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30 Mar 2020 at 01:38
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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 30 Mar 2020 at 01:38 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: 2020-03-28

Tabachnick-Cherny S, Pulliam T, Church C, et al (2020)

Polyomavirus-driven Merkel cell carcinoma: Prospects for therapeutic vaccine development.

Molecular carcinogenesis [Epub ahead of print].

Great strides have been made in cancer immunotherapy including the breakthrough successes of anti-PD-(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD-(L)1 blockade is highly effective. Yet, ~50% of patients either do not respond to therapy or develop PD-(L)1 refractory disease and, thus, do not experience long-term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor-associated antigens, mutated self-antigens, or immunogenic viral oncoproteins are currently being developed to augment T-cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T-antigen (T-Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T-Ag elicits specific B- and T-cell immune responses in most persons with virus-positive MCC (VP-MCC), and ongoing T-Ag expression is required to drive VP-MCC cell proliferation, therapeutic vaccination with T-Ag is a rational potential component of immunotherapy. Failure of the endogenous T-cell response to clear VP-MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T-cell activity against tumor cells. Here, we review the relevant underlying biology of VP-MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP-MCC patients could potentially benefit from a therapeutic vaccine.

RevDate: 2020-03-28

Michelson AP, McDonough S, Willman CL, et al (2020)

Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia.

Scientific reports, 10(1):5486 pii:10.1038/s41598-020-62345-9.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P < 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.

RevDate: 2020-03-27

Disis MLN (2020)

JAMA Oncology-The Year in Review, 2019.

JAMA oncology pii:2763305 [Epub ahead of print].

RevDate: 2020-03-27

Jones SMW, Shulman LJ, Richards JE, et al (2020)

Mechanisms for the testing effect on patient-reported outcomes.

Contemporary clinical trials communications, 18:100554 pii:100554.

The testing effect is when patient-reported outcomes (PRO) improve with repeated administration without intervention. The testing effect can confound interpretation of clinical trials using PROs as endpoints. This study investigated potential mechanisms. The parent study (n = 302) investigated a self-management intervention for depression. We qualitatively analyzed exit interview feedback from the 89 control group participants completing the last assessment. Participants reported several perceived benefits from control group participation including novel mechanisms (study participation was meaningful, emotional support, appreciating outreach), a possible negative testing effect and mechanisms previously identified (behavioral change).

RevDate: 2020-03-26

Chlebowski RT, Aragaki AK, Anderson GL, et al (2020)

Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women.

Cancer [Epub ahead of print].

After reports from the Women's Health Initiative randomized trial evaluating estrogen plus progestin, there was a sudden, substantial, and sustained decrease in all categories of menopausal hormone therapy, and the first reduction in age-adjusted breast cancer incidence in more than 20 years was seen in 2003-2004 among US women 50 years of age or older. Subsequent trends in breast cancer incidence have been described, but most reports have not focused on the postmenopausal age group or fully engaged the potential influence of reduced hormone therapy on breast cancer incidence trends by race/ethnicity. To address this gap, this commentary examines trends for annual age-adjusted breast cancer incidence over a 40-year period from 1975 to 2015 for white and black women on the basis of findings from the Surveillance, Epidemiology, and End Results 9 registries. Overall, the sharp decline in breast cancer incidence seen in 2003-2004 was followed in the subsequent decade by a continued low breast cancer incidence plateau in white women that has largely persisted. In contrast, a new discordance between breast cancer incidence trends in black and white women has emerged. In the 2005-2015 decade, a sustained increase in breast cancer incidence in black women has resulted in annual incidence rates comparable, for the first time, to those in white women. This commentary explores the hypothesis that the over-decade-long and discordant changes in breast cancer incidence rates in postmenopausal black and white women are, to a large extent, associated with changes in hormone therapy use in these 2 groups.

RevDate: 2020-03-26

Ueda M, Stefan T, Stetson L, et al (2020)

Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia.

Frontiers in oncology, 10:327.

Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42-82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1-3) prior therapies. Oral lithium carbonate 300 mg was given 2-3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1-7 and 15-21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60-502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38- AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.

RevDate: 2020-03-26

Kaluza J, Harris HR, Håkansson N, et al (2020)

Adherence to the WCRF/AICR 2018 recommendations for cancer prevention and risk of cancer: prospective cohort studies of men and women.

British journal of cancer pii:10.1038/s41416-020-0806-x [Epub ahead of print].

BACKGROUND: In 2018, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) issued revised recommendations for cancer prevention. We examined the relation between adherence to these recommendations and risk of total cancer in two population-based Swedish prospective cohorts (29,451 men and 25,349 women).

METHODS: Standardized-WCRF/AICR 2018 and simplified-WCRF/AICR 2018 adherence scores were constructed based on the WCRF/AICR recommendations for body weight, physical activity, diet, alcohol consumption and dietary supplement use. Data were collected using a self-administered questionnaire.

RESULTS: During the 15.4 years of follow-up, 12,693 incident cancers were ascertained. The multivariable HR between extreme categories of the Standardized-WCRF/AICR 2018 score (4.1-7 vs. 0-2) was 0.88 (95% CI = 0.82-0.95) and for the Simplified score (5-8 vs. 0-2) was 0.85 (95% CI = 0.80-0.90); each 1-score increment in recommendation adherence was associated with 3% (95% CI = 1-5%) and 4% (95% CI = 2-5%) decreased risk, respectively. Based on the Simplified scoring, most participants (>90%) did not meet WCRF/AICR 2018 recommendations regarding consumption of plant foods, limited consumption of red/processed meat and 'fast food'/processed food, and <50% of participants met the weight and physical activity recommendations.

CONCLUSIONS: Adherence to the 2018WCRF/AICR recommendations substantially reduced the risk of total cancer. Given that many people do not meet the recommendations, there is a great potential for cancer prevention.

RevDate: 2020-03-25

Bellissimo DC, Chen CH, Zhu Q, et al (2020)

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling.

Blood advances, 4(6):1145-1158.

RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.

RevDate: 2020-03-25

Shore ND, Morrow MP, McMullan T, et al (2020)

CD8+ T Cells Impact Rising PSA in Biochemically Relapsed Cancer Patients Using Immunotherapy Targeting Tumor-Associated Antigens.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(20)30134-9 [Epub ahead of print].

The management of men with prostate cancer (PCa) with biochemical recurrence following local definitive therapy remains controversial. Early use of androgen deprivation therapy (ADT) leads to significant side effects. Developing an alternative, clinically effective, and well-tolerated therapy remains an unmet clinical need. INO-5150 is a synthetic DNA therapy that includes plasmids encoding for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA), and INO-9012 is a synthetic DNA plasmid encoding for interleukin-12 (IL-12). This phase 1/2, open-label, multi-center study enrolled men with PCa with rising PSA after surgery and/or radiation therapy. Patients were enrolled into one of four treatment arms: arm A, 2 mg of INO-5150; arm B, 8.5 mg of INO-5150; arm C, 2 mg of INO-5150 + 1 mg of INO-9012; and arm D, 8.5 mg of INO-5150 + 1 mg of INO-9012. Patients received study drug with electroporation on day 0 and on weeks 3, 12, and 24, and they were followed for up to 72 weeks. Sixty-two patients were enrolled. Treatment was well tolerated. 81% (50/62) of patients completed all visits. 85% (53/62) remained progression-free at 72 weeks. PSA doubling time (PSADT) was increased when assessed in patients with day 0 PSADT ≤12 months. Immunogenicity was observed in 76% (47/62) of patients by multiple assessments. Analysis indicated that CD38 and perforin co-positive CD8 T cell frequency correlated with attenuated PSA rise (p = 0.05, n = 50).

RevDate: 2020-03-24

Comstock CE, Gatsonis C, Newstead GM, et al (2020)

Comparison of Abbreviated Breast MRI vs Digital Breast Tomosynthesis for Breast Cancer Detection Among Women With Dense Breasts Undergoing Screening.

JAMA, 323(8):746-756.

Importance: Improved screening methods for women with dense breasts are needed because of their increased risk of breast cancer and of failed early diagnosis by screening mammography.

Objective: To compare the screening performance of abbreviated breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT) in women with dense breasts.

Cross-sectional study with longitudinal follow-up at 48 academic, community hospital, and private practice sites in the United States and Germany, conducted between December 2016 and November 2017 among average-risk women aged 40 to 75 years with heterogeneously dense or extremely dense breasts undergoing routine screening. Follow-up ascertainment of cancer diagnoses was complete through September 12, 2019.

Exposures: All women underwent screening by both DBT and abbreviated breast MRI, performed in randomized order and read independently to avoid interpretation bias.

Main Outcomes and Measures: The primary end point was the invasive cancer detection rate. Secondary outcomes included sensitivity, specificity, additional imaging recommendation rate, and positive predictive value (PPV) of biopsy, using invasive cancer and ductal carcinoma in situ (DCIS) to define a positive reference standard. All outcomes are reported at the participant level. Pathology of core or surgical biopsy was the reference standard for cancer detection rate and PPV; interval cancers reported until the next annual screen were included in the reference standard for sensitivity and specificity.

Results: Among 1516 enrolled women, 1444 (median age, 54 [range, 40-75] years) completed both examinations and were included in the analysis. The reference standard was positive for invasive cancer with or without DCIS in 17 women and for DCIS alone in another 6. No interval cancers were observed during follow-up. Abbreviated breast MRI detected all 17 women with invasive cancer and 5 of 6 women with DCIS. Digital breast tomosynthesis detected 7 of 17 women with invasive cancer and 2 of 6 women with DCIS. The invasive cancer detection rate was 11.8 (95% CI, 7.4-18.8) per 1000 women for abbreviated breast MRI vs 4.8 (95% CI, 2.4-10.0) per 1000 women for DBT, a difference of 7 (95% CI, 2.2-11.6) per 1000 women (exact McNemar P = .002). For detection of invasive cancer and DCIS, sensitivity was 95.7% (95% CI, 79.0%-99.2%) with abbreviated breast MRI vs 39.1% (95% CI, 22.2%-59.2%) with DBT (P = .001) and specificity was 86.7% (95% CI, 84.8%-88.4%) vs 97.4% (95% CI, 96.5%-98.1%), respectively (P < .001). The additional imaging recommendation rate was 7.5% (95% CI, 6.2%-9.0%) with abbreviated breast MRI vs 10.1% (95% CI, 8.7%-11.8%) with DBT (P = .02) and the PPV was 19.6% (95% CI, 13.2%-28.2%) vs 31.0% (95% CI, 17.0%-49.7%), respectively (P = .15).

Conclusions and Relevance: Among women with dense breasts undergoing screening, abbreviated breast MRI, compared with DBT, was associated with a significantly higher rate of invasive breast cancer detection. Further research is needed to better understand the relationship between screening methods and clinical outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT02933489.

RevDate: 2020-03-24

Hall ET, Fernandez-Lopez E, Silk AW, et al (2020)

Immunologic Characteristics of Nonmelanoma Skin Cancers: Implications for Immunotherapy.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 40:1-10.

In this review, we summarize the immunology of nonmelanoma skin cancers (NMSCs) and the clinical data with immunotherapy in this heterogeneous group of cancers that include basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), and Merkel cell carcinoma (MCC). NMSCs are exceedingly common, and their treatment consumes substantial health care resources. Annual global mortality from NMSCs is comparable to that from malignant melanoma. Although the majority of NMSCs are localized at diagnosis and are treated effectively with surgery, metastases (nodal and distant) can sometimes arise and require systemic therapy. Given the success of immunotherapy in treating cutaneous melanoma, there has been an increasing interest in studying the immunology of NMSCs. Immunocompromised patients have a substantially higher risk of developing NMSCs (particularly CSCC and MCC), suggesting a role of the immune system in the pathogenesis of these cancers. Similar to cutaneous melanoma, the pathogenesis of BCC, CSCC, and virus-negative MCC is related to DNA damage from ultraviolet radiation exposure, and these cancers have a very high tumor mutational burden, which likely results in higher levels of tumor neoantigens that may be targets for the immune system. Viral antigens in virus-positive MCC are also strongly immunogenic. Emerging data from clinical trials of immune checkpoint inhibitors in NMSCs look very promising and are rapidly changing the treatment landscape of these cancers. Specifically, pembrolizumab and avelumab are U.S. Food and Drug Administration-approved for treatment of metastatic MCC and cemiplimab for metastatic CSCC. Several ongoing trials are investigating novel immunotherapies (monotherapies as well as combination) for treatment of NMSCs.

