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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 27 May 2022 at 01:42 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

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RevDate: 2022-05-26

Kuderer NM, GH Lyman (2022)

COVID-19 vaccine effectiveness in patients with cancer: remaining vulnerabilities and uncertainties.

The Lancet. Oncology pii:S1470-2045(22)00252-2 [Epub ahead of print].

RevDate: 2022-05-26

Chen GL, Onstad L, Martin PJ, et al (2022)

Durable discontinuation of systemic therapy in patients affected by chronic graft versus host disease.

Haematologica [Epub ahead of print].

Successful treatment of chronic graft-versus-host disease (GVHD) often requires long term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GVHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from 2 prospectively followed cohorts from the chronic GVHD Consortium (N=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half received non-myeloablative conditioning. The median time from HCT to chronic GVHD diagnosis was 7.7 (range 1.0 - 141.3) months, and the median time from chronic GVHD onset to enrollment into the cohorts was 0.9 (range 0.0-12.0) months. The cumulative incidence estimate of durable ST discontinuation was 32% (95% CI: 28%-37%) at 10 years after cohort enrollment. Among patients who discontinued ST, the median time from chronic GVHD diagnosis to durable ST discontinuation was 3.6 (range 1.2-10.5) years. In multivariate analysis, patients who received myeloablative conditioning, had chronic GVHD manifested as moderate / severe lower gastrointestinal (GI) involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower GI involvement and cord blood (vs. peripheral blood) as a graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue systemic treatment permanently, most patients require prolonged systemic treatment. Viewing chronic GVHD in this way has implications for management approaches.

RevDate: 2022-05-25

Andrlová H, Miltiadous O, Kousa AI, et al (2022)

MAIT and Vδ2 unconventional T cells are supported by a diverse intestinal microbiome and correlate with favorable patient outcome after allogeneic HCT.

Science translational medicine, 14(646):eabj2829.

Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells.

RevDate: 2022-05-25

Gilada T, Schnittman SR, White E, et al (2022)

Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use.

Open forum infectious diseases, 9(6):ofac155 pii:ofac155.

Background: Primary human immunodeficiency virus (HIV) is characterized by dynamic changes in viral load and innate and adaptive immune responses; it is unclear the extent to which time from acquisition to antiretroviral therapy (ART) initiation and substance use impact these immunologic changes.

Methods: We studied plasma immune activation biomarkers, viral load, and CD4+ and CD8+ cell counts in participants from the Sabes primary infection study in Peru, who had been randomized to begin ART immediately after diagnosis vs 24 weeks later. We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks.

Results: Compared to participants enrolled >30 days after HIV acquisition, participants enrolled during acute infection (≤30 days) had higher mean interferon (IFN)-γ and IFN-α2a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled >30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1α, TNF-α, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline.

Conclusions: IFN-γ and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.

RevDate: 2022-05-24

Crist SB, Nemkov T, Dumpit RF, et al (2022)

Publisher Correction: Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells.

RevDate: 2022-05-24

Lee EJ, Saraiva LR, Hanchate NK, et al (2022)

Odor blocking of stress hormone responses.

Scientific reports, 12(1):8773.

Scents have been employed for millennia to allay stress, but whether or how they might do so is largely unknown. Fear and stress induce increases in blood stress hormones controlled by hypothalamic corticotropin releasing hormone neurons (CRHNs). Here, we report that two common odorants block mouse stress hormone responses to three potent stressors: physical restraint, predator odor, and male-male social confrontation. One odorant inhibits restraint and predator odor activation of excitatory neurons upstream of CRHNs in the bed nucleus of the stria terminalis (BNSTa). In addition, both activate inhibitory neurons upstream of CRHNs in the hypothalamic ventromedial nucleus (VMH) and silencing of VMH inhibitory neurons hinders odor blocking of stress. Together, these findings indicate that odor blocking can occur via two mechanisms: (1) Inhibition of excitatory neurons that transmit stress signals to CRHNs and (2) activation of inhibitory neurons that act directly or indirectly to inhibit stressor activation of CRHNs.

RevDate: 2022-05-24

Wu W, Bhatraju PK, Cobb N, et al (2022)

Radiographic Findings and Association With Clinical Severity and Outcomes in Critically Ill Patients With COVID-19.

Current problems in diagnostic radiology pii:S0363-0188(22)00059-7 [Epub ahead of print].

PURPOSE: To describe evolution and severity of radiographic findings and assess association with disease severity and outcomes in critically ill COVID-19 patients.

MATERIALS AND METHODS: This retrospective study included 62 COVID-19 patients admitted to the intensive care unit (ICU). Clinical data was obtained from electronic medical records. A total of 270 chest radiographs were reviewed and qualitatively scored (CXR score) using a severity scale of 0-30. Radiographic findings were correlated with clinical severity and outcome.

RESULTS: The CXR score increases from a median initial score of 10 at hospital presentation to the median peak CXR score of 18 within a median time of 4 days after hospitalization, and then slowly decreases to a median last CXR score of 15 in a median time of 12 days after hospitalization. The initial and peak CXR score was independently associated with invasive MV after adjusting for age, gender, body mass index, smoking, and comorbidities (Initial, odds ratio [OR]: 2.11 per 5-point increase, confidence interval [CI] 1.35-3.32, P= 0.001; Peak, OR: 2.50 per 5-point increase, CI 1.48-4.22, P= 0.001). Peak CXR scores were also independently associated with vasopressor usage (OR: 2.28 per 5-point increase, CI 1.30-3.98, P= 0.004). Peak CXR scores strongly correlated with the duration of invasive MV (Rho = 0.62, P< 0.001), while the initial CXR score (Rho = 0.26) and the peak CXR score (Rho = 0.27) correlated weakly with the sequential organ failure assessment score. No statistically significant associations were found between radiographic findings and mortality.

CONCLUSIONS: Evolution of radiographic features indicates rapid disease progression and correlate with requirement for invasive MV or vasopressors but not mortality, which suggests potential nonpulmonary pathways to death in COVID-19.

RevDate: 2022-05-24

Munshi PN, Chen Y, Ahn KW, et al (2022)

Outcomes of Autologous Hematopoietic Cell Transplantation in Older Patients with Diffuse Large B Cell Lymphoma.

Transplantation and cellular therapy pii:S2666-6367(22)01320-3 [Epub ahead of print].

BACKGROUND: Data for outcomes after autologous hematopoietic cell transplant (auto-HCT) in DLBCL patients ≥70 years are limited OBJECTIVES: : Auto-HCT is feasible on older DLBCL patients STUDY DESIGN: : Using the CIBMTR database, we compared outcomes of auto-HCT in DLBCL patients aged 60-69 years (n=363) versus ≥70 years (n=103) between 2008 and 2019. Non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models RESULTS: : All patients received BEAM conditioning. On univariate analysis, in the 60-69 years versus ≥70 years cohorts, 100-day NRM was 3% versus 4%, 5-year REL was 47% versus 45%, 5-year PFS 40% versus 38% and 5-year OS 55% versus 41% respectively. On multivariate analysis, patients ≥70 had no significant difference in NRM (HR 1.43, 95% CI 0.85-2.39), REL (HR 1.11, 95% CI 0.79-1.56), PFS (HR 1.23, 95% CI 0.92-1.63) compared to patients 60-69 years. Patients ≥70 years had a higher mortality (HR 1.39, 95% CI 1.05-1.85, p=0.02), likely due to inferior post-relapse OS in this cohort (HR 1.82, 95% CI 1.27-2.61, p=0.001). DLBCL was the major cause of death in both cohorts (62% vs. 59%) CONCLUSION: : Older patients should not be denied auto-HCT solely based on chronological age.

RevDate: 2022-05-24

Valinetz ED, Matemo D, Gersh JK, et al (2022)

Isoniazid preventive therapy and TB transcriptional signatures in people with HIV.

AIDS (London, England) pii:00002030-990000000-00017 [Epub ahead of print].

OBJECTIVES: To examine the association between isoniazid preventive therapy (IPT) or nontuberculous mycobacteria (NTM) sputum culture positivity and tuberculosis (TB) transcriptional signatures in people with HIV.

DESIGN: Cross-sectional study.

METHODS: We enrolled adults living with HIV who were IPT-naive or had completed IPT more than 6 months prior at HIV care clinics in western Kenya. We calculated TB signatures using gene expression data from qRT-PCR. We used multivariable linear regression to analyze the association between prior receipt of IPT or NTM sputum culture positivity with a transcriptional TB risk score, RISK6 (range 0-1). In secondary analyses, we explored the association between IPT or NTM positivity and four other TB transcriptional signatures.

RESULTS: Among 381 participants, 99.7% were receiving antiretroviral therapy and 86.6% had received IPT (completed median of 1.1 years prior). RISK6 scores were lower (mean difference 0.10; 95% confidence interval (CI): 0.06-0.15; P < 0.001) among participants who received IPT than those who did not. In a model that adjusted for age, sex, duration of ART, and plasma HIV RNA, the RISK6 score was 52.8% lower in those with a history of IPT (P < 0.001). No significant association between year of IPT receipt and RISK6 scores was detected. There was no association between NTM sputum culture positivity and RISK6 scores.

CONCLUSION: In people with HIV, IPT was associated with significantly lower RISK6 scores compared with persons who did not receive IPT. These data support investigations of its performance as a TB preventive therapy response biomarker.

RevDate: 2022-05-24

Pal SK, Somford DM, Grivas P, et al (2022)

Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.

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

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

RevDate: 2022-05-23

Wilkens AB, Fulton E, Pont MJ, et al (2022)

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Blood pii:485320 [Epub ahead of print].

Adoptive transfer of T-cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients, but can be limited by poor T-cell expansion and persistence in vivo. Less-differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate anti-tumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance therapeutic efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages, and in memory CD8+ T-cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation and enhance proliferation and anti-tumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production, and studied the effects on differentiation, transcription factor expression, cytokine production and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T-cells, and upregulated expression of AhR and c-MAF, driving heightened production of IL-22, IL-10 and Granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to co-transferred CD8+ CAR-T, driving improved expansion and curative anti-tumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T-cells engineered with tumor-targeting receptors.

