demonstrated incorrect knowledge and expectations about the uses of genomic results provided in the study despite most indicating that they had enough information to understand benefits and risks.

RevDate: 2021-04-15

Ni Y, Szpiro AA, Young MT, et al (2021)

Associations of Pre- and Postnatal Air Pollution Exposures with Child Blood Pressure and Modification by Maternal Nutrition: A Prospective Study in the CANDLE Cohort.

Environmental health perspectives, 129(4):47004.

BACKGROUND: Limited data suggest air pollution exposures may contribute to pediatric high blood pressure (HBP), a known predictor of adult cardiovascular diseases.

METHODS: We investigated this association in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study, a sociodemographically diverse pregnancy cohort in the southern United States with participants enrolled from 2006 to 2011. We included 822 mother-child dyads with available address histories and a valid child blood pressure measurement at 4-6 y. Systolic (SBP) and diastolic blood pressures (DBP) were converted to age-, sex-, and height-specific percentiles for normal-weight U.S. children. HBP was classified based on SBP or DBP ≥ 90 th percentile. Nitrogen dioxide (NO 2) and particulate matter ≤ 2.5 μ m in aerodynamic diameter (PM 2.5) estimates in both pre- and postnatal windows were obtained from annual national models and spatiotemporal models, respectively. We fit multivariate Linear and Poisson regressions and explored multiplicative joint effects with maternal nutrition, child sex, and maternal race using interaction terms.

RESULTS: Mean PM 2.5 and NO 2 in the prenatal period were 10.8 [standard deviation (SD): 0.9] μ g / m 3 and 10.0 (SD: 2.4) ppb, respectively, and 9.9 (SD: 0.6) μ g / m 3 and 8.8 (SD: 1.9) ppb from birth to the 4-y-old birthday. On average, SBP percentile increased by 14.6 (95% CI: 4.6, 24.6), and DBP percentile increased by 8.7 (95% CI: 1.4, 15.9) with each 2 - μ g / m 3 increase in second-trimester PM 2.5 . PM 2.5 averaged over the prenatal period was only significantly associated with higher DBP percentiles [β = 11.6 (95% CI: 2.9, 20.2)]. Positive associations of second-trimester PM 2.5 with SBP and DBP percentiles were stronger in children with maternal folate concentrations in the lowest quartile (p interaction = 0.05 and 0.07, respectively) and associations with DBP percentiles were stronger in female children (p interaction = 0.05). We did not detect significant association of NO 2 , road proximity, and postnatal PM 2.5 with any outcomes.

CONCLUSIONS: The findings suggest that higher prenatal PM 2.5 exposure, particularly in the second trimester, is associated with elevated early childhood blood pressure. This adverse association could be modified by pregnancy folate concentrations. https://doi.org/10.1289/EHP7486.

RevDate: 2021-04-02

Chalasani P, Farr K, Wu V, et al (2021)

Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer.

Breast cancer research and treatment [Epub ahead of print].

BACKGROUND: Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician's choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile.

METHODS: We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy.

FINDINGS: We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients.

INTERPRETATION: Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

RevDate: 2021-04-04

Xu Y, Zhang L, Liu Y, et al (2021)

Dopamine receptor DOP-1 engages a sleep pathway to modulate swimming in C. elegans.

iScience, 24(4):102247.

Animals require robust yet flexible programs to support locomotion. Here we report a pathway that connects the D1-like dopamine receptor DOP-1 with a sleep mechanism to modulate swimming in C. elegans. We show that DOP-1 plays a negative role in sustaining swimming behavior. By contrast, a pathway through the D2-like dopamine receptor DOP-3 negatively regulates the initiation of swimming, but its impact fades quickly over a few minutes. We find that DOP-1 and the GPCR kinase (G-protein-coupled receptor kinase-2) function in the sleep interneuron RIS, where DOP-1 modulates the secretion of a sleep neuropeptide FLP-11. We further show that DOP-1 and FLP-11 act in the same pathway to modulate swimming. Together, these results delineate a functional connection between a dopamine receptor and a sleep program to regulate swimming in C. elegans. The temporal transition between DOP-3 and DOP-1 pathways highlights the dynamic nature of neuromodulation for rhythmic movements that persist over time.

RevDate: 2021-04-08

Saegusa T, Ma T, Li G, et al (2020)

Variable Selection in Threshold Regression Model with Applications to HIV Drug Adherence Data.

Statistics in biosciences, 12(3):376-398.