RevDate: 2020-03-24

Xia Z, Su YR, Petersen P, et al (2020)

Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.

Cancer medicine [Epub ahead of print].

BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.

METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.

RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5), PSMC5 (P = 4.51 × 10-4) and CD33 (P = 2.71 × 10-4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5) and SCN1B (P = 2.76 × 10-4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5).

CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

RevDate: 2020-03-24

Sheng IY, Diaz-Montero CM, Rayman P, et al (2020)

Blood Myeloid-Derived Suppressor Cells Correlate with Neutrophil-to-Lymphocyte Ratio and Overall Survival in Metastatic Urothelial Carcinoma.

Targeted oncology pii:10.1007/s11523-020-00707-z [Epub ahead of print].

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC.

OBJECTIVE: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC.

PATIENTS AND METHODS: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death.

RESULTS: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS.

CONCLUSIONS: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

RevDate: 2020-03-24

Lee EJ, Hanchate NK, Kondoh K, et al (2020)

A psychological stressor conveyed by appetite-linked neurons.

Science advances, 6(12):eaay5366 pii:aay5366.

Mammals exhibit instinctive reactions to danger critical to survival, including surges in blood stress hormones. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) control stress hormones but how diverse stressors converge on CRHNs is poorly understood. We used sRNA profiling to define CRHN receptors for neurotransmitters and neuromodulators and then viral tracing to localize subsets of upstream neurons expressing cognate receptor ligands. Unexpectedly, one subset comprised POMC (proopiomelanocortin)-expressing neurons in the arcuate nucleus, which are linked to appetite suppression. The POMC neurons were activated by one psychological stressor, physical restraint, but not another, a predator odor. Chemogenetic activation of POMC neurons induced a stress hormone response, mimicking a stressor. Moreover, their silencing markedly reduced the stress hormone response to physical restraint, but not predator odor. These findings indicate that POMC neurons involved in appetite suppression also play a major role in the stress hormone response to a specific type of psychological stressor.

RevDate: 2020-03-24

Kang JH, VoPham T, Laden F, et al (2020)

Cohort Study of Non-melanoma Skin Cancer and the Risk of Exfoliation Glaucoma.

Journal of glaucoma [Epub ahead of print].

PRECIS: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of non-melanoma skin cancer was associated with a 40% higher exfoliation glaucoma risk.

PURPOSE: To evaluate the relationship between non-melanoma skin cancer (a marker of ultraviolet radiation exposure) and exfoliation glaucoma (XFG).

METHODS: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye exams. From 1984 (women)/1988 (men), we asked about basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) history separately; in prior years, we asked about any non-melanoma skin cancer history in a single question. SCC was confirmed with histopathology reports while BCC and any early (<1984/<1988) non-melanoma skin cancer history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks (MVRR; 95% confidence intervals [CIs]) with Cox proportional hazards models that were stratified by age (in months), 2-year time period at risk and average lifetime residential latitude.

RESULTS: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any non-melanoma skin cancer history (MVRR=1.40; 95% CI=1.08,1.82); the association was observed even with 4 and 8 year lags in non-melanoma skin cancer history. Also, the non-melanoma skin cancer association was stronger in younger (<65▒y; MVRR=2.56; 95% CI=1.62,4.05) versus older participants (≥65▒y; MVRR=1.25; 95% CI=0.94,1.66; p for interaction=0.01) and those living in northern latitudes (≥42° north; MVRR=1.92; 95% CI=1.28,2.88) versus more southern latitudes (<42° north; MVRR=1.19; 95% CI=0.86,1.66; p for interaction=0.04).

CONCLUSIONS: Non-melanoma skin cancer was associated with higher XFG risk, particularly among younger participants and those living in Northern US.

RevDate: 2020-03-24

Buckee CO, Balsari S, Chan J, et al (2020)

Aggregated mobility data could help fight COVID-19.

RevDate: 2020-03-24

Wei AH, Roberts AW, Spencer A, et al (2020)

Targeting MCL-1 in hematologic malignancies: Rationale and progress.

Blood reviews pii:S0268-960X(20)30022-9 [Epub ahead of print].

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.

RevDate: 2020-03-24

Dayan GH, Langevin E, Gilbert PB, et al (2020)

Assessment of the long-term efficacy of a dengue vaccine against symptomatic, virologically-confirmed dengue disease by baseline dengue serostatus.

Vaccine pii:S0264-410X(20)30384-4 [Epub ahead of print].

CYD-TDV is a live, attenuated, tetravalent dengue vaccine licensed in 21 countries. We undertook a post-hoc analysis of the long-term efficacy of CYD-TDV during the surveillance expansion phase (SEP) of two Phase III studies (CYD14 in the Asia-Pacific region; CYD15 in Latin America). The SEP included approximately Year 5 and the entire Year 6 of follow-up after the first study injection. Vaccine efficacy against symptomatic virologically-confirmed dengue (VCD) was assessed by participant age (any age, ≥9, <9, 2-5, and 6-8 years at the time of the first injection) and baseline dengue serostatus using a case-cohort framework. Baseline dengue serostatus was estimated by several methods including logistic regression-based multiple imputation (MI) to predict PRNT50 with key predictor being Month 13 (M13) anti-non-structural protein (NS1) titers; superlearner-based imputation by targeted minimum loss based estimation (TMLE); and M13 anti-NS1 titer threshold 9 EU/mL (NS1 M13). There were 436 symptomatic VCD cases (CYD14: n = 360; CYD15: n = 76) during the SEP. Vaccine efficacy in seropositive participants aged ≥9 years was assessed by MI (47.9% [95% CI 19.4; 66.3]), TMLE (53.0% [95% CI 23; 71]), and NS1 M13 (52.4% [95% CI 30.8; 67.3]). Vaccine efficacy estimates were lower in seropositive individuals aged <9 years compared with individuals ≥9 years. Among seropositive individuals aged 2-5 and 6-8 years, vaccine efficacy across the different approaches for assessing serostatus ranged from between -25.7 to 36.9% and 44.4 to 64.7% during the SEP, respectively. In the pooled CYD14/15 data of seronegatives, vaccine efficacy was null to modest. In conclusion, CYD-TDV was shown to maintain efficacy against symptomatic VCD in seropositive participants aged ≥9 years up to six years after the first dose. Persistence of efficacy was also observed in seropositive participants aged 6-8 years.

RevDate: 2020-03-23

Navarro-Costa PA, Molaro A, Misra CS, et al (2020)

Sex and suicide: The curious case of Toll-like receptors.

PLoS biology, 18(3):e3000663 pii:PBIOLOGY-D-20-00025 [Epub ahead of print].

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as 'suicidal' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.

RevDate: 2020-03-23

Correnti CE, Hallinan JP, Doyle LA, et al (2020)

Engineering and functionalization of large circular tandem repeat protein nanoparticles.

Nature structural & molecular biology pii:10.1038/s41594-020-0397-5 [Epub ahead of print].

Protein engineering has enabled the design of molecular scaffolds that display a wide variety of sizes, shapes, symmetries and subunit compositions. Symmetric protein-based nanoparticles that display multiple protein domains can exhibit enhanced functional properties due to increased avidity and improved solution behavior and stability. Here we describe the creation and characterization of a computationally designed circular tandem repeat protein (cTRP) composed of 24 identical repeated motifs, which can display a variety of functional protein domains (cargo) at defined positions around its periphery. We demonstrate that cTRP nanoparticles can self-assemble from smaller individual subunits, can be produced from prokaryotic and human expression platforms, can employ a variety of cargo attachment strategies and can be used for applications (such as T-cell culture and expansion) requiring high-avidity molecular interactions on the cell surface.

RevDate: 2020-03-23

Izzo F, Lee SC, Poran A, et al (2020)

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nature genetics pii:10.1038/s41588-020-0595-4 [Epub ahead of print].

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1-3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.

RevDate: 2020-03-23

Einsele H, Ljungman PT, MJ Boeckh (2020)

How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.

Blood pii:452747 [Epub ahead of print].

CMV reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation (allo-HCT) in spite of novel diagnostic technologies, several novel prophylactic agents and further improvement in preemptive therapy and treatment for established CMV disease. Today treatment decisions for CMV reactivation are becoming increasingly difficult and have to consider whether the patient has received antiviral prophylaxis, the patient`s individual risk profile for CMV disease, CMV-specific T cell reconstitution as well as both the CMV viral load and the potential drug-resistance detected at the time of initiation of antiviral therapy. Thus, we increasingly use personalized treatment strategies for the recipient of an allograft with CMV reactivation based on prior use of anti-CMV prophylaxis, viral load, the assessment of CMV-specific T cell immunity, and the molecular assessment of resistance to antiviral drugs.

RevDate: 2020-03-23

Martin PJ (2020)

How I treat steroid-refractory acute graft-versus-host disease.

Blood pii:452748 [Epub ahead of print].

Steroid-resistant or refractory acute GVHD (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field been driven by the premise that persistent GVHD results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others. Truth be told, we do not know how to treat SR-aGVHD. Preclinical work during the past decade has provided fresh insights into the pathogenesis of acute GVHD, and translation of these insights toward development of more effective treatments for patients with SR-aGVHD has at last begun. Given the limited state of current knowledge, this "How I Treat" review highlights the overriding imperative to avoid harm in caring for patients with SR-aGVHD. Prospective trials that are widely available are urgently needed to advance the field.

RevDate: 2020-03-23

Looker KJ, Johnston C, Welton NJ, et al (2020)

The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study.

BMJ global health, 5(3):e001875 pii:bmjgh-2019-001875.

Introduction: Herpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15-49 years old.

Methods: We developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made.

Results: We estimated that 187 million people aged 15-49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world's population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120-296 million). However, the estimates were sensitive to the model assumptions.

Conclusion: Our study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.

RevDate: 2020-03-22

Muhsen IN, Bar M, Savani BN, et al (2020)

Follow-up issues in survivors of hematologic malignancies - Current stance and future perspectives.

Blood reviews pii:S0268-960X(20)30024-2 [Epub ahead of print].

Cancer care advances have led to increased numbers of cancer survivors and to improved understanding of late effects of cancers and their therapies and survivorship issues. Long-term follow-up of cancer patients is crucial in preventing and managing many of the late effects of cancers and their therapies. However, the literature has highlighted the high rates of loss to follow-up (loss to FU) after cancer treatment, particularly in patients with hematologic malignancies. In this review, we performed a systematic search of published literature on issues pertaining to loss to FU in survivors of hematologic malignancies, highlighting the predictors of increased or decreased rates of loss to FU. We found that the literature on survivors of adulthood cancers is very limited, in contrast to articles discussing young adult survivors of childhood cancers. Predictors and barriers of loss to FU were found to be variable in different studies; however, they shared some common themes, including disease-related, logistic, financial and educational factors. Furthermore, we discuss the potential interventions to mitigate the loss to FU, along with discussing research priorities in this area.

RevDate: 2020-03-21

Mato AR, Roeker LE, Jacobs R, et al (2020)

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK inhibition as an Effective Strategy.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-3815 [Epub ahead of print].