RevDate: 2022-05-23

Ko LK, Scarinci IC, Bouchard EG, et al (2022)

A Framework for Equitable Partnerships to Promote Cancer Prevention and Control in Rural Settings.

JNCI cancer spectrum, 6(2):.

Rural populations continue to experience persistent cancer disparities compared with urban populations particularly in cancers that can be prevented or detected early through screening and vaccination. Although the National Cancer Institute and the larger cancer research community have identified rural community partnerships as the foundation for reducing the disparities, we have identified limited application of community-based participatory research in cancer prevention and control research. Guided by the Community-Based Participatory Research Conceptual Model and our collective experience, we provide a framework for a community-cancer center partnership that focuses on promoting health equity. In this commentary, we articulate that the partnership process must foster capacity for communities and cancer centers, strive for rural representation in clinical trials and biobanking, build a pipeline for dissemination and implementation research, and create a bidirectional flow of knowledge between communities and academic institutions. Authentic partnerships with rural communities should be the ultimate goal of cancer centers, and the process described in this commentary can serve as an initial platform to build capacity and continue to strive toward that goal.

RevDate: 2022-05-23

Yang JJ, Yu D, White E, et al (2022)

Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts.

JNCI cancer spectrum, 6(2):.

BACKGROUND: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisure-time physical activity (LTPA) with all-cause and lung cancer-specific mortality among incident lung cancer patients.

METHODS: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer-specific mortality after adjustment for major prognostic factors and lifetime smoking history.

RESULTS: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate = 20.9%, 95% CI = 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR = 0.93, 95% CI = 0.88 to 0.99), but not with lung cancer-specific mortality (multivariable-adjusted HR = 0.99, 95% CI = 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction = .008 for all-cause mortality and .003 for lung cancer-specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariable-adjusted HRs were 0.80 (95% CI = 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI = 0.65 to 0.99) for lung cancer-specific mortality.

CONCLUSIONS: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer.

RevDate: 2022-05-23

Qiu X, Brown LG, Conner JL, et al (2022)

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

JCI insight, 7(10): pii:157164.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

RevDate: 2022-05-23

Bracis C, Moore M, Swan DA, et al (2022)

Improving vaccination coverage and offering vaccine to all school-age children allowed uninterrupted in-person schooling in King County, WA: Modeling analysis.

Mathematical biosciences and engineering : MBE, 19(6):5699-5716.

The rapid spread of highly transmissible SARS-CoV-2 variants combined with slowing pace of vaccination in Fall 2021 created uncertainty around the future trajectory of the epidemic in King County, Washington, USA. We analyzed the benefits of offering vaccination to children ages 5-11 and expanding the overall vaccination coverage using mathematical modeling. We adapted a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington, to simulate scenarios of vaccinating children aged 5-11 with different starting dates and different proportions of physical interactions (PPI) in schools being restored. Dynamic social distancing was implemented in response to changes in weekly hospitalizations. Reduction of hospitalizations and estimated time under additional social distancing measures are reported over the 2021-2022 school year. In the scenario with 85% vaccination coverage of 12+ year-olds, offering early vaccination to children aged 5-11 with 75% PPI was predicted to prevent 756 (median, IQR 301-1434) hospitalizations cutting youth hospitalizations in half compared to no vaccination and largely reducing the need for additional social distancing measures over the school year. If, in addition, 90% overall vaccination coverage was reached, 60% of remaining hospitalizations would be averted and the need for increased social distancing would almost certainly be avoided. Our work suggests that uninterrupted in-person schooling in King County was partly possible because reasonable precaution measures were taken at schools to reduce infectious contacts. Rapid vaccination of all school-aged children provides meaningful reduction of the COVID-19 health burden over this school year but only if implemented early. It remains critical to vaccinate as many people as possible to limit the morbidity and mortality associated with future epidemic waves.

RevDate: 2022-05-23

Byeon S, Werner B, Falter R, et al (2022)

Proteomic Identification of Phosphorylation-Dependent Septin 7 Interactors that Drive Dendritic Spine Formation.

Frontiers in cell and developmental biology, 10:836746 pii:836746.

Septins are a family of cytoskeletal proteins that regulate several important aspects of neuronal development. Septin 7 (Sept7) is enriched at the base of dendritic spines in excitatory neurons and mediates both spine formation and spine and synapse maturation. Phosphorylation at a conserved C-terminal tail residue of Sept7 mediates its translocation into the dendritic spine head to allow spine and synapse maturation. The mechanistic basis for postsynaptic stability and compartmentalization conferred by phosphorylated Sept7, however, is unclear. We report herein the proteomic identification of Sept7 phosphorylation-dependent neuronal interactors. Using Sept7 C-terminal phosphopeptide pulldown and biochemical assays, we show that the 14-3-3 family of proteins specifically interacts with Sept7 when phosphorylated at the T426 residue. Biochemically, we validate the interaction between Sept7 and 14-3-3 isoform gamma and show that 14-3-3 gamma is also enriched in the mature dendritic spine head. Furthermore, we demonstrate that interaction of phosphorylated Sept7 with 14-3-3 protects it from dephosphorylation, as expression of a 14-3-3 antagonist significantly decreases phosphorylated Sept7 in neurons. This study identifies 14-3-3 proteins as an important physiological regulator of Sept7 function in neuronal development.

RevDate: 2022-05-23

Abdul-Mutakabbi JC, Hirsch EB, Ko C, et al (2022)

A call to action: A need for initiatives that increase equitable access to COVID-19 therapeutics.

Lancet Regional Health. Americas pii:S2667-193X(22)00080-1 [Epub ahead of print].

RevDate: 2022-05-22

Garzia NA, Cushing-Haugen K, Chiu YH, et al (2022)

Pesticide residue intake from fruit and vegetable consumption and risk of laparoscopically-confirmed endometriosis.

F&S science pii:S2666-335X(22)00040-4 [Epub ahead of print].

OBJECTIVE: To examine the association between intake of fruits and vegetables with high versus low pesticide residue burden and diagnosis of laparoscopically-confirmed endometriosis. The etiology of endometriosis is not well understood, but dietary factors may influence risk. Pesticides may act as endocrine disruptors and intake of pesticide contaminated food is a common exposure pathway.

DESIGN: Prospective cohort study. Hazard Ratios (HR) and 95% confidence intervals (95% CI) were calculated using multivariable Cox proportional hazard models to evaluate high and low pesticide residue fruit and vegetable intake in relation to diagnosis of laparoscopically-confirmed endometriosis.

SETTING: Not Applicable.

PATIENTS: Premenopausal US women (n=52,053) of the Nurses' Health Study II, aged 34-53 years at study baseline (1999) were followed up until 2013. Diet was assessed every four years using a validated food frequency questionnaire. A previously developed and validated Pesticide Residue Burden Score (PRBS), based upon the USDA Pesticide Data Program, was used to assign fruits and vegetables to pesticide residue groups (high/low).

INTERVENTION: Not Applicable.

MAIN OUTCOME MEASURES: Cases of laparoscopically-confirmed endometriosis were identified from self-reports to validated questionnaires.

RESULTS: During 14 years of follow-up, 956 incidence cases of laparoscopically-confirmed endometriosis were reported. No association was observed between intake of high or low PRBS fruit and vegetable intake and endometriosis (HR for 5th versus 1st quintile: high PRBS intake=0.94, 95% CI=0.73-1.23; ptrend=0.33; low PRBS intake=1.07, 95% CI=0.82-1.40; ptrend=0.61). No associations were observed for high or low PRBS fruit and vegetable intake by fertility status.

CONCLUSIONS: No clear associations were observed between high or low PRBS fruit and vegetable intake and endometriosis risk among premenopausal women. To our knowledge, this is the first study to evaluate the association between dietary pesticide residue intake and endometriosis. Further research is needed, particularly that which evaluates this association among a younger population of women (adolescence or early adulthood) and evaluates dietary exposure to specific pesticides or chemical families.

RevDate: 2022-05-23

Elyanow R, Snyder TM, Dalai SC, et al (2022)

T cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity.

JCI insight, 7(10): pii:150070.

BACKGROUNDMeasuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T cell responses, but these responses vary with disease severity and individual characteristics.METHODSA T cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T cell testing was assessed and compared with serologic testing.RESULTSSARS-CoV-2-specific T cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T cell testing was most apparent in recovered, nonhospitalized individuals sampled > 150 days after initial illness, suggesting greater sensitivity than serology at later time points and in individuals with less severe disease. T cell testing identified SARS-CoV-2 infection in 68% (55 of 81) of samples with undetectable nAb titers (<1:40) and in 37% (13 of 35) of samples classified as negative by 3 antibody assays.CONCLUSIONThese results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.TRIAL REGISTRATIONSpecimens were accrued under trial NCT04338360 accessible at clinicaltrials.gov.FUNDINGThis work was funded by Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, NIAID, Fred Hutchinson Joel Meyers Endowment, Fast Grants, and American Society for Transplantation and Cell Therapy.

RevDate: 2022-05-21

Crandall CJ, Larson J, Cene CW, et al (2022)

Relationship of Social Connectedness with Decreasing Physical Activity during the COVID-19 Pandemic among Older Women Participating in the Women's Health Initiative Study.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6590196 [Epub ahead of print].

BACKGROUND: Aging is generally accompanied by decreasing physical activity, which is associated with a decline in many health parameters, leading to recommendations for older adults to increase or at least maintain physical activity (PA).

METHODS: We determined relationships between social connectedness and decreasing or increasing PA levels during the COVID-19 pandemic among 41,443 participants of the Women's Health Initiative Extension Study. Outcomes of logistic regression models were decreasing PA activity (reference: maintaining or increasing) and increasing PA activity (reference: maintaining or decreasing). The main predictor was social connectedness as a combined variable: not living alone (reference: living alone) and communicating with others outside the home more than once/week (reference: once/week or less). We adjusted for age, race, ethnicity, body mass index, physical function level, and education.

RESULTS: Compared with participants who were not socially connected, socially connected participants had lower odds of decreasing PA (adjusted odds ratio 0.91, 95% confidence interval 0.87-0.95). Odds of increasing PA (vs. decreasing or maintaining PA) were not significantly different among socially connected and not socially connected participants. Associations between social connectedness and decreasing PA did not significantly differ by age (<85 vs. ≥85 years), race/ethnicity (non-Hispanic White vs. other races/ethnicity), education (college vs. 75).