The threshold regression model is an effective alternative to the Cox proportional hazards regression model when the proportional hazards assumption is not met. This paper considers variable selection for threshold regression. This model has separate regression functions for the initial health status and the speed of degradation in health. This flexibility is an important advantage when considering relevant risk factors for a complex time-to-event model where one needs to decide which variables should be included in the regression function for the initial health status, in the function for the speed of degradation in health, or in both functions. In this paper, we extend the broken adaptive ridge (BAR) method, originally designed for variable selection for one regression function, to simultaneous variable selection for both regression functions needed in the threshold regression model. We establish variable selection consistency of the proposed method and asymptotic normality of the estimator of non-zero regression coefficients. Simulation results show that our method outperformed threshold regression without variable selection and variable selection based on the Akaike information criterion. We apply the proposed method to data from an HIV drug adherence study in which electronic monitoring of drug intake is used to identify risk factors for non- adherence.

RevDate: 2021-04-02

Isacchini G, Walczak AM, Mora T, et al (2021)

Deep generative selection models of T and B cell receptor repertoires with soNNia.

Proceedings of the National Academy of Sciences of the United States of America, 118(14):.

Subclasses of lymphocytes carry different functional roles to work together and produce an immune response and lasting immunity. Additionally to these functional roles, T and B cell lymphocytes rely on the diversity of their receptor chains to recognize different pathogens. The lymphocyte subclasses emerge from common ancestors generated with the same diversity of receptors during selection processes. Here, we leverage biophysical models of receptor generation with machine learning models of selection to identify specific sequence features characteristic of functional lymphocyte repertoires and subrepertoires. Specifically, using only repertoire-level sequence information, we classify CD4+ and CD8+ T cells, find correlations between receptor chains arising during selection, and identify T cell subsets that are targets of pathogenic epitopes. We also show examples of when simple linear classifiers do as well as more complex machine learning methods.

RevDate: 2021-04-12
CmpDate: 2021-04-12

Divine R, Dang HV, Ueda G, et al (2021)

Designed proteins assemble antibodies into modular nanocages.

Science (New York, N.Y.), 372(6537):.

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.

RevDate: 2021-04-01

Li E, Mezzio DJ, Campbell D, et al (2021)

Primary Prophylaxis With Biosimilar Filgrastim for Patients at Intermediate Risk for Febrile Neutropenia: A Cost-Effectiveness Analysis.

JCO oncology practice [Epub ahead of print].

PURPOSE: Temporary COVID-19 guideline recommendations have recently been issued to expand the use of colony-stimulating factors in patients with cancer with intermediate to high risk for febrile neutropenia (FN). We evaluated the cost-effectiveness of primary prophylaxis (PP) with biosimilar filgrastim-sndz in patients with intermediate risk of FN compared with secondary prophylaxis (SP) over three different cancer types.

METHODS: A Markov decision analytic model was constructed from the US payer perspective over a lifetime horizon to evaluate PP versus SP in patients with breast cancer, non-small-cell lung cancer (NSCLC), and non-Hodgkin lymphoma (NHL). Cost-effectiveness was evaluated over a range of willingness-to-pay thresholds for incremental cost per FN avoided, life year gained, and quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty.

RESULTS: Compared with SP, PP provided an additional 0.102-0.144 LYs and 0.065-0.130 QALYs. The incremental cost-effectiveness ranged from $5,660 in US dollars (USD) to $20,806 USD per FN event avoided, $5,123 to $31,077 USD per life year gained, and $7,213 to $35,563 USD per QALY gained. Over 1,000 iterations, there were 73.6%, 99.4%, and 91.8% probabilities that PP was cost-effective at a willingness to pay of $50,000 USD per QALY gained for breast cancer, NSCLC, and NHL, respectively.

CONCLUSION: PP with a biosimilar filgrastim (specifically filgrastim-sndz) is cost-effective in patients with intermediate risk for FN receiving curative chemotherapy regimens for breast cancer, NSCLC, and NHL. Expanding the use of colony-stimulating factors for patients may be valuable in reducing unnecessary health care visits for patients with cancer at risk of complications because of COVID-19 and should be considered for the indefinite future.

RevDate: 2021-04-16

Smith JW, O'Meally RN, Ng DK, et al (2021)

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics.

Chemical research in toxicology [Epub ahead of print].