PURPOSE: Venetoclax-based therapy is a standard of care option in front-line and relapsed/refractory CLL. Patient management following venetoclax discontinuation remains non-standard and poorly understood.

EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Co-primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post-venetoclax treatments stratified by treatment type (BTKi, PI3Ki, and cellular therapies).

RESULTS: We identified CLL patients who discontinued venetoclax in the front-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n=130), and 81% were idelalisib naïve (n=263). ORR to BTKi was 84% (n=44) in BTKi-naïve patients vs. 54% (n=30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

CONCLUSIONS: For BTKi naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.

RevDate: 2020-03-21

Necchi A, Gallina A, Dyrskjøt L, et al (2020)

Converging Roads to Early Bladder Cancer.

RevDate: 2020-03-21

Chow EJ, Ness KK, Armstrong GT, et al (2020)

Current and coming challenges in the management of the survivorship population.

Seminars in oncology pii:S0093-7754(20)30007-5 [Epub ahead of print].

With the widespread adoption of multimodality treatment, 5-year survival of children diagnosed with cancer has improved dramatically in the past several decades from approximately 60% in 1970 to greater than 85% currently. As a result, there are an estimated nearly half a million long-term survivors of childhood cancer living in the United States today. However, survivors have, on average, significantly greater serious medical and psychosocial late effects compared with the general population. In this review, we will discuss the current epidemiology of childhood cancer survivorship, including new methods to estimate the burden of late effects and genetic susceptibility toward late effects. We will also review the development of surveillance guidelines for childhood cancer survivors and early toxicity signals from novel agents now being tested and used increasingly to treat pediatric and adult cancers. We conclude with an overview of current models of survivorship care and areas for future research.

RevDate: 2020-03-20

Ueda M, Martins R, Hendrie PC, et al (2020)

Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.

Journal of the National Comprehensive Cancer Network : JNCCN pii:jnccn1804COVID [Epub ahead of print].

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

RevDate: 2020-03-20

Qu X, Yeung C, Coleman I, et al (2020)

Comparison of four next generation sequencing platforms for fusion detection: Oncomine by ThermoFisher, AmpliSeq by illumina, FusionPlex by ArcherDX, and QIAseq by QIAGEN.

Cancer genetics, 243:11-18 pii:S2210-7762(20)30147-2 [Epub ahead of print].

As fusion detection NGS techniques are adopted by clinical labs, assay performance comparison is urgently needed. We compared four fusion-detection assay platforms on a pilot cohort of 24 prostate cancer samples: (1) Oncomine Comprehensive panel v3; (2) AmpliSeq comprehensive panel v3; (3) The solid tumor panel of FusionPlex; and (4) The human oncology panel of QIAseq. The assays were compared for the detection of different types of fusion based on whether the partner gene or the breakpoints are known. All assays detected fusion with known gene partners and known breakpoint, represented by TMPRSS2-ERG. A fusion with known partners but unknown breakpoint, TMPRSS2-ETV4, was reported by OCAv3 and FusionPlex, but not by AICv3 because the specific breakpoint was not in the manifest, nor by QIAseq since the panel did not target the exact exons involved. For fusion with unknown partners, FusionPlex identified the largest number of ETV1 fusions because it had the highest exon coverage for ETV1. Among these, SNRPN-ETV1 and MALAT1-ETV1, were novel findings. To determine reportability of low-level calls of highly prevalent fusions, such as TMPRSS2-ERG, we propose the use of percent fusion reads over total number of reads per sample instead of the fusion read count.

RevDate: 2020-03-20

Blain M, Walter K, Sibulesky L, et al (2019)

New skin lesions in a liver transplant recipient.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 19(10):2955-2957.

RevDate: 2020-03-20

Stevens EA, Jenkins IC, Beppu LW, et al (2020)

Targeted Sequencing Improves DIPSS-Plus Prognostic Scoring in Myelofibrosis Patients Undergoing Allogeneic Transplant.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30144-0 [Epub ahead of print].

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the only therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematological and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 MF patients to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with three or more mutations in addition to JAK2 or CALR mutations had a higher post-transplant relapse rate and non-relapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the highest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for non-transplanted patients and support the proposed transplant risk classification incorporating mutational information.

RevDate: 2020-03-20

Haanen J, Ernstoff MS, Wang Y, et al (2020)

Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(20)36364-X [Epub ahead of print].

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids (CS) and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressant drugs (nSIs) could be replaced by specific selective immunosuppressant drugs (SI) following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

RevDate: 2020-03-19

Rybak MJ, Le J, Lodise TP, et al (2020)

Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists pii:5810200 [Epub ahead of print].

RevDate: 2020-03-19

Antar AAR, Jenike KM, Jang S, et al (2020)

Longitudinal study reveals HIV-1-infected CD4+ T cell dynamics during long-term antiretroviral therapy.

The Journal of clinical investigation pii:135953 [Epub ahead of print].

Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal proliferation or HIV-1-specific CTL pressure shape the provirus landscape, we performed the intact proviral DNA assay (IPDA) and obtained 661 near-full length provirus sequences from eight individuals with suppressed viral loads on ART at time points seven years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later timepoints or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a similar distribution of defective provirus types and escaped or unrecognized epitopes as the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.

RevDate: 2020-03-19

Liu Z, Yoshimi A, Wang J, et al (2020)

Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization.

Cancer discovery pii:2159-8290.CD-19-1330 [Epub ahead of print].

Although mutations in the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the PP2A phosphatase subunit PPP2R5A, increasing c-MYC S62 and BCL2 S70 phosphorylation which, in turn, promote MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.

RevDate: 2020-03-19

Poramba-Liyanage DW, Korthout T, Cucinotta CE, et al (2020)

Inhibition of transcription leads to rewiring of locus-specific chromatin proteomes.

Genome research pii:gr.256255.119 [Epub ahead of print].

Transcription of a chromatin template involves the concerted interaction of many different proteins and protein complexes. Analyses of specific factors showed that these interactions change during stress and upon developmental switches. However, how the binding of multiple factors at any given locus is coordinated has been technically challenging to investigate. Here we employed Epi-Decoder in yeast to systematically decode, at one transcribed locus, the chromatin binding changes of hundreds of proteins in parallel upon perturbation of transcription. Taking advantage of improved Epi-Decoder libraries, we observed broad rewiring of local chromatin proteomes following chemical inhibition of RNA polymerase. Rapid reduction of RNA polymerase II binding was accompanied by reduced binding of many other core transcription proteins and gain of chromatin remodelers. In quiescent cells, where strong transcriptional repression is induced by physiological signals, eviction of the core transcriptional machinery was accompanied by the appearance of quiescent-cell specific repressors and rewiring of the interactions of protein-folding factors and metabolic enzymes. These results show that Epi-Decoder provides a powerful strategy for capturing the temporal binding dynamics of multiple chromatin proteins under varying conditions and cell states. The systematic and comprehensive delineation of dynamic local chromatin proteomes will greatly aid in uncovering protein-protein relationships and protein functions at the chromatin template.

RevDate: 2020-03-19

Neumeyer S, Butterbach K, Banbury BL, et al (2020)

Genetic predictors of circulating 25-hydroxyvitamin D and prognosis after colorectal cancer.

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-19-1409 [Epub ahead of print].

BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) concentrations in colorectal cancer (CRC) patients have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence CRC mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and CRC-specific survival.

METHODS: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. Based on data from the International Survival Analysis in Colorectal Cancer Consortium (ISACC) the individual genetic variants and a weighted genetic risk score were tested for association with overall and CRC-specific survival using Cox proportional hazards models in 7 657 stage I-IV CRC patients of which 2 438 died from any cause and 1 648 died from CRC.

RESULTS: The 25(OH)D decreasing allele of single nucleotide polymorphism (SNP) rs2282679 (GC) was associated with poorer CRC-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed non-significant associations with increased overall (HR=1.54, 95% CI:0.86-2.78) and CRC-specific mortality (HR=1.76, 95% CI:0.86-3.58). A significant increased risk of overall mortality was observed in women (HR=3.26, 95% CI:1.45-7.33, p-value for heterogeneity=0.01) and normal-weight individuals (HR=4.14, 95% CI:1.50-11.43, p-value for heterogeneity=0.02).

CONCLUSIONS: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or CRC-specific survival, although power might have been an issue.

IMPACT: Further studies are warranted to investigate the association in specific subgroups.

RevDate: 2020-03-18

Tarlock K, Alonzo T, Wang YC, et al (2020)

Prognostic Impact of CSF3R Mutations in Favorable Risk Childhood Acute Myeloid Leukemia.

Blood pii:452717 [Epub ahead of print].

RevDate: 2020-03-18

Song MJ, Potter B, Doyle JJ, et al (2020)

Gene Balance Predicts Transcriptional Responses Immediately Following Ploidy Change in Arabidopsis thaliana.

The Plant cell pii:tpc.19.00832 [Epub ahead of print].

The Gene Balance Hypothesis postulates that there is selection on gene copy number (gene dosage) to preserve stoichiometric balance among interacting proteins. This presupposes that gene product abundance is governed by gene dosage, and that gene dosage responses are consistent for interacting genes in a dosage balance-sensitive network or complex. Gene dosage responses, however, have rarely been quantified and the available data suggest that they are highly variable. We sequenced the transcriptomes of two synthetic autopolyploid accessions of Arabidopsis thaliana and their diploid progenitors, as well as one natural tetraploid and its synthetic diploid produced via haploid induction, to estimate transcriptome size and dosage responses immediately following ploidy change. Similar to what has been observed in previous studies, overall transcriptome size does not exhibit a simple doubling in response to genome doubling, and individual gene dosage responses are highly variable in all three accessions, indicating that expression is not strictly coupled with gene dosage. Nonetheless, putatively dosage balance-sensitive gene groups (GO terms, metabolic networks, gene families, and predicted interacting proteins) exhibit smaller and more coordinated dosage responses than do putatively dosage-insensitive gene groups, suggesting that constraints on dosage balance operate immediately following whole genome duplication, and that duplicate gene retention patterns are shaped by selection to preserve dosage balance.

RevDate: 2020-03-18

Raghunandan R, Mayer BT, Flores-Garcia Y, et al (2020)

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein.

Malaria journal, 19(1):113 pii:10.1186/s12936-020-03181-0.

BACKGROUND: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models.

METHODS: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity.

RESULTS: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs.

CONCLUSION: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

RevDate: 2020-03-18

Gorfine M, Schlesinger M, L Hsu (2020)

K-sample omnibus non-proportional hazards tests based on right-censored data.

Statistical methods in medical research [Epub ahead of print].

RevDate: 2020-03-17

McDermott CL, Engelberg RA, Sibley J, et al (2020)

The Association between Chronic Conditions, End-of-Life Health Care Use, and Documentation of Advance Care Planning among Patients with Cancer.

Journal of palliative medicine [Epub ahead of print].

Background: Multiple chronic conditions (MCCs) are associated with increased intensity of end-of-life (EOL) care, but their effect is not well explored in patients with cancer. Objective: We examined EOL health care intensity and advance care planning (ACP) documentation to better understand the association between MCCs and these outcomes. Design: Retrospective cohort study. Setting/Subjects: Patients aged 18+ years at UW Medicine who died during 2010-2017 with poor prognosis cancer, with or without chronic liver disease, chronic pulmonary disease, coronary artery disease, dementia, diabetes with end-stage organ damage, end-stage renal disease, heart failure, or peripheral vascular disease. Measurements: ACP documentation 30+ days before death, in-hospital death, and inpatient or intensive care unit (ICU) admission in the last 30 days. We performed logistic regression for outcomes. Results: Of 15,092 patients with cancer, 10,596 (70%) had 1+ MCCs (range 1-8). Patients with cancer and heart failure had highest odds of hospitalization (odds ratio [OR] 1.67, 95% confidence interval [CI] 1.46-1.91), ICU admission (OR 2.06, 95% CI 1.76-2.41), or in-hospital death (OR 1.62, 95% CI 1.43-1.84) versus patients with cancer and other conditions. Patients with ACP 30+ days before death had lower odds of in-hospital death (OR 0.65, 95% CI 0.60-0.71), hospitalization (OR 0.67, 95% CI 0.61-0.74), or ICU admission (OR 0.71, 95% CI 0.64-0.80). Conclusions: Patients with ACP 30+ days before death had lower odds of high-intensity EOL care. Further research needs to explore how to best use ACP to ensure patients receive care aligned with patient and family goals for care.