CONCLUSIONS: Social connectedness was associated with lower odds of decreasing PA among older women during the pandemic. These findings could inform the development of future interventions to help older women avoid decreasing PA..

RevDate: 2022-05-20

Wang Z, Choi SW, Chami N, et al (2022)

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.

Frontiers in endocrinology, 13:863893.

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, P obesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, P extremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, P obesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, P extremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.

RevDate: 2022-05-20

Johnson BE, Baik CS, Mazieres J, et al (2022)

Clinical Outcomes With Dabrafenib Plus Trametinib in a Clinical Trial Versus Real-World Standard of Care in Patients With BRAF-Mutated Advanced NSCLC.

JTO clinical and research reports, 3(5):100324 pii:S2666-3643(22)00048-0.

Introduction: BRAF mutations are rare in patients with NSCLC, and treatment options are limited. Dabrafenib plus trametinib (dab-tram) was approved for BRAF V600-mutated advanced NSCLC (aNSCLC), based on results from a phase 2 study (NCT01336634). This retrospective analysis compared the effectiveness of dab-tram, based on previously reported clinical trial data, versus real-world standard of care in patients with BRAF-mutated aNSCLC.

Methods: Real-world cohorts were derived from a deidentified real-world database (2011-2020) and included patients with BRAF-mutated aNSCLC receiving first-line platinum-based chemotherapy (PBC), first-line immune checkpoint inhibitors (ICIs) plus PBC, or second-line ICIs. Weighting by odds was used to estimate the average treatment effect of the treated.

Results: For first-line dab-tram versus PBC, the hazard ratio (HR; 95% confidence interval) for death in unweighted and weighted analyses was 0.65 (0.39-1.1) and 0.51 (0.29-0.92; p = 0.03), respectively; unweighted and weighted median overall survival was 17.3 (12.3-40.2) versus 14.5 (9.2-19.6) months and 17.3 (14.6-not reached) versus 9.7 (6.4-19.6) months, respectively. Hazard ratio of death in unweighted and weighted analyses was 0.56 (0.29-1.1) and 0.57 (0.28-1.17), respectively, with first-line dab-tram versus PBC plus ICI, and 0.65 (0.39-1.07) and not reported (Cox proportional-hazards assumption violated), respectively, with second-line dab-tram versus ICI.

Conclusions: In this indirect comparison in patients with BRAF-mutated aNSCLC, the risk of death was lower and median overall survival was longer with first-line dab-tram versus PBC. In analyses of dab-tram versus first-line PBC plus ICI or second-line ICI, sample sizes were small and findings were inconclusive with overlapping confidence intervals. Despite some limitations, the study provides useful data for this rare patient population.

RevDate: 2022-05-19

Amonoo HL, Harnedy LE, Deary EC, et al (2022)

Peer support in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT): a qualitative study.

Bone marrow transplantation [Epub ahead of print].

Peer support, a distinctive form of social support in which patients share emotional, social, and practical help based on their own lived experience of illness and treatment, positively impacts patient-reported outcomes in cancer populations. However, data on peer support experiences among hematopoietic stem cell transplant (HSCT) recipients are limited. We conducted semi-structured qualitative interviews among 12 allogeneic HSCT recipients who were ≤6 months post transplant without any complications and 13 allogeneic HSCT recipients >6 months post transplant and living with chronic graft-versus-host disease. Interviews explored patients' experiences with peer support and their preferences for a peer support intervention tailored to the needs of HSCT recipients. While the majority (70%) of participants reported no formal experience with peer support, most (83%) articulated themes of potential benefits of peer support (e.g., managing expectations and uncertainty that accompany HSCT). Most participants (60%) reported a preference for a peer support intervention prior to the HSCT hospitalization. Despite the limited data on peer support interventions among HSCT recipients and lack of formal peer support experience in most of our cohort, our study shows that HSCT recipients clearly acknowledge the potential benefits of a peer support intervention, and they prefer that it start prior to transplantation.

RevDate: 2022-05-20
CmpDate: 2022-05-17

Ettinger DS, Wood DE, Aisner DL, et al (2022)

Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(5):497-530.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

RevDate: 2022-05-20
CmpDate: 2022-05-17

Griffiths EA, Roy V, Alwan L, et al (2022)

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(5):436-442.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

RevDate: 2022-05-19

Li S, Sok P, Xu K, et al (2022)

Epigenome-Wide Association Study of Acute Lymphoblastic Leukemia in Children with Down Syndrome.

Blood advances pii:485310 [Epub ahead of print].

RevDate: 2022-05-19

Nourmohammad A (2022)

T cell immune responses deciphered.

Science (New York, N.Y.), 376(6595):796-797.

A machine-learning approach reveals antigen encoding that predicts T cell responses.

RevDate: 2022-05-19

Palacios R, Lewis FM, Reyes CL, et al (2022)

A pilot feasibility study of Conexiones, a telephone-delivered cancer parenting education program for Hispanic mothers.

Journal of psychosocial oncology [Epub ahead of print].

OBJECTIVE: To test the short-term impact of Conexiones, a culturally adapted cancer parenting education program for diagnosed child-rearing Hispanic mothers.

DESIGN: Single group, pre-post-test design.

SAMPLE: 18 U.S. Hispanic mothers diagnosed within 2 years with early-stage cancer (0-III) raising a child (5-17 years).

METHODS: Participants completed consent, baseline measures, and five telephone-delivered Conexiones sessions at 2-week intervals from trained patient educators in English or Spanish. Outcomes were assessed at baseline and at 3 months.

RESULTS: Maternal depressed mood, parenting self-efficacy, and parenting quality significantly improved. Children's anxious/depressed mood tended to significantly improve. Outcomes did not co-vary with mothers' level of acculturation.

CONCLUSIONS: Conexiones appears to positively improve Hispanic mothers' distress and parenting competencies; efficacy testing is warranted within a larger randomized control trial.

A brief, culturally adapted cancer parenting education program has potential to enhance Hispanic mothers' and children's behavioral-emotional adjustment to a mother's cancer.

RevDate: 2022-05-19

Rathbun MM, Shipley MM, Bowen CD, et al (2022)

Comparison of herpes simplex virus 1 genomic diversity between adult sexual transmission partners with genital infection.

PLoS pathogens, 18(5):e1010437 pii:PPATHOGENS-D-21-02313.

Herpes simplex virus (HSV) causes chronic infection in the human host, characterized by self-limited episodes of mucosal shedding and lesional disease, with latent infection of neuronal ganglia. The epidemiology of genital herpes has undergone a significant transformation over the past two decades, with the emergence of HSV-1 as a leading cause of first-episode genital herpes in many countries. Though dsDNA viruses are not expected to mutate quickly, it is not yet known to what degree the HSV-1 viral population in a natural host adapts over time, or how often viral population variants are transmitted between hosts. This study provides a comparative genomics analysis for 33 temporally-sampled oral and genital HSV-1 genomes derived from five adult sexual transmission pairs. We found that transmission pairs harbored consensus-level viral genomes with near-complete conservation of nucleotide identity. Examination of within-host minor variants in the viral population revealed both shared and unique patterns of genetic diversity between partners, and between anatomical niches. Additionally, genetic drift was detected from spatiotemporally separated samples in as little as three days. These data expand our prior understanding of the complex interaction between HSV-1 genomics and population dynamics after transmission to new infected persons.

RevDate: 2022-05-19

Towlerton AMH, Ravishankar S, Coffey DG, et al (2022)

Serial Analysis of the T-Cell Receptor β-Chain Repertoire in People Living With HIV Reveals Incomplete Recovery After Long-Term Antiretroviral Therapy.

Frontiers in immunology, 13:879190.

Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4+ T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor β-chain (TRB) repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the TRB repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis. TRB repertoires were characterized via high-throughput sequencing of the TRB variable region performed on genomic DNA extracted from unsorted peripheral blood mononuclear cells. Additional laboratory and clinical metadata including serial measurements of HIV viral load and CD4 + T-cell count were available for all individuals in the cohort. A previously published control group of 189 TRB repertoires from peripheral blood samples of adult bone marrow transplant donors was evaluated for comparison. ART initiation in PLHIV was associated with a sustained reduction in viral load and a significant increase in TRB repertoire diversity. However, repertoire diversity in PLHIV remained significantly lower than in the control group even after long-term ART. The composition of TRB repertoires of PLHIV after ART also remained perturbed compared to the control cohort, as evidenced by large persistent private clonal expansions, reduced efficiency in the generation of TRB CDR3 amino acid sequences, and a narrower range of CDR3 lengths. Network analysis revealed an antigen-experienced structure in the TRB repertoire of PLHIV both before and after ART initiation that was quite distinct from the structure of control repertoires, with a slight shift toward a more naïve structure observed after ART initiation. Though we observe significant improvement in TRB repertoire diversity with durable viral suppression in PLHIV on long-term ART, the composition and structure of these repertoires remain significantly perturbed compared to the control cohort of adult bone marrow transplant donors.

RevDate: 2022-05-18

Martinek J, Lin J, Kim KI, et al (2022)

Transcriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function.

Cell reports. Medicine, 3(5):100621.

Modulation of immune function at the tumor site could improve patient outcomes. Here, we analyze patient samples of metastatic melanoma, a tumor responsive to T cell-based therapies, and find that tumor-infiltrating T cells are primarily juxtaposed to CD14+ monocytes/macrophages rather than melanoma cells. Using immunofluorescence-guided laser capture microdissection, we analyze transcriptomes of CD3+ T cells, CD14 + monocytes/macrophages, and melanoma cells in non-dissociated tissue. Stromal CD14+ cells display a specific transcriptional signature distinct from CD14+ cells within tumor nests. This signature contains LY75, a gene linked with antigen capture and regulation of tolerance and immunity in dendritic cells (DCs). When applied to TCGA cohorts, this gene set can distinguish patients with significantly prolonged survival in metastatic cutaneous melanoma and other cancers. Thus, the stromal CD14+ cell signature represents a candidate biomarker and suggests that reprogramming of stromal macrophages to acquire DC function may offer a therapeutic opportunity for metastatic cancers.