Outdoor air pollution, a spatially and temporally complex mixture, is a human carcinogen. However, ambient measurements may not reflect subject-level exposures, personal monitors do not assess internal dose, and spot assessments of urinary biomarkers may not recapitulate chronic exposures. Nucleophilic sites in serum albumin-particularly the free thiol at Cys34-form adducts with electrophiles. Due to the 4-week lifetime of albumin in circulation, accumulating adducts can serve as intermediate- to long-residence biomarkers of chronic exposure and implicate potential biological effects. Employing nanoflow liquid chromatography-high-resolution mass spectrometry (nLC-HRMS) and parallel reaction monitoring (PRM), we have developed and validated a novel targeted albumin adductomics platform capable of simultaneously monitoring dozens of Cys34 adducts per sample in only 2.5 μL of serum, with on-column limits of detection in the low-femtomolar range. Using this platform, we characterized the magnitude and impact of ambient outdoor air pollution exposures with three repeated measurements over 84 days in n = 26 nonsmoking women (n = 78 total samples) from Qidong, China, an area with a rising burden of lung cancer incidence. In concordance with seasonally rising ambient concentrations of NO2, SO2, and PM10 measured at stationary monitors, we observed elevations in concentrations of Cys34 adducts of benzoquinone (p < 0.05), benzene diol epoxide (BDE; p < 0.05), crotonaldehyde (p < 0.01), and oxidation (p < 0.001). Regression analysis revealed significant elevations in oxidation and BDE adduct concentrations of 300% to nearly 700% per doubling of ambient airborne pollutant levels (p < 0.05). Notably, the ratio of irreversibly oxidized to reduced Cys34 rose more than 3-fold during the 84-day period, revealing a dramatic perturbation of serum redox balance and potentially serving as a portent of increased pollution-related mortality risk. Our targeted albumin adductomics assay represents a novel and flexible approach for sensitive and multiplexed internal dosimetry of environmental exposures, providing a new strategy for personalized biomonitoring and prevention.

RevDate: 2021-04-13

Ledet EM, Burgess EF, Sokolova AO, et al (2021)

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

The Prostate, 81(7):433-439.

BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.

METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.

RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.

CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

RevDate: 2021-04-01

Fleury ME, JM Unger (2021)

Patient Willingness to Enroll in Cancer Clinical Trials When Sites Return to Prepandemic Status-Reply.

JAMA oncology pii:2777902 [Epub ahead of print].

RevDate: 2021-04-15

Ogimi C, Xie H, Waghmare A, et al (2021)

Risk factors for seasonal human coronavirus lower respiratory tract infection after hematopoietic cell transplantation.

Blood advances, 5(7):1903-1914.

Data are limited regarding risk factors for lower respiratory tract infection (LRTI) caused by seasonal human coronaviruses (HCoVs) and the significance of virologic documentation by bronchoalveolar lavage (BAL) on outcomes in hematopoietic cell transplant (HCT) recipients. We retrospectively analyzed patients undergoing allogeneic HCT (4/2008-9/2018) with HCoV (OC43/NL63/HKU1/229E) detected by polymerase chain reaction during conditioning or post-HCT. Risk factors for all manifestations of LRTI and progression to LRTI among those presenting with HCoV upper respiratory tract infection (URTI) were analyzed by logistic regression and Cox proportional hazard models, respectively. Mortality rates following HCoV LRTI were compared according to virologic documentation by BAL. A total of 297 patients (61 children and 236 adults) developed HCoV infection as follows: 254 had URTI alone, 18 presented with LRTI, and 25 progressed from URTI to LRTI (median, 16 days; range, 2-62 days). Multivariable logistic regression analyses showed that male sex, higher immunodeficiency scoring index, albumin <3 g/dL, glucose >150 mg/dL, and presence of respiratory copathogens were associated with occurrence of LRTI. Hyperglycemia with steroid use was associated with progression to LRTI (P < .01) in Cox models. LRTI with HCoV detected in BAL was associated with higher mortality than LRTI without documented detection in BAL (P < .01). In conclusion, we identified factors associated with HCoV LRTI, some of which are less commonly appreciated to be risk factors for LRTI with other respiratory viruses in HCT recipients. The association of hyperglycemia with LRTI might provide an intervention opportunity to reduce the risk of LRTI.

RevDate: 2021-04-02

Labrecque MP, Alumkal JJ, Coleman IM, et al (2021)

The heterogeneity of prostate cancers lacking AR activity will require diverse treatment approaches.

Endocrine-related cancer pii:ERC-21-0002.R1 [Epub ahead of print].

The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.

RevDate: 2021-04-02
CmpDate: 2021-04-02

Nagana Gowda GA, D Raftery (2021)

NMR-Based Metabolomics.

Advances in experimental medicine and biology, 1280:19-37.

Nuclear magnetic resonance (NMR) spectroscopy is a major analytical method used in the growing field of metabolomics. Although NMR is relatively less sensitive than mass spectrometry, this analytical platform has numerous characteristics including its high reproducibility and quantitative abilities, its nonselective and noninvasive nature, and the ability to identify unknown metabolites in complex mixtures and trace the downstream products of isotope labeled substrates ex vivo, in vivo, or in vitro. Metabolomic analysis of highly complex biological mixtures has benefitted from the advances in both NMR data acquisition and analysis methods. Although metabolomics applications span a wide range of disciplines, a majority has focused on understanding, preventing, diagnosing, and managing human diseases. This chapter describes NMR-based methods relevant to the rapidly expanding metabolomics field.