RevDate: 2020-03-17

Jing L, Ott M, Church CD, et al (2020)

Prevalent and diverse intratumoral oncoprotein-specific CD8+ T cells within polyoma virus-driven Merkel cell carcinomas.

Cancer immunology research pii:2326-6066.CIR-19-0647 [Epub ahead of print].

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AAs). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TILs) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DCs). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of MCPyV+ MCC patients had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope-rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicate that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.

RevDate: 2020-03-17

Diamantopoulos LN, Khaki AR, Sonpavde GP, et al (2019)

Central Nervous System Metastasis in Patients With Urothelial Carcinoma: Institutional Experience and a Comprehensive Review of the Literature.

Clinical genitourinary cancer pii:S1558-7673(19)30359-3 [Epub ahead of print].

INTRODUCTION: Central nervous system (CNS) metastasis in patients with urothelial carcinoma (UC) is uncommon and poorly understood. We aimed to explore the clinical behavior and outcomes of this unique patient population.

MATERIALS AND METHODS: We performed a retrospective analysis of patients with UC and CNS metastasis, treated in our institution (2006-2018), along with an exploratory patient-point meta-analysis of a similar patient population derived from a comprehensive literature review. Data regarding diagnosis, management, and outcomes were extracted. Overall survival, time to CNS metastasis (TTCM), and residual survival (RS) from CNS involvement to death were calculated (Kaplan-Meier method). Cox regression was used for testing key clinicopathologic associations.

RESULTS: We identified 20 "institutional" and 154 "literature" patients with adequate data granularity for analysis. Median TTCM was 17.7 (institutional cohort) and 10 (literature cohort) months. Most patients who developed CNS metastases had previous non-CNS metastasis (15/20 [75%] and 103/154 [67%], respectively). CNS lesions without previous history of metastasis were identified in 5/20 (25%) and 33/154 (21%) cases and those patients had a shorter TTCM. CNS lesions in the absence of known UC history were also documented in 18/154 (12%) literature cases. Multifocal CNS disease was associated with shorter RS in both cohorts in univariate, but not multivariate, analysis.

CONCLUSION: We observed a variability in disease presentation and course, with a subset of patients showing an early predilection for CNS insult, potentially reflecting a diverse underlying biology. Genomic profiling studies, elucidating the molecular landscape, and driving future treatments should be considered in this setting.

RevDate: 2020-03-17

Pescatello LS, Buchner DM, Jakicic JM, et al (2020)


Medicine and science in sports and exercise, 52(4):1003-1004.

RevDate: 2020-03-16

Ording AG, Christensen LB, Bjørge T, et al (2020)

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Acta oncologica (Stockholm, Sweden) [Epub ahead of print].

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

RevDate: 2020-03-19

Hodonsky CJ, Baldassari AR, Bien SA, et al (2020)

Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics.

BMC genomics, 21(1):228.

BACKGROUND: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population.

RESULTS: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP.

CONCLUSION: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.

RevDate: 2020-03-20

Iovino L, M Shadman (2020)

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape.

Current treatment options in oncology, 21(4):24.

OPINION STATEMENT: Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a "great treatment option" to the "preferred choice" for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the "watch and wait" strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.

RevDate: 2020-03-14

Parsons HA, Rhoades J, Reed SC, et al (2020)

Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-3005 [Epub ahead of print].

PURPOSE: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1000-fold lower error rate than conventional sequencing.

EXPERIMENTAL DESIGN: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within six months following metastatic diagnosis and 142 patients with stage 0-III breast cancer who received curative-intent treatment with most sampled at surgery and one year post-op. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

RESULTS: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median 57, range 2-346). Clinical sensitivity was 81% (n=13/16) in newly diagnosed MBC, 23% (n=7/30) at post-op and 19% (n=6/32) at one year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at one year was strongly associated with distant recurrence (HR=20.8 [95%CI: 7.3-58.9]). Median lead time from first positive sample to recurrence was 18.9 months (range: 3.4-39.2 months).

CONCLUSIONS: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

RevDate: 2020-03-14

Heck AM, Russo J, Wilusz J, et al (2020)

YTHDF2 destabilizes m6A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells.

RNA (New York, N.Y.) pii:rna.073502.119 [Epub ahead of print].

N6-methyladenosine (m6A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m6A-specific RNA binding proteins. Despite accumulating evidence that m6A plays an important role in modulating pluripotency, the influence of m6A reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an m6A reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of m6A-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated upregulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts.

RevDate: 2020-03-14

Matesan MC, Fisher DR, Wong R, et al (2020)

Biokinetics of Radiolabeled Monoclonal Antibody BC8: Differences in Biodistribution and Dosimetry among Hematologic Malignancies.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.119.234443 [Epub ahead of print].

We reviewed 111In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time-points) were obtained after infusion of the 111In-DOTA-BC8 (176-406 MBq) in 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in males), and two marrow sites (acetabulum and sacrum) and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 hours post-infusion and percent of administered activity was determined. Radiation absorbed doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (S.D.) of administered activity (52 patients), which cleared monoexponentially with biological half-time of 293 ± 157 hours (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biological half-time 271 ± 185 hours (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biological half-time of 243 ± 144 hours (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with half-times of 215 ± 107 hours (43 patients) or longer (5 patients). Whole-body retention half-times averaged 198 ± 75 hours. Splenic uptake was higher in the AML/MDS group when compared to the lymphoma group (p ≤ 0.05) and to the multiple myeloma group (p ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed between the three malignancy groups. Average calculated radiation absorbed doses per unit administered activity for a therapy infusions of 90Y-DOTA-BC8 were for red marrow: 470 ± 260 cGy/MBq, liver 1100 ± 330 cGy/MBq, spleen 4120 ± 1950 cGy/MBq, total body 7520 ± 20 cGy/MBq, osteogenic cells 290 ± 200 cGy/MBq, and kidneys 240 ± 200 cGy/MBqR. Conclusion:111In-DOTA-BC8 had long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were calculated for spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake among leukemia/MDS group when compared to lymphoma and multiple myeloma groups.

RevDate: 2020-03-16

Lee CJ, Kim S, Tecca HR, et al (2020)

Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia.

Blood advances, 4(6):983-992.

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

RevDate: 2020-03-13

Schwartz NRM, Crane DA, Doody DR, et al (2020)

Assessment of the Accuracy of Identification of Selected Disabilities and Conditions in Hospital Discharge Data for Pregnant Women.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

BACKGROUND: Linked birth certificate-hospital discharge records are a valuable resource for examining pregnancy outcomes among women with disability conditions. Few studies relying on these data have been able to assess the accuracy of identification of pre-existing disability conditions. We assessed the accuracy of International Classification of Diseases version 9 (ICD9) codes for identifying selected physical, sensory, and intellectual conditions that may result in disability. As ICD9 codes were utilized until recently in most states, this information is useful to inform analyses with these records.

METHODS: We reviewed 280 of 311 (90%) medical records of pregnant women with disabilities based on ICD9 codes and 390 of 8,337 (5%) records of pregnant women without disabilities who had deliveries at a large university medical center. We estimated sensitivity, specificity, and positive predictive values (PPV) using the medical record as gold standard. We adjusted for verification bias using inverse probability weighting and imputation.

RESULTS: The estimated sensitivity of ICD9 codes to identify women with disabilities with deliveries 2009-2012 was 44%; PPV was 98%, improving over time. Although sensitivity was <50% for some conditions, PPVs were 87%-100% for all conditions except intellectual disability (67%). Many physical conditions had complete verification and no underreporting.

CONCLUSIONS: These results are helpful for new studies using historical data comparing outcomes among women with and without these conditions, and to inform interpretation of results from earlier studies. Assessment of the accuracy of disabilities as identified by ICD version 10 codes is warranted.

RevDate: 2020-03-13

Han CJ, Gigic B, Schneider M, et al (2020)

Risk factors for cancer-related distress in colorectal cancer survivors: one year post surgery.

Journal of cancer survivorship : research and practice pii:10.1007/s11764-019-00845-y [Epub ahead of print].

PURPOSES: Cancer-related distress is known to persist long after completion of treatment. Factors related to distress are largely unexplored in colorectal cancer (CRC) survivors. We examined changes over time and risk factors for distress in CRC patients over the first year after surgery.

METHODS: We included 212 CRC patients with data at 6 and 12 months post-surgery from the ColoCare Study in Heidelberg, Germany. Sociodemographic and lifestyle factors, social support, and health-related quality of life (HrQOL) prior to surgery were evaluated as predictors of cancer-related distress. Distress was measured with the Cancer and Treatment Distress instrument (CTXD). Linear regression analyses examined associations between risk factors and distress.

RESULTS: Distress subscale scores varied significantly over time: health burden subscale score increased (P < .001), while finances (P = .004), medical demands (P < .001), and identity (P < .001) subscale scores decreased over time. Uncertainty and family strain subscale scores did not change. Younger age, lower income, advanced tumor stage, poorer social support, and poorer baseline HrQOL predicted higher level distress at 6 and 12 months.

CONCLUSION: Cancer-related distress continues unresolved after surgery. Although some risk factors are difficult to alter, those at highest risk can be identified earlier for possible preventive strategies.

Screening for risk factors pre-surgery would allow for targeted interventions including strategies to improve resources for those with low support, thereby reducing long-term distress in CRC survivors.

RevDate: 2020-03-16

Luedtke A, Carone M, Simon N, et al (2020)

Learning to learn from data: Using deep adversarial learning to construct optimal statistical procedures.

Science advances, 6(9):eaaw2140.

Traditionally, statistical procedures have been derived via analytic calculations whose validity often relies on sample size growing to infinity. We use tools from deep learning to develop a new approach, adversarial Monte Carlo meta-learning, for constructing optimal statistical procedures. Statistical problems are framed as two-player games in which Nature adversarially selects a distribution that makes it difficult for a statistician to answer the scientific question using data drawn from this distribution. The players' strategies are parameterized via neural networks, and optimal play is learned by modifying the network weights over many repetitions of the game. Given sufficient computing time, the statistician's strategy is (nearly) optimal at the finite observed sample size, rather than in the hypothetical scenario where sample size grows to infinity. In numerical experiments and data examples, this approach performs favorably compared to standard practice in point estimation, individual-level predictions, and interval estimation.

RevDate: 2020-03-13

Al-Kindi SG, Buzkova P, Shitole SG, et al (2020)

Soluble CD14 and Risk of Heart Failure and its Subtypes in Older Adults.

Journal of cardiac failure pii:S1071-9164(19)30779-1 [Epub ahead of print].

BACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.

METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as preserved [HFpEF] and 419 as reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (HR 1.56 per doubling, 95% CI 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling 1.10, 95% CI 1.06-1.15), IL-6 (HR 1.18, 95% CI 1.10-1.25), and WBC (HR 1.24, 95% CI 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR 1.50, 95% CI 1.07-2.10) but not HFrEF (HR 0.99, 95% CI 0.67-1.49).

CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.

RevDate: 2020-03-13

Kanate AS, Majhail NS, Savani BN, et al (2020)

Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy: Guidelines for Hematopoietic Transplantation and Cellular Therapy.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30114-2 [Epub ahead of print].