RevDate: 2022-05-18

Smith GL, Banegas MP, Acquati C, et al (2022)

Navigating financial toxicity in patients with cancer: A multidisciplinary management approach.

CA: a cancer journal for clinicians [Epub ahead of print].

Approximately one-half of individuals with cancer face personal economic burdens associated with the disease and its treatment, a problem known as financial toxicity (FT). FT more frequently affects socioeconomically vulnerable individuals and leads to subsequent adverse economic and health outcomes. Whereas multilevel systemic factors at the policy, payer, and provider levels drive FT, there are also accompanying intervenable patient-level factors that exacerbate FT in the setting of clinical care delivery. The primary strategy to intervene on FT at the patient level is financial navigation. Financial navigation uses comprehensive assessment of patients' risk factors for FT, guidance toward support resources, and referrals to assist patient financial needs during cancer care. Social workers or nurse navigators most frequently lead financial navigation. Oncologists and clinical provider teams are multidisciplinary partners who can support optimal FT management in the context of their clinical roles. Oncologists and clinical provider teams can proactively assess patient concerns about the financial hardship and employment effects of disease and treatment. They can respond by streamlining clinical treatment and care delivery planning and incorporating FT concerns into comprehensive goals of care discussions and coordinated symptom and psychosocial care. By understanding how age and life stage, socioeconomic, and cultural factors modify FT trajectory, oncologists and multidisciplinary health care teams can be engaged and informative in patient-centered, tailored FT management. The case presentations in this report provide a practical context to summarize authors' recommendations for patient-level FT management, supported by a review of key supporting evidence and a discussion of challenges to mitigating FT in oncology care. CA Cancer J Clin. 2022;72:000-000.

RevDate: 2022-05-18

Wu NL, Phipps AI, Krull KR, et al (2022)

Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant.

Blood advances pii:485290 [Epub ahead of print].

Survivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively impact quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21y at HCT and alive ≥2y following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n=1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2y (interquartile range [IQR] 56.8-70.5) and a median 12.0y (IQR 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4-31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all p<0.01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (OR 2.13, 95% CI 1.46-3.10) and sleep impairment (OR 4.41, 95% CI 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

RevDate: 2022-05-18

Crook ZR, Girard EJ, Sevilla GP, et al (2022)

Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager.

Science translational medicine, 14(645):eabn0402.

Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity (KD = 202 pM) PD-L1-binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development.

RevDate: 2022-05-18

Wang G, Liu S, Han F, et al (2022)

Robust functional principal component analysis via a functional pairwise spatial sign operator.

Biometrics [Epub ahead of print].

Functional principal component analysis (FPCA) has been widely used to capture major modes of variation and reduce dimensions in functional data analysis. However, standard FPCA based on the sample covariance estimator does not work well if the data exhibits heavy-tailedness or outliers. To address this challenge, a new robust functional principal component analysis approach based on a functional pairwise spatial sign (PASS) operator, termed PASS FPCA, is introduced. We propose robust estimation procedures for eigenfunctions and eigenvalues. Theoretical properties of the PASS operator are established, showing that it adopts the same eigenfunctions as the standard covariance operator and also allows recovering ratios between eigenvalues. We also extend the proposed procedure to handle functional data measured with noise. Compared to existing robust FPCA approaches, the proposed PASS FPCA requires weaker distributional assumptions to conserve the eigenspace of the covariance function. Specifically, existing work are often built upon a class of functional elliptical distributions, which requires inherently symmetry. In contrast, we introduce a class of distributions called the weakly functional coordinate symmetry (weakly FCS), which allows for severe asymmetry and is much more flexible than the functional elliptical distribution family. The robustness of the PASS FPCA is demonstrated via extensive simulation studies, especially its advantages in scenarios with non-elliptical distributions. The proposed method was motivated by and applied to analysis of accelerometry data from the Objective Physical Activity and Cardiovascular Health Study, a large-scale epidemiological study to investigate the relationship between objectively measured physical activity and cardiovascular health among older women. This article is protected by copyright. All rights reserved.

RevDate: 2022-05-18

Yaghjyan L, McLaughlin E, Lehman A, et al (2022)

Associations of coffee/caffeine consumption with postmenopausal breast cancer risk and their interactions with postmenopausal hormone use.

European journal of nutrition [Epub ahead of print].

PURPOSE: We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use.

METHODS: Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk.

RESULTS: The median follow-up time for our cohort was 18.3 years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors.

CONCLUSION: We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors.

RevDate: 2022-05-18

Geiger EJ, Liu W, Srivastava DK, et al (2022)

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

Clinical orthopaedics and related research pii:00003086-990000000-00748 [Epub ahead of print].

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.

QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?

METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys.

RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups.

CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient.

LEVEL OF EVIDENCE: Level III, therapeutic study.

RevDate: 2022-05-18

Sun S, Serrano MG, Fettweis JM, et al (2022)

Race, the Vaginal Microbiome, and Spontaneous Preterm Birth.

mSystems [Epub ahead of print].

Previous studies have investigated the associations between the vaginal microbiome and preterm birth, with the aim of determining whether differences in community patterns meaningfully alter risk and could therefore be the target of intervention. We report on vaginal microbial analysis of a nested case-control subset of the Pregnancy, Infection, and Nutrition (PIN) Study, including 464 White women (375 term birth and 89 spontaneous preterm birth, sPTB) and 360 Black women (276 term birth and 84 sPTB). We found that the microbiome of Black women has higher alpha-diversity, higher abundance of Lactobacillus iners, and lower abundance of Lactobacillus crispatus. However, among women who douche, there were no significant differences in microbiome by race. The sPTB-associated microbiome exhibited a lower abundance of L. crispatus, while alpha diversity and L. iners were not significantly associated with sPTB. For each order of magnitude increase in the normalized relative abundance of L. crispatus, multivariable adjusted odds of sPTB decreased by approximately 20% (odds ratio, 0.81; 95% confidence interval, 0.70, 0.94). When we considered the impact of douching, associations between the microbiome and sPTB were limited to women who do not douche. We also observed strong intercorrelations between a range of maternal factors, including poverty, education, marital status, age, douching, and race, with microbiome effect sizes in the range of 1.8 to 5.2% in univariate models. Therefore, race may simply be a proxy for other socially driven factors that differentiate microbiome community structures. Future work will continue to refine reliable microbial biomarkers for preterm birth across diverse cohorts. IMPORTANCE Approximately 10% of all pregnancies in the United States end in preterm birth, and over 14% of pregnancies end in preterm birth among Black women. Knowledge on the associations between vaginal microbiome and preterm birth is important for understanding the potential cause and assessing risk of preterm birth. Our study is one of the largest studies performed to date to investigate the associations between vaginal microbiome and spontaneous preterm birth (sPTB), with stratified design for Black and White women. We found that the vaginal microbiome was different between Black and White women. The vaginal microbiome was associated with sPTB, and a lower abundance of L. crispatus increased the risk of sPTB independent of racial differences in microbial community structures. Furthermore, we also found that vaginal douching obscured the associations between vaginal microbiome, race, and preterm birth, suggesting that vaginal douching is an important factor to consider in future studies.

RevDate: 2022-05-17

Thangavelu G, Andrejeva G, Bolivar-Wagers S, et al (2022)

Retinoic acid signaling acts as a rheostat to balance Treg function.

Cellular & molecular immunology [Epub ahead of print].

Regulatory T cells (Tregs) promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses. Under certain inflammatory conditions, Tregs can lose their lineage stability and function. Previous studies have reported that ex vivo exposure to retinoic acid (RA) enhances Treg function and stability. However, it is unknown how RA receptor signaling in Tregs influences these processes in vivo. Herein, we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor (DN) RARα in all T cells. Despite the fact that DNRARα conventional T cells are hypofunctional, Tregs had increased CD25 expression, STAT5 pathway activation, mTORC1 signaling and supersuppressor function. Furthermore, DNRARα Tregs had increased inhibitory molecule expression, amino acid transporter expression, and metabolic fitness and decreased antiapoptotic proteins. Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist. Unexpectedly, Treg-specific expression of DNRARα resulted in distinct phenotypes, such that a single allele of DNRARα in Tregs heightened their suppressive function, and biallelic expression led to loss of suppression and autoimmunity. The loss of Treg function was not cell intrinsic, as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARα and wild-type bone marrow maintained the enhanced suppressive capacity. Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling. Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

RevDate: 2022-05-18

Corey L, MD Miner (2022)

Accelerating clinical trial development in vaccinology: COVID-19 and beyond.

Current opinion in immunology, 76:102206 pii:S0952-7915(22)00053-X [Epub ahead of print].

The remarkable success of the US government-backed COVID-19 vaccine development in 2020 offers several lessons on how to effectively foster rapid vaccine discovery and development. Conceptually, the formation of a public-private partnership that included innovative government and academic involvement at all levels of the program was instrumental in promulgating and overseeing the effort. Decades of NIH-sponsored research on vaccine backbones, immunogen design, and clinical trial operations enabled evaluation of vaccine candidates within months of pathogen discovery. Operation Warp Speed fostered industry participation, permitted accelerated movement from preclinical/early phase to efficacy trials, and developed structured clinical trial testing that allowed independent assessment of, yet reasonable comparison between, each vaccine platform by harmonizing protocols, endpoints, laboratories, and statistical analytical criteria for efficacy. This coordinated effort by the US government, pharmaceutical companies, regulators, and academic research institutions resulted in the streamlined, safe, and transparent development and deployment of multiple COVID-19 vaccines in under a year. Lessons learned from this collaborative endeavor should be used to advance additional vaccines of public health importance.

RevDate: 2022-05-17

Ceppi F, Wilson AL, Annesley C, et al (2022)

Modified manufacturing process modulates CD19CAR T-cell engraftment fitness and leukemia-free survival in pediatric and young adult subjects.

Cancer immunology research pii:698994 [Epub ahead of print].

T cells modified to express a chimeric-antigen receptor (CAR)targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the co-stimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a 2nd generation CD19-specific CAR with 4-1BB costimulation co-expressed with the EGFRt cell surface tag (NCT02028455). Following completion of the phase 1 study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting mid-culture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase 2 arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia, and improved leukemia-free survival with SCRI-CAR19v2 as compared to SCRI-CAR19v1.