RevDate: 2021-04-14
CmpDate: 2021-04-14

Mbala-Kingebeni P, Pratt C, Mutafali-Ruffin M, et al (2021)

Ebola Virus Transmission Initiated by Relapse of Systemic Ebola Virus Disease.

The New England journal of medicine, 384(13):1240-1247.

During the 2018-2020 Ebola virus disease (EVD) outbreak in North Kivu province in the Democratic Republic of Congo, EVD was diagnosed in a patient who had received the recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) (Merck). His treatment included an Ebola virus (EBOV)-specific monoclonal antibody (mAb114), and he recovered within 14 days. However, 6 months later, he presented again with severe EVD-like illness and EBOV viremia, and he died. We initiated epidemiologic and genomic investigations that showed that the patient had had a relapse of acute EVD that led to a transmission chain resulting in 91 cases across six health zones over 4 months. (Funded by the Bill and Melinda Gates Foundation and others.).

RevDate: 2021-04-09

Balkus JE, Neradilek M, Fairlie L, et al (2021)

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review.

PloS one, 16(3):e0248423.

A systematic chart review was performed to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at facilities in Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare, Zimbabwe to provide comparisons with estimates from an ongoing clinical trial evaluating the safety of two biomedical HIV prevention interventions in pregnancy. A multi-site, cross-sectional chart review was conducted at Maternal Obstetric Units and hospitals where women participating in the ongoing clinical trial would be expected to deliver. All individuals delivering at the designated facilities or admitted for postpartum care within seven days of a delivery elsewhere (home, health clinic, etc.) were included in the review. Data were abstracted for pregnancy outcomes, pregnancy complications, maternal and neonatal death, and congenital anomalies. Data from 10,138 records were abstracted across all four sites (Blantyre n = 2,384; Johannesburg n = 1,888; Kampala n = 3,708; Chitungwiza and Harare n = 2,158), which included 10,426 pregnancy outcomes. The prevalence of preterm birth was 13% (range across sites: 10.4-20.7) and 4.1% of deliveries resulted in stillbirth (range: 3.1-5.5). The most commonly noted pregnancy complication was gestational hypertension, reported among 4.4% of pregnancies. Among pregnancies resulting in a live birth, 15.5% were low birthweight (range: 13.8-17.4) and 2.0% resulted in neonatal death (range:1.2-3.2). Suspected congenital anomalies were noted in 1.2% of pregnancies. This study provides systematically collected data on background rates of pregnancy outcomes, pregnancy complications and neonatal outcomes that can be used as a reference in support of ongoing HIV prevention studies. In addition, estimates from this study provide important background data for future studies of investigational products evaluated in pregnancy in these urban settings.

RevDate: 2021-03-31

Bricker JB, Mull KE, Sullivan BM, et al (2021)

Efficacy of telehealth acceptance and commitment therapy for weight loss: a pilot randomized clinical trial.

Translational behavioral medicine pii:6206292 [Epub ahead of print].

Telehealth coaching for weight loss has high population-level reach but limited efficacy. To potentially improve on this limitation, the purpose of this study was to determine the preliminary efficacy of the first known telephone coaching acceptance and commitment therapy (ACT) intervention for weight loss. A two-arm, stratified, individually randomized pilot trial comparing ACT (n = 53) with standard behavioral therapy (SBT; n = 52) was used for this study. Both interventions were delivered in 25 telephone coaching calls (15-20 min each) over a 12 month period. Weight was measured at baseline and 3, 6, and 12 month postrandomization follow-ups. Recruited from 32 U.S. states, participants were of mean age 40.7, 42% male, 34% racial/ethnic minority, and mean baseline body mass index of 34.3. Fractions of 10% or more scale-reported weight loss: 15% for ACT versus 4% for SBT at 3 month follow-up (N = 86; odds ratio [OR] = 4.61; 95% confidence interval [CI]: 0.79, 26.83), 24% for ACT versus 13% for SBT at 6 month follow-up (N = 72; OR = 2.45; 95% CI: 0.65, 9.23), 30% for ACT versus 30% for SBT at 12 month follow-up (N = 57; OR = 0.93; 95% CI: 0.28, 3.09). Fractions of 10% or more self-reported weight loss at 12 month follow-up: 25% for ACT versus 15% for SBT (N = 75; OR = 2.38; 95% CI: 0.68, 8.34). The conclusion of the study was the preliminary evidence that telephone coaching ACT may be efficacious for weight loss.


RJR Experience and Expertise


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.


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.


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.


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.


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.


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.


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.


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.

Research Gate page for R J Robbins

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Curriculum Vitae for R J Robbins

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