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years, the field has not only seen an improvement in transplantation technology thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells including chimeric antigen receptor T-cell (CART-cell) and T-cell receptors (TCRs) has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established multi-stakeholder task force consisting of transplant experts, payer representatives and a patient advocate to provide guidance on indications for HCT and IECT. This manuscript presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence, (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but has been shown to be effective therapy, (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exist but large clinical trials and observational studies are not feasible, (4) Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option, and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

RevDate: 2020-03-13

Hamadani M, Khanal M, Ahn KW, et al (2020)

Higher total body irradiation dose-intensity in fludarabine/TBI-based reduced-intensity conditioning regimen is associated with inferior survival in non-Hodgkin lymphoma patients undergoing allogeneic transplantation: Flu/2Gy TBI vs Flu/4Gy TBI in NHL.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30112-9 [Epub ahead of print].

INTRODUCTION: Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI.

METHODS: In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS).

RESULTS: At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts.

CONCLUSIONS: In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.

RevDate: 2020-03-20

Means AR, Kemp CG, Gwayi-Chore MC, et al (2020)

Evaluating and optimizing the consolidated framework for implementation research (CFIR) for use in low- and middle-income countries: a systematic review.

Implementation science : IS, 15(1):17.

BACKGROUND: The Consolidated Framework for Implementation Research (CFIR) is a determinants framework that may require adaptation or contextualization to fit the needs of implementation scientists in low- and middle-income countries (LMICs). The purpose of this review is to characterize how the CFIR has been applied in LMIC contexts, to evaluate the utility of specific constructs to global implementation science research, and to identify opportunities to refine the CFIR to optimize utility in LMIC settings.

METHODS: A systematic literature review was performed to evaluate the use of the CFIR in LMICs. Citation searches were conducted in Medline, CINAHL, PsycINFO, CINAHL, SCOPUS, and Web of Science. Data abstraction included study location, study design, phase of implementation, manner of implementation (ex., data analysis), domains and constructs used, and justifications for use, among other variables. A standardized questionnaire was sent to the corresponding authors of included studies to determine which CFIR domains and constructs authors found to be compatible with use in LMICs and to solicit feedback regarding ways in which CFIR performance could be improved for use in LMICs.

RESULTS: Our database search yielded 504 articles, of which 34 met final inclusion criteria. The studies took place across 21 countries and focused on 18 different health topics. The studies primarily used qualitative study designs (68%). Over half (59%) of the studies applied the CFIR at study endline, primarily to guide data analysis or to contextualize study findings. Nineteen (59%) of the contacted authors participated in the survey. Authors unanimously identified culture and engaging as compatible with use in global implementation research. Only two constructs, patient needs and resources and individual stages of change were commonly identified as incompatible with use. Author feedback centered on team level influences on implementation, as well as systems characteristics, such as health system architecture. We propose a "Characteristics of Systems" domain and eleven novel constructs be added to the CFIR to increase its compatibility for use in LMICs.

CONCLUSIONS: These additions provide global implementation science practitioners opportunities to account for systems-level determinants operating independently of the implementing organization. Newly proposed constructs require further reliability and validity assessments.


RevDate: 2020-03-18

Karalexi MA, Dessypris N, Ma X, et al (2020)

Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis.

European journal of cancer (Oxford, England : 1990), 130:1-11 pii:S0959-8049(20)30033-2 [Epub ahead of print].

AIM: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.

METHODS: Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.

RESULTS: A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.

CONCLUSIONS: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.

RevDate: 2020-03-12

Hatch EM, DL Levy (2020)

Nucleus structure and dynamics.

Molecular biology of the cell, 31(6):397.

RevDate: 2020-03-12

Sung AD, Jauhari S, Siamakpour-Reihani S, et al (2020)

Microtransplantation in Older Patients with AML: A Pilot Study of Safety, Efficacy and Immunologic Effects.

American journal of hematology [Epub ahead of print].

Older AML patients have low remission rates and poor survival outcomes with standard chemotherapy. Microtransplantation (MST) refers to infusion of allogeneic hematopoietic stem cells without substantial engraftment. MST has been shown to improve clinical outcomes compared with chemotherapy alone. This is the first trial reporting on broad correlative studies to define immunologic mechanisms of action of MST in older AML patients. Older patients with newly diagnosed AML were eligible for enrollment, receiving induction chemotherapy with cytarabine and idarubicin (7+3). MST was administered 24 hours later. Patients with CR were eligible for consolidation with high dose cytarabine and a second cycle of MST. Responses were evaluated according to standard criteria per NCCN. Immune correlative studies were performed. Sixteen patients were enrolled and received 7+3 and MST (median age 73 years). Nine (56%) had high-risk and seven (44%) had standard-risk cytogenetics. Ten episodes of CRS were observed. No cases of GVHD or treatment-related mortality were reported. EFS was 50% at 6 months and 19% at 1 year. OS was 63% at 6 months and 44% at 1 year. Donor microchimerism was not detected. Longitudinal changes were noted in NGS, TCR sequencing, and cytokine assays. Addition of MST to induction and consolidation chemotherapy was well tolerated in older AML patients. Inferior survival outcomes in our study may be attributed to a higher proportion of very elderly patients with high-risk features. Potential immunologic mechanisms of activity of MST include attenuation of inflammatory cytokines and emergence of tumor-specific T cell clones. This article is protected by copyright. All rights reserved.

RevDate: 2020-03-12

Zhang J, Kim S, Li L, et al (2020)

Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer.

The Prostate [Epub ahead of print].

BACKGROUND: The prostate-specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene-conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten-KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures.

METHODS: For proteomics, four pairs of whole prostates from tissue-specific conditional knockout Pten-KO mice (12-15 weeks of age) and their respective wild-type littermates housed in the same cages were analyzed by 8-plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real-time quantitative reverse transcription-polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks.

RESULTS: At the macromolecular level, proteomic and transcriptomic analyses complement and cross-validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten-KO prostate tumors. Suppressed expression patterns in the Pten-KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor-kappaB, and P53 in the Pten-KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten-KO prostate tumors.

CONCLUSIONS: Our work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho- and immunobiology of Pten-loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.

RevDate: 2020-03-12

Chang ET, Lau EC, SH Moolgavkar (2020)

Smoking, air pollution, and lung cancer risk in the Nurses' Health Study cohort: time-dependent confounding and effect modification.

Critical reviews in toxicology [Epub ahead of print].

The proportional hazards (PH) model is commonly used in epidemiology despite the stringent assumption of proportionality of hazards over time. We previously showed, using detailed simulation data, that the impact of a modest risk factor cannot be estimated reliably using the PH model in the presence of confounding by a strong, time-dependent risk factor. Here, we examine the same and related issues using a real dataset. Among 97,303 women in the prospective Nurses' Health Study cohort from 1994 through 2010, we used PH regression to investigate how effect estimates for cigarette smoking are affected by increasingly detailed specification of time-dependent exposure characteristics. We also examined how effect estimates for fine particulate matter (PM2.5), a modest risk factor, are affected by finer control for time-dependent confounding by smoking. The objective of this analysis is not to present a credible estimate of the impact of PM2.5 on lung cancer risk, but to show that estimates based on the PH model are inherently unreliable. The best-fitting model for cigarette smoking and lung cancer included pack-years, duration, time since cessation, and an age-by-pack-years interaction, indicating that the hazard ratio (HR) for pack-years was significantly modified by age. In the fully adjusted best-fitting model for smoking including pack-years, the HR per 10-µg/m3 increase in PM2.5 was 1.06 (95% confidence interval (CI) = 0.90, 1.25); the HR for PM2.5 in the full cohort ranged between 1.02 and 1.10 in models with other smoking adjustments, indicating a residual confounding effect of smoking. The HR for PM2.5 was statistically significant only among former smokers when adjusting for smoking pack-years (HR = 1.35, 95% CI = 1.00, 1.82 in the best-fitting smoking model), but not in models adjusting for smoking duration and average packs (pack-years divided by duration). The association between cumulative smoking and lung cancer is modified by age, and improved model fit is obtained by including multiple time-varying components of smoking history. The association with PM2.5 is residually confounded by smoking and modified by smoking status. These findings underscore limitations of the PH model and emphasize the advantages of directly estimating hazard functions to characterize time-varying exposure and risk. The hazard function, not the relative hazard, is the fundamental measure of risk in a population. As a consequence, the use of time-dependent PH models does not address crucial issues introduced by temporal factors in epidemiological data.

RevDate: 2020-03-18

Feng H, Schorpp K, Jin J, et al (2020)

Transferrin Receptor Is a Specific Ferroptosis Marker.

Cell reports, 30(10):3411-3423.e7.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.

RevDate: 2020-03-11

Jagasia M, Perales MA, Schroeder MA, et al (2020)

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 2 trial.

Blood pii:452638 [Epub ahead of print].

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label, phase 2 study (ClinicalTrials.gov identifier, NCT02953678), patients aged ≥12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally starting at 5 mg twice daily plus corticosteroids until treatment failure, unacceptable toxicity, or death. The primary endpoint was overall response rate (ORR) at Day 28; the key secondary endpoint was duration of response (DOR) at 6 months. As of July 2, 2018, 71 patients received ≥1 dose of ruxolitinib. Forty-eight patients (67.6%) had grade III/IV aGVHD at enrollment. At Day 28, 39 patients (54.9% [95% CI, 42.7%-66.8%]) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At Day 28, 24/43 patients (55.8%) receiving ruxolitinib and corticosteroids had a ≥50% corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

RevDate: 2020-03-11

Steineck A, Wiener L, Mack JW, et al (2020)

Psychosocial care for children receiving chimeric antigen receptor (CAR) T-cell therapy.

Pediatric blood & cancer [Epub ahead of print].

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, this new paradigm has introduced unique considerations specific to the patients receiving CAR T-cell therapy, including prognostic uncertainty, symptom management, and psychosocial support. With increasing availability, there is a growing need for evidence-based recommendations that address the specific psychosocial needs of the children who receive CAR T-cell therapy and their families. To guide and standardize the psychosocial care offered for patients receiving CAR T-cell therapy, we propose the following recommendations for addressing psychosocial support.

RevDate: 2020-03-13

Van Horn L, Aragaki AK, Howard BV, et al (2020)

Eating Pattern Response to a Low-Fat Diet Intervention and Cardiovascular Outcomes in Normotensive Women: The Women's Health Initiative.

Current developments in nutrition, 4(3):nzaa021.

Background: Women without cardiovascular disease (CVD) or hypertension at baseline assigned to intervention in the Women's Health Initiative Dietary Modification (DM) trial experienced 30% lower risk of coronary heart disease (CHD), whereas results in women with hypertension or prior CVD could have been confounded by postrandomization use of statins.

Objectives: Intervention participants reported various self-selected changes to achieve the 20% total fat goals. Reviewed are intervention compared with comparison group HRs for CHD, stroke, and total CVD in relation to specific dietary changes in normotensive participants.

Methods: Dietary change was assessed by comparing baseline with year 1 FFQ data in women (n = 10,371) without hypertension or CVD at baseline with intake of total fat above the median to minimize biases due to use of the FFQ in trial eligibility screening.

Results: Intervention participants self-reported compensating reduced energy intake from total fat by increasing carbohydrate and protein. Specifically they increased plant protein, with those in the upper quartile (increased total protein by ≥3.3% of energy) having a CHD HR of 0.39 (95% CI: 0.22, 0.71), compared with 0.92 (95% CI: 0.57, 1.48) for those in the lower quartile of change (decreased total protein ≥0.6% of energy), with P-trend of 0.04. CHD HR did not vary significantly with change in percentage energy from carbohydrate, and stroke HR did not vary significantly with any macronutrient changes. Scores reflecting adherence to recommended dietary patterns including the Dietary Approaches to Stop Hypertension Trial and the Healthy Eating Index showed favorable changes in the intervention group.