RevDate: 2022-05-17

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

Circulating free testosterone and risk of aggressive prostate cancer: prospective and Mendelian randomization analyses in international consortia.

International journal of cancer [Epub ahead of print].

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14,944 cases and 36,752 controls, including 1,870 aggressive prostate cancers). In Mendelian randomization (MR) analyses, using instruments identified using UK Biobank (up to 194,453 men) and outcome data from PRACTICAL (up to 79,148 cases and 61,106 controls, including 15,167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD=1.23, 95% CI=1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI=1.02-1.28; Phet =0.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR:1.20,1.08-1.34; blood-based:1.03,1.01-1.05) and early-onset prostate cancer (MR:1.37,1.09-1.73; blood-based:1.08,0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

RevDate: 2022-05-17

Giovenco D, Pettifor A, Powers KA, et al (2022)

Intimate partner violence and oral HIV pre-exposure prophylaxis adherence among young African women.

AIDS (London, England) pii:00002030-990000000-00015 [Epub ahead of print].

OBJECTIVE: To estimate the effect of intimate partner violence (IPV) on oral PrEP adherence among adolescent girls and young women (AGYW).

DESIGN: We conducted a secondary analysis of data from HIV Prevention Trials Network 082 (HPTN 082), a multisite prospective study designed to assess oral PrEP adherence among AGYW in southern Africa.

METHODS: We estimated the relative prevalence of high PrEP adherence 3 and 6 months after initiation among AGYW 16-25 years who reported a history of any IPV in the past year at enrollment versus AGYW who did not, both overall and by age. High adherence was defined as an intracellular tenofovir-diphosphate concentration at least 700 fmol/punch in dried blood spots.

RESULTS: Among 409 PrEP-initiating AGYW, half (49%) reported experiencing any IPV by a current/recent partner in the year prior to enrollment. Overall, a similar proportion of AGYW who reported IPV had high PrEP adherence at months 3 and 6 as AGYW who did not report IPV. There was, however, evidence of effect modification by age at month 3: among AGYW less than 21 years, those who reported IPV were less than half as likely to have high adherence [adjusted PR (aPR) = 0.43, 95% confidence interval (CI) 0.22-0.86]; among AGYW aged 21 years, those who reported IPV were more than twice as likely to have high adherence (aPR = 2.21, 95% CI 1.34-3.66). At month 6, effect estimates within each age stratum were consistent in direction to those at month 3.

CONCLUSION: IPV events may either impede or motivate PrEP adherence among African AGYW, with age appearing to be an important consideration for IPV-related adherence interventions.

RevDate: 2022-05-16

Johnson KM, Jiao B, Ramsey SD, et al (2022)

Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance.

Blood advances pii:485129 [Epub ahead of print].

Sickle cell disease (SCD) is a severe monogenic disease associated with high morbidity, mortality, and a disproportionate burden on Black and Hispanic communities. Our objective was to estimate the total healthcare costs and total out-of-pocket costs attributable to SCD among commercially insured individuals over their non-elderly lifetimes (0-64 years of age). We constructed a retrospective cohort of individuals with diagnosed SCD using Truven Health Marketscan commercial claims data from 2007-2018, compared with matched controls from the Medical Expenditure Panel Survey. We estimated Kaplan-Meier sample average costs using previously reported survival curves for SCD and controls. 20,891 individuals with SCD and 33,588 controls were included in our analysis. The SCD sample had a mean age of 25.7 (SD 17.4) years; 58.0% were female. Survival-adjusted costs of SCD peaked at age 13-24 years and declined at older ages. There was no significant difference in total medical costs or OOP costs between the sexes. SCD-attributable costs over 0-64 years of age were estimated to be $1.6 million (95%CI: $1.3M, $1.9M) and $1.7 million (95% CI: $1.4M, $2.1M) for females and males with SCD, respectively. The corresponding OOP estimates were $42,395 (95%CI: $34,756, $50,033) for females and $45,091 (95% CI: $36,491, $53,691) for males. These represent a 907% and 285% increase in total medical and OOP costs over controls, respectively. Although limited to the commercially insured population, these results indicate that the direct economic burden of SCD is substantial and peaks at younger ages, suggesting the need for curative and new medical therapies.

RevDate: 2022-05-16

Schwartz SM, Urfer SR, White M, et al (2022)

Lifetime prevalence of malignant and benign tumors in companion dogs: cross-sectional analysis of Dog Aging Project (DAP) baseline survey.

Veterinary and comparative oncology [Epub ahead of print].

Although cancer is widely regarded as a major contributor to canine morbidity and mortality, its frequency in companion dogs has only infrequently been characterized. We analyzed cross-sectional data from the baseline survey of owners of 27,541 living companion dogs enrolled in the Dog Aging Project as of December 31 2020 to estimate the lifetime prevalence of malignant and benign tumors and several potentially-associated characteristics. Survey questions elicited information on history of "cancer or tumors" including organ site and histologic type. Owners reported 819 malignant tumors (56% sited in the skin, muscle, or other soft tissue) and 404 benign tumors (69% sited in the skin, muscle, or other soft tissue). The lifetime prevalence of malignant tumors (29.7/1000 dogs) was approximately double the lifetime prevalence of benign tumors (14.7/1000 dogs). Lifetime prevalence of both malignant and benign tumors increased with dog age at survey completion. There were no statistically discernable differences in age-adjusted lifetime prevalence of malignant (prevalence ratio (PR) = 0.93 [95% confidence interval (CI) 0.82, 1.07] or benign tumors (PR=1.10, 95% CI 0.91, 1.34) in mixed vs. purebred dogs. The lifetime prevalence of malignant tumors increased with increasing dog size class; compared to toy and small dogs, the age-adjusted PRs (95% CIs) for medium, standard, large, and giant dogs were 1.65 (1.28, 2.11), 2.92 (2.35, 3.64), 3.67 (2.92, 4.62) and 2.99 (1.23, 4.02), respectively. Similar though less pronounced patterns in relation to dog size class were observed for benign tumors. Ongoing prospective data collection will permit future studies on risk factors for canine tumor incidence.

RevDate: 2022-05-16

Moralez EA, Boren RL, Lebel DL, et al (2022)

Teaching Strategies During the COVID-19 Pandemic: Tailoring Virtual Learning for Public Health and Cancer Health Disparities Education.

Frontiers in public health, 10:845400.

The COVID-19 pandemic has dramatically impacted higher education institutions in the United States (US). Given the dangers of close social interaction in spreading COVID-19, colleges and universities closed their campuses to minimize and often restrict face-to-face instruction of any kind, including supplemental skill development training and experiential learning. In exchange, higher education institutions implemented online learning strategies to continue education for students, including in-person experiential field experiences. This paper describes the adaptation of an in-person experiential field experience into an eight-day virtual workshop as a result of COVID-19 restrictions along with results from participant surveys evaluating pre-and post-test changes in knowledge and their overall assessment of the virtual workshop. This workshop, the Public Health and Cancer Research Workshop (PHCRW), was tailored for students from health-related graduate programs with the primary goal of introducing students to the causes and impacts of cancer disparities in the US/Mexico border region and research related to mitigating those disparities. The course facilitators added a professional development curriculum necessary for student success and the pursuit of advanced degrees such as academic/job interviewing skills and scientific and grant writing. The objectives were for students to (1) understand introductory and intermediate curriculum on public health, cancer, and cancer research; (2) examine the interrelationships among factors impacting public health problems; (3) describe the components of the research process; (4) describe various components of scientific writing; and (5) demonstrate professional strategies associated with school admission and employment. Students completed pre-and post- self-assessments that indicated gains in knowledge about cancer topics, particularly cancer prevention strategies (M pre = 3.43; M post = 4.43), social determinants associated with cancer (M pre = 3.29; M post = 4.43), and cancer rates by characteristics (M pre = 3.43; M post = 4.43). Additionally, students overwhelmingly stated that they appreciated the opportunity to supplement their educational experience in a virtual format. Though the virtual format proved challenging in some respects, students expressed high satisfaction with the workshop. In addition to achieving the goals, the workshop successfully increased students' skills, knowledge, and self-confidence. Despite the last-minute adaptation of the PHCRW, students' satisfaction indicated that this program was an overall success.

RevDate: 2022-05-16

Muwonge H, Kasujja H, Niyonzima N, et al (2022)

Unique circulating microRNA profiles in epidemic Kaposi's sarcoma.

Non-coding RNA research, 7(2):114-122 pii:S2468-0540(22)00007-5.

Background: Human herpesvirus 8 (HHV-8) causes Kaposi's sarcoma (KS). Kaposi sarcoma in HIV/AIDS patients is referred to as epidemic KS and is the most common HIV-related malignancy worldwide. The lack of a diagnostic assay to detect latent and early-stage disease has increased disease morbidity and mortality. Serum miRNAs have previously been used as potential biomarkers of normal physiology and disease. In the current study, we profiled unique serum miRNAs in patients with epidemic KS to generate baseline data to aid in developing a miRNA-based noninvasive biomarker assay for epidemic KS.

Methods: This was a comparative cross-sectional study involving 27 patients with epidemic KS and 27 HIV-positive adults with no prior diagnosis or clinical manifestation of KS. DNA and RNA were isolated from blood and serum collected from study participants. Nested PCR for circulating HHV-8 DNA was performed on the isolated DNA, whereas miRNA library preparation and sequencing for circulating miRNA were performed on the RNA samples. The miRge2 pipeline and EdgeR were used to analyse the sequencing data.

Results: Fifteen out of the 27 epidemic KS-positive subjects (55.6%) tested positive for HHV-8 DNA, whereas only 3 (11.1%) out of the 27 HIV-positive, KS-negative subjects tested positive for HHV-8 DNA. Additionally, we found a unique miRNA expression signature in 49 circulating miRNAs in epidemic KS subjects compared to subjects with no epidemic KS, with 41 miRNAs upregulated and 8 miRNAs downregulated. Subjects with latent KS infection had a differential upregulation of circulating miR-193a compared to HIV-positive, KS-negative subjects for whom circulating HHV-8 DNA was not detected. Further analysis of serum from epidemic KS patients revealed a miRNA signature according to KS tumor status and time since first HIV diagnosis.