Conclusions: Intervention group total fat reduction replaced with increased carbohydrate and some protein, especially plant-based protein, was related to lower CHD risk in normotensive women without CVD who reported high baseline total fat intake. This trial was registered at clinicaltrials.gov as NCT00000611. Link to the WHI trial protocol: https://www.whi.org/about/SitePages/Dietary%20Trial.aspx.

RevDate: 2020-03-13

Pan S, Hullar MAJ, Lai LA, et al (2020)

Gut Microbial Protein Expression in Response to Dietary Patterns in a Controlled Feeding Study: A Metaproteomic Approach.

Microorganisms, 8(3): pii:microorganisms8030379.

Although the gut microbiome has been associated with dietary patterns linked to health, microbial metabolism is not well characterized. This ancillary study was a proof of principle analysis for a novel application of metaproteomics to study microbial protein expression in a controlled dietary intervention. We measured the response of the microbiome to diet in a randomized crossover dietary intervention of a whole-grain, low glycemic load diet (WG) and a refined-grain, high glycemic load diet (RG). Total proteins in stools from 9 participants at the end of each diet period (n = 18) were analyzed by LC MS/MS and proteins were identified using the Human Microbiome Project (HMP) human gut microbiome database and UniProt human protein databases. T-tests, controlling for false discovery rate (FDR) <10%, were used to compare the Gene Ontology (GO) biological processes and bacterial enzymes between the two interventions. Using shotgun proteomics, more than 53,000 unique peptides were identified including microbial (89%) and human peptides (11%). Forty-eight bacterial enzymes were statistically different between the diets, including those implicated in SCFA production and degradation of fatty acids. Enzymes associated with degradation of human mucin were significantly enriched in the RG diet. These results illustrate that the metaproteomic approach is a valuable tool to study the microbial metabolism of diets that may influence host health.

RevDate: 2020-03-11

Jones CA, Hadfield J, Thomson NR, et al (2020)

The Nature and Extent of Plasmid Variation in Chlamydia trachomatis.

Microorganisms, 8(3): pii:microorganisms8030373.

Chlamydia trachomatis is an obligate intracellular pathogen of humans, causing both the sexually transmitted infection, chlamydia, and the most common cause of infectious blindness, trachoma. The majority of sequenced C. trachomatis clinical isolates carry a 7.5-Kb plasmid, and it is becoming increasingly evident that this is a key determinant of pathogenicity. The discovery of the Swedish New Variant and the more recent Finnish variant highlight the importance of understanding the natural extent of variation in the plasmid. In this study we analysed 524 plasmid sequences from publicly available whole-genome sequence data. Single nucleotide polymorphisms (SNP) in each of the eight coding sequences (CDS) were identified and analysed. There were 224 base positions out of a total 7550 bp that carried a SNP, which equates to a SNP rate of 2.97%, nearly three times what was previously calculated. After normalising for CDS size, CDS8 had the highest SNP rate at 3.97% (i.e., number of SNPs per total number of nucleotides), whilst CDS6 had the lowest at 1.94%. CDS5 had the highest total number of SNPs across the 524 sequences analysed (2267 SNPs), whereas CDS6 had the least SNPs with only 85 SNPs. Calculation of the genetic distances identified CDS6 as the least variable gene at the nucleotide level (d = 0.001), and CDS5 as the most variable (d = 0.007); however, at the amino acid level CDS2 was the least variable (d = 0.001), whilst CDS5 remained the most variable (d = 0.013). This study describes the largest in-depth analysis of the C. trachomatis plasmid to date, through the analysis of plasmid sequence data mined from whole genome sequences spanning 50 years and from a worldwide distribution, providing insights into the nature and extent of existing variation within the plasmid as well as guidance for the design of future diagnostic assays. This is crucial at a time when single-target diagnostic assays are failing to detect natural mutants, putting those infected at risk of a serious long-term and life-changing illness.

RevDate: 2020-03-10

Walls AC, Park YJ, Tortorici MA, et al (2020)

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.

Cell pii:S0092-8674(20)30262-2 [Epub ahead of print].

The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

RevDate: 2020-03-10

Higano CS, Armstrong AJ, Sartor O, et al (2020)

Reply to potential underestimation of cerebrovascular events in the PROVENGE registry for the observation, collection, and evaluation of experience data.

RevDate: 2020-03-13

Reding KW, Brubaker P, D'Agostino R, et al (2019)

Increased skeletal intermuscular fat is associated with reduced exercise capacity in cancer survivors: a cross-sectional study.

Cardio-oncology (London, England), 5:3.

Background: Cancer survivors experience on average a 20% reduction in peak exercise capacity (VO2 peak) post-cancer treatment. Intermuscular fat (IMF) is a strong predictor of reduced exercise capacity in heart failure (HF) patients; however it is unknown whether increased IMF is related to reduced VO2 peak in cancer survivors.

Methods and results: Twenty eight individuals: 14 cancer survivors > 12-months post-cancer treatment and 14 individuals without cancer were matched on age, gender, and body mass index (BMI). Participants underwent magnetic resonance imaging (MRI) assessments of IMF within the paraspinal muscles, VO2 peak and exercise-associated measures of left ventricular ejection fraction (LVEF). Blinded analyses were performed. Associations between the ratio of IMF to skeletal muscle (SM) were estimated using Pearson's partial correlation coefficients. Individuals with cancer and non-cancer comparators were of similar age (54 ± 17 versus 54 ± 15 years; p = 1.0), gender (5 men and 9 women, both groups), and BMI (27 ± 4 versus 26 ± 4; p = 0.57). Peak VO2 was 22% lower in cancer survivors versus non-cancer comparators (26.9 vs 34.3 ml/kg/min; p = 0.005), and was correlated with IMF:SM in both cancer survivors and non-cancer individuals after accounting for exercise-associated LVEF, resting LVEF, BMI, other body fat depots, and cardiovascular disease (CVD) co-morbidities (p < 0.001 to 0.08 for all adjusted correlations).

Conclusion: Among cancer survivors that previously received anthracyclines, increased intermuscular fat is associated with reduced VO2 peak even after accounting for exercise-associated cardiac function. This suggests IMF is important in the development of exercise intolerance, an outcome experienced by a large number of cancer survivors.

RevDate: 2020-03-13

Chan AY, Leiding JW, Liu X, et al (2020)

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Frontiers in immunology, 11:239.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

RevDate: 2020-03-10

Parayath NN, MM Amiji (2020)

Preparation of Hyaluronic Acid-Based Nanoparticles for Macrophage-Targeted MicroRNA Delivery and Transfection.

Methods in molecular biology (Clifton, N.J.), 2118:99-110.

Skewing the macrophage polarity to achieve a favorable phenotype is a recently investigated therapeutic strategy in multiple disease/dysfunctional conditions such as inflammation, tumors, autoimmune disorders, and tissue repairs. However, delivering the therapeutic agent specifically to the macrophages has been a challenge in this field. Here, we describe the synthesis of hyaluronic acid (HA)-based nanoparticles for targeting CD44 receptors on the macrophages. The HA backbone is modified with cationic polyethyleneimine (PEI) for efficient encapsulation of microRNA into the self-assembling nanoparticles for targeted delivery to macrophages.

RevDate: 2020-03-10

Guadamuz JS, Durazo-Arvizu RA, Daviglus ML, et al (2020)

Citizenship Status and the Prevalence, Treatment, and Control of Cardiovascular Disease Risk Factors Among Adults in the United States, 2011-2016.

Circulation. Cardiovascular quality and outcomes, 13(3):e006215.

RevDate: 2020-03-09

Chiorean EG, Nandakumar G, Fadelu T, et al (2020)

Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline.

JCO global oncology, 6:414-438.

PURPOSE: To provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer.

METHODS: ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings.

RESULTS: Existing sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% on all recommendations.

RECOMMENDATIONS: Common elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting.Additional information is available at www.asco.org/resource-stratified-guidelines.

RevDate: 2020-03-09

Xue E, Xie H, Leisenring WM, et al (2020)

High incidence of herpes zoster after cord blood hematopoietic cell transplant despite longer duration of antiviral prophylaxis.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5801118 [Epub ahead of print].

BACKGROUND: Cord blood transplant (CBT) recipients have a high incidence of herpes zoster (HZ) in the context of short-term peri-transplant antiviral prophylaxis. In 2009, international guidelines recommended HZ prophylaxis for at least 1 year after hematopoietic cell transplant (HCT). The impact of longer-term antiviral prophylaxis on HZ incidence after CBT is unknown.

METHODS: We retrospectively analyzed varicella-zoster virus (VZV) seropositive CBT recipients who were transplanted between 2006-2016. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ and used Cox proportional hazards regression to identify variables associated with HZ.

RESULTS: The study cohort consisted of 227 patients. Among 1-year survivors, 91% were still receiving prophylaxis, for a median duration of 20.6 months. HZ occurred in 44 patients (19%) at a median of 23.6 months. The cumulative incidence of HZ by 1-year post-CBT was 1.8% (95% CI, 0.1%-4%) but increased to 26% (95% CI, 19%-33%) by 5 years. In a multivariable analysis, acute graft-versus-host disease was associated with increased risk, whereas antiviral prophylaxis was associated with reduced risk for HZ (adjusted hazard ratio, 0.19; 95% confidence interval, 0.09-0.4). There was no association between CD4+ T cell counts at 1-year post-CBT and subsequent risk for HZ.

CONCLUSIONS: We found a high incidence of HZ after CBT despite antiviral prophylaxis for >1 year. Based on these findings, we suggest longer duration of prophylaxis for HZ after CBT; prophylactic compliance, VZV-specific immune monitoring, and vaccination to mitigate HZ after CBT also require further study.

RevDate: 2020-03-09

Snoeyenbos Newman G, Bauer K, Karpenko A, et al (2020)

Evaluation of the National STD Curriculum: Reach, Utilization, and Engagement.

Sexually transmitted diseases [Epub ahead of print].

BACKGROUND: With increasing rates of sexually transmitted infections (STIs) in the United States, there is a critical need to educate health professionals on the prevention, diagnosis, and treatment of STIs. The National STD Curriculum (NSTDC, https://www.std.uw.edu) is a free, online curriculum, funded by the Centers for Disease Control and Prevention (CDC). The purpose of this paper is to evaluate the reach, utilization, and engagement of users with the curriculum.

METHODS: Data on NSTDC utilization was collected for 24 months after the February 1, 2017 launch. For all users, Google Analytics was used to determine total number of users, geographic location, age and sex, and average session duration. For registered users, additional data analysis included work-role, demographics, and completion of self-study modules, check-on-learning questions, and question banks. User satisfaction was measured on a 5-point Likert scale.

RESULTS: During the evaluation period, 136,270 individual users accessed the NSTDC, including 24,652 registered users. Among all registered users, 10,660 (43.2%) were registered nurses, 2,810 (11.4%) physicians, 4,942 (20.1%) Advanced Practice Nurses and Physician Assistants, and 6,213 (25.2%) non-clinicians. Among registered users, 18,533 (75.2%) completed at least 1 module, 7,898 (32.0%) completed all 7 modules, and 19,804 (80.4%) answered optional check-on-learning questions. Median satisfaction with the content was (5) Very Satisfied (IQR 4-5).

CONCLUSIONS: The NSTDC is a free, guideline-based, online curriculum with novel dual-functionality that has achieved extensive reach with a broad array of health professionals who engage deeply with the material. The wide usage of NSTDC demonstrates the need for high-quality, unbiased, free content in user-focused formats.

RevDate: 2020-03-09

Haggerty CL, Ness RB, Totten PA, et al (2020)

Presence and concentrations of select bacterial vaginosis-associated bacteria are associated with increased risk of pelvic inflammatory disease.

Sexually transmitted diseases [Epub ahead of print].

In a vaginal 16S ribosomal RNA gene quantitative PCR study of 17 pelvic inflammatory disease (PID) cases and 17 controls who tested positive for Chlamydia trachomatis, women who additionally tested positive for Atopobium vaginae, Sneathia spp., BVAB-TM7, Megasphaera spp., Eggerthella-like bacterium or Mobiluncus spp. were more likely to develop PID.

RevDate: 2020-03-09

Minnie SA, GR Hill (2020)

Immunotherapy of multiple myeloma.

The Journal of clinical investigation pii:129205 [Epub ahead of print].

Multiple myeloma (MM), a bone marrow-resident hematological malignancy of plasma cells, has remained largely incurable despite dramatic improvements in patient outcomes in the era of myeloma-targeted and immunomodulatory agents. It has recently become clear that T cells from MM patients are able to recognize and eliminate myeloma, although this is subverted in the majority of patients who eventually succumb to progressive disease. T cell exhaustion and a suppressive bone marrow microenvironment have been implicated in disease progression, and once these are established, immunotherapy appears largely ineffective. Autologous stem cell transplantation (ASCT) is a standard of care in eligible patients and results in immune effects beyond cytoreduction, including lymphodepletion, T cell priming via immunogenic cell death, and inflammation; all occur within the context of a disrupted bone marrow microenvironment. Recent studies suggest that ASCT reestablishes immune equilibrium and thus represents a logical platform in which to intervene to prevent immune escape. New immunotherapies based on checkpoint inhibition targeting the immune receptor TIGIT and the deletion of suppressive myeloid populations appear attractive, particularly after ASCT. Finally, the immunologically favorable environment created after ASCT may also represent an opportunity for approaches utilizing bispecific antibodies or chimeric antigen receptor (CAR) T cells.

RevDate: 2020-03-09

Seftel MD, Kuxhausen M, Burns L, et al (2020)


RevDate: 2020-03-07

Nash SH, Greenley R, Dietz-Chavez D, et al (2020)

Incorporating Participant and Clinical Feedback into a Community-Based Participatory Research Study of Colorectal Cancer Among Alaska Native People.

Journal of community health pii:10.1007/s10900-020-00796-x [Epub ahead of print].

Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) globally. We are developing a community-based participatory research (CBPR) informed program to understand risk and protective factors contributing to these high rates. In 2018, we conducted a pilot study to test feasibility of recruiting participants from the Alaska Native Medical Center CRC Screening Clinic into a prospective epidemiologic study. Post-pilot study completion, we conducted focus groups (n = 2) with participants and key informant interviews (n = 7) with research and clinical staff to understand study experiences. During 106 days of recruitment, 30 participants enrolled in the pilot study. Over half (60%) were female, and most (67%) were aged 40-59 years. Key themes that emerged from the participant focus groups were: the desire to contribute to improving the health of AN people as a key driver of participation; an overall positive experience with the study; the benefit of clinical staff notifying patients about the study; the need to clearly explain the purpose of each biospecimen collected; barriers to participation; and, the importance of returning study results to the community. Key themes from research and clinical staff interviews included: the study not interfering with clinical duties; the importance of relationships between clinical and research staff; the importance of research staff flexibility; and, comments on specific study procedures. As part of the CBPR process, this feedback will be incorporated into study protocols. We are building this pilot work into a larger prospective study that will inform primary prevention programs.

RevDate: 2020-03-09

Künzli M, Schreiner D, Pereboom TC, et al (2020)

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity.

Science immunology, 5(45):.

CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (Tcm) cells, whereas the existence and functional significance of long-lived T follicular helper (Tfh) cells are controversial. Here, we show that Tfh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant Tfh cells with high expression of hallmark Tfh markers to at least 400 days after infection, by which time Tcm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived Tfh cells are transcriptionally distinct from Tcm cells, maintain stemness and self-renewal gene expression, and, in contrast to Tcm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived Tfh cells from Tcm cells. Unexpectedly, long-lived Tfh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to Tfh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of Tfh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish Tfh cells as an attractive target for the induction of durable adaptive immunity.

RevDate: 2020-03-07

Gopal AK, Levy R, Houot R, et al (2020)

First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-2973 [Epub ahead of print].

PURPOSE: In this phase I study (NCT01307267) we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular (FL) and other CD20+ non-Hodgkin lymphomas (NHLs).

EXPERIMENTAL DESIGN: Primary objectives were to assess treatment safety and tolerability for estimating the maximum tolerated dose (MTD), using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D).

RESULTS: Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks [Q4W]) and rituximab (375 mg/m2 weekly) in the dose escalation groups or utomilumab (1.2 mg/kg Q4W) plus rituximab in the dose expansion cohort. No patient experienced DLTThe MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg Q4W. The majority of the utomilumab treatment-related adverse events (AEs) were grade 1-2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03-10 mg/kg dose range. A low incidence (1.5%) of treatment-induced anti-drug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI 12.1, 33.0%) in all patients with NHL, including 4 complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function.

CONCLUSIONS: Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.

RevDate: 2020-03-07

Chinazzi M, Davis JT, Ajelli M, et al (2020)

The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak.

Science (New York, N.Y.) pii:science.aba9757 [Epub ahead of print].

Motivated by the rapid spread of COVID-19 in Mainland China, we use a global metapopulation disease transmission model to project the impact of travel limitations on the national and international spread of the epidemic. The model is calibrated based on internationally reported cases, and shows that at the start of the travel ban from Wuhan on 23 January 2020, most Chinese cities had already received many infected travelers. The travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community.

RevDate: 2020-03-07

Bandini M, Pederzoli F, Madison R, et al (2020)

Unfavorable Cancer-specific Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients With Bladder Cancer and Squamous Cell Variant: A Multi-institutional Study.

Clinical genitourinary cancer pii:S1558-7673(20)30033-1 [Epub ahead of print].

BACKGROUND: Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs).

PATIENTS AND METHODS: We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n = 283; 45%), other subtypes (n = 95; 15%), micropapillary (n = 85; 14%), adenocarcinoma (n = 65; 10%), small cell (n = 54; 8.6%), and sarcomatous (n = 47; 7.6%). Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV.

RESULTS: Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n = 44; 9.8%) had had worse CSS (median CSS, 33 vs. 116 months; P < .001) and higher mortality rates (hazard ratio, 2.1; P = .03) compared with those with pure UC (n = 328; 72.9%). The results of the analyses were also confirmed when the pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed a lower rate of clinical-to-pathologic downstaging (odds ratio, 0.4; P = .03) compared with UC.

CONCLUSIONS: SCC was the HV exhibiting the lowest effect of NAC in terms of activity and CSS. Compared with pure UC, SCC seemed to be insensitive to traditional NAC regimens.

RevDate: 2020-03-06

Yan AP, Chen Y, Henderson TO, et al (2020)

Adherence to Surveillance for Second Malignant Neoplasms and Cardiac Dysfunction in Childhood Cancer Survivors: A Childhood Cancer Survivor Study.

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

PURPOSE: To evaluate childhood cancer survivors' adherence to surveillance protocols for late effects of treatment and to determine the factors affecting adherence.

METHODS: Between 2014 and 2016, 11,337 survivors and 2,146 siblings in the Childhood Cancer Survivor Study completed a survey ascertaining adherence to Children's Oncology Group (COG) guidelines for survivors at high risk for second malignant neoplasms or cardiac dysfunction and to the American Cancer Society (ACS) cancer screening guidelines for average-risk populations. Adherence rates and factors affecting adherence were analyzed.

RESULTS: Median age at diagnosis was 7 years (range, 0-20.9 years), and median time from diagnosis was 29 years (range, 15-47 years). Among high-risk survivors, adherence to COG breast, colorectal, skin, and cardiac surveillance was 12.6% (95% CI, 10.0% to 15.3%), 37.0% (34.1% to 39.9%), 22.3% (21.2% to 23.4%), and 41.4% (40.1% to 42.7%), respectively. Among average-risk survivors, adherence to ACS breast, cervical, and colorectal screening was 57.1% (53.2% to 61.0%), 83.6% (82.7% to 84.5%), and 68.5% (64.7% to 72.2%), respectively. Twenty-seven percent of survivors and 20.0% of primary care providers (PCPs) had a survivorship care plan (SCP). For high-risk survivors, SCP possession was associated with increased adherence to COG breast (22.3% v. 8.1%; prevalence ratio [PR], 2.52; CI, 1.59 to 4.01), skin (34.8% v 23.0%; PR, 1.16; CI, 1.01 to 1.33), and cardiac (67.0% v 33.1%; PR, 1.73; CI, 1.55 to 1.92) surveillance. For high-risk survivors, PCP possession of a SCP was associated only with increased adherence to COG skin cancer surveillance (36.9% v 23.2%; PR, 1.24; CI, 1.08 to 1.43).

CONCLUSION: Guideline adherence is suboptimal. Although survivor SCP possession is associated with better adherence, few survivors and PCPs have one. New strategies to improve adherence are needed.

RevDate: 2020-03-06

Silhol R, Boily MC, Dimitrov D, et al (2020)

Understanding the HIV epidemic among MSM in Baltimore: a modelling study estimating the impact of past HIV interventions and who acquired and contributed to infections.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

INTRODUCTION: Men who have sex with men (MSM) in the United States (US) are disproportionately affected by HIV. We estimated the impact of past interventions and contribution of different population groups to incident MSM HIV infections.

SETTING: Baltimore, US METHODS:: We used a deterministic model, parameterised and calibrated to demographic and epidemic Baltimore MSM data, to estimate the fraction of HIV infections among MSM averted by condoms and antiretroviral therapy (ART) over 1984-2017 and the fraction of infections acquired and transmission contributed by MSM from different demographic groups and disease and care continuum stages over 10-year periods from 1988 to 2017, using population attributable fractions (PAFs).

RESULTS: Condom use and ART averted 19% (95% uncertainty interval: 14-25%) and 23% (15-31%) of HIV infections that would have occurred since 1984 and 1996, respectively. Over 2008-2017, 46% (41-52%) of incident infections were acquired by, and 35% (27-49%) of transmissions contributed by MSM aged 18-24 years old (who constitute 27% of all MSM, 19% of HIV+ MSM). MSM with undiagnosed HIV infection, those with diagnosed infection but not in care, and those on ART contributed to 41% (31-54%), 46% (25-56%), and 14% (7-28%) of transmissions, respectively.

CONCLUSION: Condoms and ART have modestly impacted the HIV epidemic among Baltimore MSM to date. Interventions reaching MSM with diagnosed infection who are not in care should be implemented since the largest percentage of HIV transmissions among Baltimore MSM are attributed to this group.

RevDate: 2020-03-06

González HM, Tarraf W, González KA, et al (2020)

Diabetes, Cognitive Decline, and Mild Cognitive Impairment Among Diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging Results (HCHS/SOL).

Diabetes care pii:dc19-1676 [Epub ahead of print].

OBJECTIVE: Hispanics/Latinos are the largest ethnic/racial group in the U.S., have the highest prevalence of diabetes, and are at increased risk for neurodegenerative disorders. Currently, little is known about the relationship between diabetes and cognitive decline and disorders among diverse Hispanics/Latinos. The purpose of this study is to clarify these relationships in diverse middle-aged and older Hispanics/Latinos.

RESEARCH DESIGN AND METHODS: The Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) is an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). HCHS/SOL is a multisite (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA), probability sampled (i.e., representative of targeted populations), and prospective cohort study. Between 2016 and 2018, SOL-INCA enrolled diverse Hispanics/Latinos ages ≥50 years (n = 6,377). Global cognitive decline and mild cognitive impairment were the primary outcomes.