Conclusions: This study reveals unique circulating miRNA profiles in the serum of patients with epidemic KS versus HIV-infected subjects with no KS, as well as in subjects with latent KS. Many of the dysregulated miRNAs in epidemic KS patients were previously reported to have crucial roles in KS infection and latency, highlighting their promising roles as potential biomarkers of latent or active KS infection.

RevDate: 2022-05-15

Phung Q, Lin MJ, Xie H, et al (2022)

Fragment Size-Based Enrichment of Viral Sequences in Plasma Cell-Free DNA.

The Journal of molecular diagnostics : JMD, 24(5):476-484.

Sequencing of plasma cell-free DNA (cfDNA) is a promising milieu for broad-based cancer and infectious disease diagnostics. The performance of cfDNA sequencing for infectious disease diagnostics is chiefly limited by inadequate analytical sensitivity. The current study investigated whether the analytical sensitivity of cfDNA sequencing for viral diagnostics could be improved by selective sequencing of short cfDNA fragments, given prior observations of shorter fragment size distribution in microbial and cytomegalovirus-derived cfDNA compared with human-derived cfDNA. It shows that the shorter plasma cfDNA fragment size distribution is a general feature of multiple DNA viruses, including adenovirus [interquartile range (IQR), 87 to 165 bp], herpes simplex virus 2 (IQR, 114 to 195 bp), human herpesvirus 6 (IQR, 145 to 176 bp), and varicella zoster virus (IQR, 98 to 182 bp), compared with human (IQR, 148 to 178 bp). It was used to further optimize a size selection-based cfDNA sequencing method, demonstrating an enrichment of viral sequences up to 16.6-fold, with a median fold enrichment of 6.7×, 4.6×, 2.2×, and 10.3× for adenovirus, herpes simplex virus 2, human herpesvirus 6, and varicella zoster virus, respectively. These findings demonstrate a simple yet scalable method for enhanced detection of DNA viremia that maintains the unbiased nature of cfDNA sequencing.

RevDate: 2022-05-13

Kim J, Li C, Wang H, et al (2022)

Translational development of a tumor junction opening technology.

Scientific reports, 12(1):7753.

Our goal is to overcome treatment resistance in ovarian cancer patients which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2) positive tight junctions between malignant cells that prevents drug penetration into the tumor. We have generated JO4, a recombinant protein that binds to DSG2 resulting in the transient opening of junctions in epithelial tumors. Here we present studies toward the clinical translation of c-JO4 in combination with PEGylated liposomal doxorubicin/Doxil for ovarian cancer therapy. A manufacturing process for cGMP compliant production of JO4 was developed resulting in c-JO4. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous c-JO4 plus Doxil (four cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against c-JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL-6 and TNFα. Pretreatment with steroids and cyclophosphamide reduced anti-c-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.

RevDate: 2022-05-13

Janet Ho J, Jones KF, Sager Z, et al (2022)

Barriers to Buprenorphine Prescribing for Opioid Use Disorder in Hospice and Palliative Care.

Journal of pain and symptom management pii:S0885-3924(22)00706-0 [Epub ahead of print].

CONTEXT: Hospice and palliative care (HPC) clinicians increasingly care for patients with concurrent painful serious illness and opioid use disorder (OUD) or opioid misuse; however, only a minority of HPC clinicians have an X-waiver license or actively use it to prescribe buprenorphine as medication treatment for OUD.

OBJECTIVES: To understand barriers for HPC clinicians to obtaining an X-waiver and prescribing buprenorphine as medication treatment for OUD.

METHODS: We performed content analysis on 100 survey responses from members of the national Buprenorphine Peer Support Network, a group of HPC clinicians interested in buprenorphine, on X-waiver status, barriers to obtaining an X-waiver, and barriers to active prescribing.

RESULTS: Of 100 HPC clinicians surveyed, only 26 of 57 HPC clinicians with X-waivers had ever prescribed. Prominent barriers included discomfort managing concurrent pain, buprenorphine, and OUD; concerns about impacts on practice; unsupportive practice culture; insufficient practice support; patient facing challenges; and regulatory policies.

CONCLUSIONS: Despite HPC clinicians' interest in buprenorphine prescribing for OUD, several steps are needed to facilitate the practice, including clinician education tailored to pain and to clinical challenges faced by HPC clinicians, mentorship on buprenorphine use, and cultural and practice changes to dismantle systemic stigma towards addiction. We propose evidence-based steps derived from our survey findings that individual clinicians, HPC leaders, and national HPC organizations can take to improve care for patients with painful serious illness and OUD.

RevDate: 2022-05-13

Yilmaz S, Grudzen CR, Durham DD, et al (2022)

Palliative Care Needs and Clinical Outcomes of Patients with Advanced Cancer in the Emergency Department.

Journal of palliative medicine [Epub ahead of print].

Background: Older adults with cancer use the emergency department (ED) for acute concerns. Objectives: Characterize the palliative care needs and clinical outcomes of advanced cancer patients in the ED. Design: A planned secondary data analysis of the Comprehensive Oncologic Emergencies Research Network (CONCERN) data. Settings/Subjects: Cancer patients who presented to the 18 CONCERN affiliated EDs in the United States. Measurements: Survey included demographics, cancer type, functional status, symptom burden, palliative and hospice care enrollment, and advance directive code status. Results: Of the total (674/1075, 62.3%) patients had advanced cancer and most were White (78.6%) and female (50.3%); median age was 64 (interquartile range 54-71) years. A small proportion of them were receiving palliative (6.5% [95% confidence interval; CI 3.0-7.6]; p = 0.005) and hospice (1.3% [95% CI 1.0-3.2]; p = 0.52) care and had a higher 30-day mortality rate (8.3%, [95% CI 6.2-10.4]). Conclusions: Patients with advanced cancer continue to present to the ED despite recommendations for early delivery of palliative care.

RevDate: 2022-05-13

Lindsay J, Othman J, Kong Y, et al (2021)

SUBA-Itraconazole for Primary Antifungal Prophylaxis After Allogeneic Hematopoietic Cell Transplantation.

Open forum infectious diseases, 8(11):ofab502 pii:ofab502.

Background: Itraconazole (ITZ) is an effective agent when used as primary invasive fungal disease (IFD) prophylaxis, but is limited by drug tolerability and variability in serum concentrations. A new formulation, SUBA-itraconazole (for "super bioavailability"; S-ITZ), addresses the limitations of conventional ITZ formulations.

Methods: We conducted a retrospective cohort study at 2 Australian centers to evaluate the safety, tolerability, and effectiveness of S-ITZ as primary antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients without grade II-IV acute graft-vs-host disease, from day 1 until approximately day 100 (cohort A) or day 1 until neutrophil engraftment (cohort B). A total of 204 patients and 1410 trough plasma ITZ concentrations were assessed.

Results: The incidence of breakthrough proven/probable IFD at day 180 was 1.0% (95% confidence interval [CI], .2%-3.2%), with 1.6% in cohort A and 0% in cohort B, and overall fungal-free survival of proven/probable IFD was 82.9% (95% CI, 76.8%-87.4%). Preengraftment early permanent S-ITZ discontinuation was 3.4% overall, with no significant difference between cohorts. No patients required cessation due to gastrointestinal intolerance attributed to S-ITZ. The geometric mean trough plasma ITZ concentration was 1130ng/mL (interquartile range, 566-1801ng/mL; coefficient of variation, 56.57%) and the median time to achieve therapeutic levels was 10 days.

Conclusions: S-ITZ is a safe and well-tolerated oral formulation and is a novel alternative for primary IFD prophylaxis after HCT.

RevDate: 2022-05-13

Himbert C, Hathaway CA, Daniels B, et al (2022)

Factors associated with changes in exercise behaviors during the COVID-19 pandemic.

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

PURPOSE: There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified characteristics associated with these changes among cancer patients.

METHODS: Cancer patients (n = 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups.

RESULTS: One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all p < 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all p < 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all p < 0.05), although rural-urban status was not identified as a strong predictor.

CONCLUSION: A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.

RevDate: 2022-05-13

Schwartz NRM, Afeiche MC, Terry KL, et al (2022)

Glycemic Index, Glycemic Load, Fiber, and Gluten Intake and Risk of Laparoscopically-Confirmed Endometriosis in Premenopausal Women.

The Journal of nutrition pii:6584846 [Epub ahead of print].

BACKGROUND: The etiology of endometriosis is not well understood. Limited evidence suggests that dietary factors influence risk, but prospective data related to carbohydrate, fiber, and gluten consumption are scarce. Despite this, recommendations concerning fiber, gluten intake and endometriosis are pervasive in the lay literature.

OBJECTIVE: To investigate the association between carbohydrate quality (glycemic index [GI] and glycemic load [GL]), fiber intake (total, legume, vegetable, cruciferous vegetable, fruit, cereal), and gluten intake and incident laparoscopically-confirmed endometriosis.

METHODS: A prospective cohort study using data collected from 81,961 premenopausal women in the Nurses' Health Study II (mean age = 36 in 1991). Diet was assessed with a validated food frequency questionnaire every four years. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% confidence intervals (CI).

RESULTS: 3,810 incident cases of laparoscopically-confirmed endometriosis were reported over 24 years of follow-up. Women in the highest quintile of GI had 12% (95% CI = 1.01-1.23, ptrend = 0.03) higher risk of endometriosis diagnosis than those in the lowest quintile. Total vegetable and cruciferous vegetable fiber intake were also associated with higher risk (highest vs lowest quintile RR = 1.13, 95% CI = 1.02-1.24, ptrend = 0.004; RR = 1.17, 95% CI = 1.06-1.29, ptrend = 0.02; respectively). Higher intake of fruit fiber was associated with lower risk of endometriosis but the association was not significant after adjusting for AHEI. Gluten intake was also associated with lower risk (highest vs lowest quintile = 0.91, 95% CI = 0.80-1.02, ptrend = 0.01), but these results were not consistent in direction nor statistical significance across sensitivity analyses. No association was observed for GL, total, legume, or cereal fiber intake.

CONCLUSIONS: Our findings suggest that carbohydrate quality and specific types of fiber - total vegetable and cruciferous vegetable fiber - are associated with endometriosis diagnosis in premenopausal women. These results also indicate it is unlikely that gluten intake is a strong factor in the etiology or symptomatology of endometriosis.