RESULTS: Prevalent diabetes at visit 1, but not incident diabetes at visit 2, was associated with significantly steeper global cognitive decline (βGC = -0.16 [95% CI -0.25; -0.07]; P < 0.001), domain-specific cognitive decline, and higher odds of MCI (odds ratio 1.74; [95% CI 1.34; 2.26]; P < 0.001) compared with no diabetes in age- and sex-adjusted models.

CONCLUSIONS: Diabetes was associated with cognitive decline and increased MCI prevalence among diverse Hispanics/Latinos, primarily among those with prevalent diabetes at visit 1. Our findings suggest that significant cognitive decline and MCI may be considered additional disease complications of diabetes among diverse middle-aged and older Hispanics/Latinos.

RevDate: 2020-03-06

Thompson JA, Schneider BJ, Brahmer J, et al (2020)

NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(3):230-241.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

RevDate: 2020-03-06

Flaig TW, Spiess PE, Agarwal N, et al (2020)

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(3):329-354.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

RevDate: 2020-03-20

Gonzales P, Grieco A, White E, et al (2020)

Safety of oral naltrexone in HIV-positive men who have sex with men and transgender women with alcohol use disorder and initiating antiretroviral therapy.

PloS one, 15(3):e0228433.

HIV disproportionately affects men who have sex with men (MSM) and transgender women (TW). These populations use alcohol more heavily than the general population, and alcohol use disorders (AUDs) are more prevalent among them. Naltrexone (NTX) has documented efficacy and safety as a medication-assisted therapy for AUD. Its use has not been well-examined in persons with HIV (PWH) newly initiating antiretroviral therapy (ART) where the possibility of hepatotoxicity may be increased when initating multiple new medications. This study assessed the safety of oral NTX treatment (50 mg daily) initiated concomitantly with antiretroviral therapy (ART) in a double-blind randomized placebo-controlled trial of NTX in MSM/TW in Lima, Peru among MSM and TW with AUD (AUDIT score ≥ 8). We analyzed adverse event data from ART-naïve participants (N = 155) who were randomized (2:1) to initiate ART plus NTX (N = 103) or ART plus placebo (N = 52). Participants were monitored for 24 weeks while taking ART plus NTX/placebo, followed by 24 weeks receiving ART alone. Over 48 weeks, 135 grade 2 or 3 adverse events were reported, resulting in 1.3 clinical adverse events per participant equally represented in both treatment and placebo arms. Two serious adverse events occurred among two participants receiving NTX; neither was attributed to the study medication. No significant differences were found in the proportion of subjects reporting any adverse events between treatment arms across all time-points. These results suggest NTX is safe in MSM/TW PWH with AUD newly initiating ART, as no excess of clinical adverse events or transaminase elevation was associated with NTX use.

RevDate: 2020-03-19

Whitney BM, Guthrie BL, Srinivasan S, et al (2020)

Changes in key vaginal bacteria among postpartum African women initiating intramuscular depot-medroxyprogesterone acetate.

PloS one, 15(3):e0229586.

BACKGROUND: The ECHO trial has relieved apprehension about intramuscular depot medroxyprogesterone acetate (DMPA-IM), however it is still important to understand how DMPA-IM affects the vaginal environment. We sought to describe how DMPA-IM initiation influences vaginal bacteria associated with HIV acquisition in postpartum women.

METHODS: Vaginal swabs were collected for Nugent score determination and taxon-specific quantitative PCR of eight bacteria. Enrollment occurred at contraceptive initiation (DMPA-IM or non-hormonal contraception (non-HC)) and repeat vaginal swabs were collected after three months. Generalized estimating equations were used to estimate changes in Nugent score, total bacterial load, and taxa concentrations among contraceptive groups.

RESULTS: Women who chose DMPA-IM (n = 33) were more likely to be married (97%vs.67%) and have resumed intercourse since delivery (52%vs.29%) compared to women who chose non-HC (n = 21). After three months, significant decreases in the concentrations of Sneathia species, Mycoplasma hominis, and Parvimonas species Type 1 were seen among non-HC users, however concentrations remained stable among DMPA-IM users; contraceptive method was associated with significantly different changes in M. hominis concentration between groups (p = 0.010).

CONCLUSIONS: Our findings suggest that postpartum use of DMPA-IM and non-HC may have differential impacts on the vaginal concentrations of some bacteria that have previously been associated with HIV acquisition.

RevDate: 2020-03-20

Haidar G, Boeckh M, N Singh (2020)

Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence.

The Journal of infectious diseases, 221(Supplement_1):S23-S31.

This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.

RevDate: 2020-03-05

Prentice RL, Pettinger M, Neuhouser ML, et al (2020)

Can dietary self-reports usefully complement blood concentrations for estimation of micronutrient intake and chronic disease associations?.

The American journal of clinical nutrition pii:5781195 [Epub ahead of print].

BACKGROUND: We recently presented associations between serum-based biomarkers of carotenoid and tocopherol intake and chronic disease risk in a Women's Health Initiative (WHI) Measurement Precision subcohort (n = 5488). Questions remain as to whether self-reported dietary data can usefully augment such biomarkers or can be calibrated using biomarkers for reliable disease association estimation in larger WHI cohorts.

OBJECTIVES: The aims were to examine the potential of FFQ data to explain intake variation in a WHI Feeding Study and to compare association parameter estimates and their precision from studies based on biomarker-calibrated FFQ intake in larger WHI cohorts, with those previously presented.

METHODS: Serum-based intake measures were augmented by using FFQ data in a WHI Feeding Study (n = 153). Corresponding calibration equations were generated, both in a companion Nutritional Biomarker Study (n = 436) and in the previously mentioned subcohort (n = 5488), by regressing these intake measures on dietary data and participant characteristics, for α- and β-carotene, lutein plus zeaxanthin, and α-tocopherol. The supplemental value of FFQ data was considered by examining the fraction of feeding study intake variation explained by these regression models. Calibrated intake and disease association analyses were evaluated by comparisons with previously reported subcohort results.

RESULTS: The inclusion of FFQ data led to some increases in feeding study intake variation explained (total R2 of ∼50%). Calibrated intake estimates explained 25-75% of serum-based intake variation, whether developed using either of the 2 cohort subsamples. Related disease associations for micronutrients were precisely estimated in larger WHI cohorts (n = 76,691) but were often closer to the null compared with previously reported associations.

CONCLUSIONS: FFQ data may usefully augment blood concentrations in estimating the intake of carotenoids and tocopherols. Calibrated intake estimates using FFQ, dietary supplement, and participant characteristics only may require further justification to ensure reliable estimation of related disease associations.

RevDate: 2020-03-05

Lind ML, Phipps AI, Mooney S, et al (2020)

Predictive value of three clinical criteria for sepsis (qSOFA, SIRS, and NEWS) with respect to short-term mortality in allogeneic hematopoietic cell transplant recipients with suspected infections.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5781125 [Epub ahead of print].

BACKGROUND: Sepsis, a life-threatening immunological response to an infection, disproportionality affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit endpoints in patients with suspected infections (SI) have been adopted in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate three criteria among allogeneic HCT recipients.

METHODS: We evaluated Systemic Inflammatory Response Syndrome (SIRS), quick-Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) criteria in relation to short-term mortality among HCT recipients with SIs. Data from the first 100-days post-transplant were analyzed for patients transplanted between September 2010 - July 2017. We used the following cut-points (qSOFA/SIRS: 2+; NEWS: 7+) and restricted to first SI per hospital encounter.

RESULTS: Of the 880 HCT recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of a SI. In relation to 10-day mortality, SIRS was the most sensitive: 91.3% (95% CI:72.0 - 98.9%) but least specific: 35.0% (32.6 - 37.5%) whereas qSOFA was the most specific: 90.5% (88.9 - 91.9%) but least sensitive: 47.8% (26.8 - 69.4%). NEWS was moderately sensitive 78.3% (56.3 - 92.5%) and specific 70.2% (67.8 - 72.4%).

CONCLUSION: NEWS outperformed qSOFA and SIRS, but all three criteria had low to moderate predictive accuracy and the magnitude of the known predictive limitations of qSOFA and SIRS were at least as large as in general populations. Our data suggest that population-specific sepsis criteria are needed for immunocompromised patients.

RevDate: 2020-03-08

McEwen AE, Leary SES, CM Lockwood (2020)

Beyond the Blood: CSF-Derived cfDNA for Diagnosis and Characterization of CNS Tumors.

Frontiers in cell and developmental biology, 8:45.

Genetic data are rapidly becoming part of tumor classification and are integral to prognosis and predicting response to therapy. Current molecular tumor profiling relies heavily on tissue resection or biopsy. Tissue profiling has several disadvantages in tumors of the central nervous system, including the challenge associated with invasive biopsy, the heterogeneous nature of many malignancies where a small biopsy can underrepresent the mutational profile, and the frequent lack of obtaining a repeat biopsy, which limits routine monitoring to assess therapy response and/or tumor evolution. Circulating tumor, cell-free DNA (cfDNA), has been proposed as a liquid biopsy to address some limitations of tissue-based genetics. In cancer patients, a portion of cfDNA is tumor-derived and may contain somatic genetic alterations. In central nervous system (CNS) neoplasia, plasma tumor-derived cfDNA is very low or absent, likely due to the blood brain barrier. Interrogating cfDNA in cerebrospinal fluid (CSF) has several advantages. Compared to blood, CSF is paucicellular and therefore predominantly lacks non-tumor cfDNA; however, patients with CNS-limited tumors have significantly enriched tumor-derived cfDNA in CSF. In patients with metastatic CNS disease, mutations in CSF cfDNA are most concordant with the intracranial process. CSF cfDNA can also occasionally uncover additional genetic alterations absent in concurrent biopsy specimens, reflecting tumor heterogeneity. Although CSF is enriched for tumor-derived cfDNA, absolute quantities are low. Highly sensitive, targeted methods including next-generation sequencing and digital PCR are required to detect mutations in CSF cfDNA. Additional technical and bioinformatic approaches also facilitate enhanced ability to detect tumor mutations in CSF cfDNA.

RevDate: 2020-03-06

Shikany JM, Manson JE, Shadyab AH, et al (2020)

Associations of social, physical, and financial factors with diet quality among older, community-dwelling women.

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

OBJECTIVE: This analysis examined whether specific social, physical, and financial factors were associated with diet quality among older, community-dwelling women.

METHODS: This cross-sectional analysis was conducted in a subset of 6,094 community-dwelling Women's Health Initiative participants who completed a food frequency questionnaire, administered from 2012 to 2013, and a self-administered supplemental questionnaire, administered approximately 1 year later. The supplemental questionnaire included five questions assessing social, physical, and financial factors related to eating. Diet quality was assessed with the Healthy Eating Index-2010 (HEI-2010; range of 0-100; higher score indicates a higher quality diet). The total HEI-2010 score was calculated by summing individual scores representing the intake of nine adequacy components (beneficial food groups) and three moderation components (food groups to limit). Associations of responses to the five questions on the supplemental questionnaire with HEI-2010 scores were examined with multiple linear regression, adjusting for relevant covariates.

RESULTS: Mean ± standard deviation age of participants was 78.8 ± 6.7 years. Reporting eating fewer than two meals per day, having dental or other mouth problems causing problems with eating, and not always being able to shop, cook, or feed oneself were associated with statistically significantly lower HEI-2010 scores, compared with those not reporting these issues, after multivariable adjustment: 5.37, 2.98, and 2.39 lower scores, respectively (all P values <0.0001). Reporting eating alone most of the time and not always having enough money to buy food were not associated with HEI-2010 scores.

CONCLUSIONS: Among older, community-dwelling women, eating fewer than two meals per day, dental and other mouth problems, and diminished ability to shop for food, prepare meals, and feed oneself were associated with lower diet quality. These are potential targets for interventions to improve diet quality in older women. : Video Summary:http://links.lww.com/MENO/A561.


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

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