RevDate: 2022-05-13

Gao G, Zhao F, Ahearn TU, et al (2022)

Polygenic Risk Scores for Prediction of Breast Cancer Risk in Women of African Ancestry: a Cross-Ancestry Approach.

Human molecular genetics pii:6584730 [Epub ahead of print].

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined 1) the PRSs built in the AA training dataset, and 2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odd ratio (OR) per standard deviation of the joint PRS in the validation set was 1.34 (95% CI: 1.27-1.42) with area under receiver operating characteristic curve (AUC) of 0.581. Compared to women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared to existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

RevDate: 2022-05-13

Li DY, VoPham T, Tang MC, et al (2022)

Disparities in risk of advanced stage liver cancer and mortality by race and ethnicity.

Journal of the National Cancer Institute pii:6584827 [Epub ahead of print].

BACKGROUND: In the United States liver cancer is the 5th and 7th most common cause of cancer related-death among men and women, respectively. Compared to other racial/ethnic groups in the U.S. Asian and Pacific Islander populations experience the highest incidence rates of liver cancer, but little is known about disparities in risk of advanced stage disease or risk of liver cancer mortality across these heterogenous populations. All statistical tests were 2-sided.

METHODS: In a population-based cohort of 60,146 patients 20-79 years of age diagnosed with liver cancer from 2004-2018 identified through the Surveillance, Epidemiology and End Results Program, we examined associations between race/ethnicity, including specific Asian and Pacific Islander subgroups, and risk of advanced stage liver cancer and liver cancer-specific mortality.

RESULTS: Compared to non-Hispanic White patients, non-Hispanic Black, Filipino, and Laotian patients had 30%-85% elevated odds of being diagnosed with stage IV liver cancer, while Hispanic, Vietnamese, and Chinese patients had 7-33% lower odds of being diagnosed with stage IV liver cancer (all p-values <0.05). Additionally, non-Hispanic Black, Kampuchean, and Laotian patients had 6-22% elevated hazards of liver cancer-specific mortality, and Hispanic, Vietnamese, Chinese, and Korean patients had 3-27% lower hazards of liver cancer-specific mortality (all p-values <0.05).

CONCLUSIONS: Substantial variations in risk of advanced stage liver cancer and in risk of liver cancer mortality were observed by race and ethnicity including considerable heterogeneity across individuals broadly defined as Asians and Pacific Islanders. Further efforts to understand the contributors to these disparities are needed in order to inform potential targeted screening and treatment interventions.

RevDate: 2022-05-13

Pankratz N, Wei P, Brody JA, et al (2022)

Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.

Human molecular genetics pii:6584722 [Epub ahead of print].

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

RevDate: 2022-05-13

Coleman IM, DeSarkar N, Morrissey C, et al (2022)

Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:698880 [Epub ahead of print].

PURPOSE: To determine if metastatic castration resistant prostate cancers (mCRPCs) partition into molecular phenotypes corresponding to intrinsic differentiation states and ascertain whether these subtypes exhibit specific druggable features and associate with treatment outcomes.

EXPERIMENTAL DESIGN: We used RNAseq, digital spatial profiling, and histological assessments from metastatic biopsies and patient derived xenografts to segregate mCRPCs into subtypes defined by the PAM50 breast cancer classification algorithm. Subtype associations with treatment responses in preclinical models and patients were determined.

RESULTS: Using the PAM50 algorithm we partitioned 270 mCRPC tumors into LumA (42%), LumB (24%) and Basal (34%) subtypes with classification largely driven by proliferation rates and androgen receptor (AR) activity. Most neuroendocrine tumors classified as Basal. Pathways enriched in the LumA subtype include TGFß and NOTCH signaling. LumB subtype tumors were notable for elevated MYC activity. Basal subtype tumors exhibited elevated IL6-STAT3 signaling and features of adult stem cell states. In patients where multiple tumors were evaluated, the majority had concordant PAM50 subtype determination, though a subset exhibited marked inter- and intra-tumor heterogeneity including divergent classifications between primary and metastatic sites. In preclinical models, LumA subtype tumors were responsive to androgen deprivation and docetaxel chemotherapy whereas Basal tumors were largely resistant. In clinical cohorts patients with Basal tumors demonstrated a shorter time on treatment with AR signaling inhibitors and docetaxel relative to patients with luminal subtypes.

CONCLUSIONS: Subtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.

RevDate: 2022-05-13

Lacson JCA, Forgas SM, Doyle SH, et al (2022)

Assessment of melanoma precision prevention materials incorporating MC1R genetic risk information.

Translational behavioral medicine pii:6584951 [Epub ahead of print].

Few studies have examined cognitive responses to mailed precision prevention materials. MC1R is a robust, well-described melanoma susceptibility marker. The purpose was to assess cognitive responses to generic or precision prevention materials incorporating MC1R genetic risk. Non-Hispanic White participants (n = 1134) enrolled in a randomized controlled trial received either precision prevention materials incorporating MC1R genetic risk (higher/average) or generic prevention (standard) materials. Six months after baseline, 808 (71.3%) participants reported on the amount of prevention materials read (5-point scale); believability and clarity of materials; intention to change preventive behaviors (7-point Likert scale); and recall of their MC1R genetic risk. Comparisons were conducted using Kruskal-Wallis and chi-squared tests. Overall, participants read most to all (Mdn = 4, IQR = 2) of the prevention materials, reported high believability (Mdn = 7, IQR = 1) and clarity (Mdn = 7, IQR = 1), and moderate intention to change preventive behaviors (Mdn = 5, IQR = 2). Higher-risk participants reported slightly less clarity (Mdn = 6, IQR = 2) than either average-risk (Mdn = 6, IQR = 1, p = 2.50 × 10-3) or standard participants (Mdn = 7, IQR = 1, p = 2.30 × 10-5); and slightly less believability (Mdn = 6, IQR = 1) than standard participants (Mdn = 7, IQR = 1, p = .005). Higher-risk participants were 2.21 times as likely (95% CI = 1.43-3.43) to misremember or forget their risk compared to average-risk participants; misremembering was observed only among higher-risk participants (14%). Mailed precision prevention information were mostly read, highly believable and clear, and resulted in moderate levels of intention to change sun protection behaviors, bolstering the feasibility of population-level precision prevention. Defensive reactions may explain lower clarity, believability, and higher incorrect risk recall among higher-risk participants.

RevDate: 2022-05-13

DeLucia DC, JK Lee (2022)

Development of Cancer Immunotherapies.

Cancer treatment and research, 183:1-48.

Cancer immunotherapy, or the utilization of components of the immune system to target and eliminate cancer, has become a highly active area of research in the past several decades and a common treatment strategy for several cancer types. The concept of harnessing the immune system for this purpose originated over 100 years ago when a physician by the name of William Coley successfully treated several of his cancer patients with a combination of live and attenuated bacteria, later known as "Coley's Toxins", after observing a subset of prior patients enter remission following their diagnosis with the common bacterial infection, erysipelas. However, it was not until late in the twentieth century that cancer immunotherapies were developed for widespread use, thereby transforming the treatment landscape of numerous cancer types. Pivotal studies elucidating molecular and cellular functions of immune cells, such as the discovery of IL-2 and production of monoclonal antibodies, fostered the development of novel techniques for studying the immune system and ultimately the development and approval of several cancer immunotherapies by the United States Food and Drug Association in the 1980s and 1990s, including the tuberculosis vaccine-Bacillus Calmette-Guérin, IL-2, and the CD20-targeting monoclonal antibody. Approval of the first therapeutic cancer vaccine, Sipuleucel-T, for the treatment of metastatic castration-resistant prostate cancer and the groundbreaking success and approval of immune checkpoint inhibitors and chimeric antigen receptor T cell therapy in the last decade, have driven an explosion of interest in and pursuit of novel cancer immunotherapy strategies. A broad range of modalities ranging from antibodies to adoptive T cell therapies is under investigation for the generalized treatment of a broad spectrum of cancers as well as personalized medicine. This chapter will focus on the recent advances, current strategies, and future outlook of immunotherapy development for the treatment of cancer.

RevDate: 2022-05-13

Mahajan A, Spracklen CN, Zhang W, et al (2022)

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.

Nature genetics [Epub ahead of print].

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

RevDate: 2022-05-13

Julg B, Stephenson KE, Wagh K, et al (2022)

Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.

Nature medicine [Epub ahead of print].

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

RevDate: 2022-05-13

Greenbaum AM, Fromm JR, Gopal AK, et al (2022)

Diffuse large B-cell lymphoma (DLBCL) is infiltrated with activated CD8+ T-cells despite immune checkpoint signaling.

Blood research pii:br.2022.2021145 [Epub ahead of print].

Background: B-cell non-Hodgkin lymphomas (NHL) are hematologic malignancies that arise in the lymph node. Despite this, the malignant cells are not cleared by the immune cells present. The failure of anti-tumor immunity may be due to immune checkpoints such as the PD-1/PDL-1 axis, which can cause T-cell exhaustion. Unfortunately, unlike Hodgkin lymphoma, checkpoint blockade in NHL has shown limited efficacy.

Methods: We performed an extensive functional analysis of malignant and non-malignant lymph nodes using high dimensional flow cytometry. We compared follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and lymph nodes harboring reactive hyperplasia (RH).

Results: We identified an expansion of CD8+PD1+ T-cells in the lymphomas relative to RH. Moreover, we demonstrate that these cells represent a mixture of activated and exhausted T-cells in FL. In contrast, these cells are nearly universally activated and functional in DLBCL. This is despite expression of counter-regulatory molecules such as PD-1, TIM-3, and CTLA-4, and the presence of regulatory T-cells.

Conclusions: These data may explain the failure of single-agent immune checkpoint inhibitors in the treatment of DLBCL. Accordingly, functional differences of CD8+ T-cells between FL and DLBCL may inform future therapeutic targeting strategies.

RevDate: 2022-05-13

Balle C, Armistead B, Kiravu A, et al (2022)

Factors influencing maternal microchimerism throughout infancy and its impact on infant T cell immunity.

The Journal of clinical investigation pii:148826 [Epub ahead of print].

Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day one and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4+ T cell responses. MMc was present in most infants across infancy with levels ranging from 0-1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal-infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc levels in HIV exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence MMc, which may subsequently impact infant T cell responses.

RevDate: 2022-05-13

Ngwa W, Addai BW, Adewole I, et al (2022)

Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

The Lancet. Oncology pii:S1470-2045(21)00720-8 [Epub ahead of print].

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

RevDate: 2022-05-13

Munoz FM, Beigi RH, Posavad CM, et al (2022)

Multi-site observational maternal and infant COVID-19 vaccine study (MOMI-vax): a study protocol.

BMC pregnancy and childbirth, 22(1):402.

BACKGROUND: Pregnant women were excluded from investigational trials of COVID-19 vaccines. Limited data are available to inform pregnant and postpartum women on their decisions to receive a COVID-19 vaccine.

METHODS: The goal of this observational, prospective cohort study is to evaluate the immunogenicity and safety of various Emergency Use Authorization (EUA) or licensed COVID-19 vaccines administered to pregnant or lactating women and describe the transplacental antibody transfer and kinetics of antibodies in mothers and infants. The study is adaptive, allowing additional groups to be added as new vaccines or vaccine regimens are authorized. Up to 20 clinical research institutions in the United States (U.S.) will be included. Approximately 200 pregnant women and 65 postpartum women will be enrolled per EUA or licensed COVID-19 vaccine formulation in the U.S. This study will include pregnant and postpartum women of all ages with and without chronic medical conditions. Their infants will be enrolled and followed beginning at birth in the pregnant cohort and beginning at the earliest possible time point in the postpartum cohort. Blood samples will be collected for immunogenicity outcomes and pregnancy and birth outcomes assessed among women and infants. Primary analyses will be descriptive and done by vaccine type and/or platform.

DISCUSSION: Given the long-standing and legitimate challenges of enrolling pregnant individuals into clinical trials early in the vaccine development pipeline, this study protocol describes our current study and provides a template to inform the collection of data for pregnant individuals receiving COVID-19 or other vaccines.

TRIAL REGISTRATION: NCT05031468 .

RevDate: 2022-05-13

Ruggeri A, De Wreede LC, Müller CR, et al (2022)

Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation.

Haematologica [Epub ahead of print].

Not available.

RevDate: 2022-05-11

Sasani TA, Ashbrook DG, Beichman AC, et al (2022)

A natural mutator allele shapes mutation spectrum variation in mice.

Nature [Epub ahead of print].

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature1. Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes2. We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load3,4. Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.

RevDate: 2022-05-11

Mair F, Erickson JR, Frutoso M, et al (2022)

Extricating human tumour immune alterations from tissue inflammation.

Nature [Epub ahead of print].

Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain1,2. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment3,4. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (Treg) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1+ Treg cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1- Treg cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.

RevDate: 2022-05-13

Bellmunt J, de Wit R, Fradet Y, et al (2022)

Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials.

Clinical cancer research : an official journal of the American Association for Cancer Research, 28(10):2050-2060.

PURPOSE: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).

PATIENTS AND METHODS: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05.

RESULTS: In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment.

CONCLUSIONS: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.

RevDate: 2022-05-11

In GK, Nallagangula A, Choi JS, et al (2022)

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma.

Journal for immunotherapy of cancer, 10(5):.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment.

METHODS: We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0.

RESULTS: A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate.

CONCLUSIONS: The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.

RevDate: 2022-05-11

Massanella M, Bender Ignacio RA, Lama JR, et al (2021)

Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study.

The Lancet. Microbe, 2(5):e198-e209.

BACKGROUND: Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear.

METHODS: In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups.

FINDINGS: We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group.

INTERPRETATION: Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance.

FUNDING: The US National Institutes of Health and the Canadian Institutes for Health Research.

RevDate: 2022-05-10

Moser R, Gurley KE, Nikolova O, et al (2022)

Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma.

Oncogene [Epub ahead of print].

The oncogene Ras and the tumor suppressor gene p53 are frequently co-mutated in human cancer and mutations in Ras and p53 can cooperate to generate a more malignant cell state. To discover novel druggable targets for cancers carrying co-mutations in Ras and p53, we performed arrayed, kinome focused siRNA and oncology drug phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines that also carried co-mutations in selected p53 pathway genes. These cell lines were derived from SCCs from carcinogen-treated inbred mice which harbored germline deletions or mutations in Trp53, p19Arf, Atm, or Prkdc. Both siRNA and drug phenotypic screening converge to implicate the phosphoinositol kinases, receptor tyrosine kinases, MAP kinases, as well as cell cycle and DNA damage response genes as targetable dependencies in SCC. Differences in functional kinome profiles between Ras mutant cell lines reflect incomplete penetrance of Ras synthetic lethal kinases and indicate that co-mutations cause a rewiring of survival pathways in Ras mutant tumors. This study describes the functional kinomic landscape of Ras/p53 mutant chemically-induced squamous cell carcinoma in both the baseline unperturbed state and following DNA damage and nominates candidate therapeutic targets, including the Nek4 kinase, for further development.

RevDate: 2022-05-09

Warr AJ, Anterasian C, Shah JA, et al (2022)

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.

EBioMedicine, 80:104023 pii:S2352-3964(22)00207-9 [Epub ahead of print].

BACKGROUND: The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration.

METHODS: HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants.

FINDINGS: A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy.

INTERPRETATION: Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise.

FUNDING: Thrasher Research Fund.

RevDate: 2022-05-09

Schraw JM, Bailey HD, Bonaventure A, et al (2022)

Infant Feeding Practices And Childhood Acute Leukemia: Findings From The Childhood Cancer & Leukemia International Consortium.

International journal of cancer [Epub ahead of print].

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data meta-analyses of data from sixteen studies (N=17,189 controls; N=10,782 ALL and N=1,690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4-6 months (0.88, 95% CI 0.81-0.96) or 7-12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4-6 months (OR 0.73, 95% CI 0.63-0.85) or 7-12 months (OR 0.70, 95% CI 0.53-0.92). Random effects meta-analyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age, or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

RevDate: 2022-05-09

Raiders S, Klein M, A Singhvi (2022)

Multiplexing Thermotaxis Behavior Measurement in Caenorhabditis elegans.

Bio-protocol, 12(7):e4370 pii:4370.

Thermotaxis behaviors in C. elegans exhibit experience-dependent plasticity of thermal preference memory. This behavior can be assayed either at population level, on linear temperature gradients, or at the individual animal level, by radial isothermal or microfluidic tracking of orientation. These behaviors are low-throughput as well as variable, due to the inherent sensitivity to environmental perturbations. To facilitate reproducible studies, we describe an updated apparatus design that enables simultaneous runs of three thermal preference assays, instead of single-run assays described previously. By enabling parallel runs of control and experimental conditions, this set-up enables more throughput and rigorous assessment of behavioral variability.

RevDate: 2022-05-09

Liu J, Wang H, Sun W, et al (2022)

Prioritizing Autism Risk Genes using Personalized Graphical Models Estimated from Single Cell RNA-seq Data.

Journal of the American Statistical Association, 117(537):38-51.

Hundreds of autism risk genes have been reported recently, mainly based on genetic studies where these risk genes have more de novo mutations in autism subjects than healthy controls. However, as a complex disease, autism is likely associated with more risk genes and many of them may not be identifiable through de novo mutations. We hypothesize that more autism risk genes can be identified through their connections with known autism risk genes in personalized gene-gene interaction graphs. We estimate such personalized graphs using single cell RNA sequencing (scRNA-seq) while appropriately modeling the cell dependence and possible zero-inflation in the scRNA-seq data. The sample size, which is the number of cells per individual, ranges from 891 to 1,241 in our case study using scRNA-seq data in autism subjects and controls. We consider 1,500 genes in our analysis. Since the number of genes is larger or comparable to the sample size, we perform penalized estimation. We score each gene's relevance by applying a simple graph kernel smoothing method to each personalized graph. The molecular functions of the top-scored genes are related to autism diseases. For example, a candidate gene RYR2 that encodes protein ryanodine receptor 2 is involved in neurotransmission, a process that is impaired in ASD patients. While our method provides a systemic and unbiased approach to prioritize autism risk genes, the relevance of these genes needs to be further validated in functional studies.

RevDate: 2022-05-09

Shin MB, Garcia PJ, Saldarriaga EM, et al (2022)

Cost of community-based human papillomavirus self-sampling in Peru: A micro-costing study.

Lancet Regional Health. Americas, 8:.

Background: Cost data of human papillomavirus (HPV) self-sampling programs from low-and-middle-income countries is limited. We estimated the total and unit costs associated with the Hope Project, a community-based HPV self-sampling social entrepreneurship in Peru.

Methods: We conducted a micro-costing analysis from the program perspective to determine the unit costs of (1) recruitment/training of community women (Hope Ladies); (2) Hope Ladies distributing HPV self-sampling kits in their communities and the laboratory testing; and (3) Hope Ladies linking screened women with follow-up care. A procedural manual was used to identify the program's activities. A structured questionnaire and in-depth interviews were conducted with administrators to estimate the resource/time associated with activities. We obtained unit costs for each input previously identified from budgets and expenditure reports.

Findings: From November 2018 to March 2020, the program recruited and trained 62 Hope Ladies who distributed 4,882 HPV self-sampling kits in their communities. Of the screened women, 586 (12%) tested HPV positive. The annual cost per Hope Lady recruited/trained was $147·51 (2018 USD). The cost per HPV self-sampling kit distributed/tested was $45·39, the cost per woman followed up with results was $55·64, and the cost per HPV-positive woman identified was $378·14. Personnel and laboratory costs represented 56·1% and 24·7% of the total programmatic cost, respectively.

Interpretation: Our findings indicate that implementation of a community-based HPV self-sampling has competitive prices, which increases its likelihood to be feasible in Peru. Further economic evaluation is needed to quantify the incremental benefits of HPV self-sampling compared to more established options such as Pap tests.

Funding: Thomas Francis Jr. Fellowship provided funding for data collection. The Hope Project was funded by grants from Grand Challenges Canada (TTS-1812-21131), Uniting for Health Innovation, Global Initiative Against HPV and Cervical Cancer, University of Manitoba, and the John E. Fogarty International Center (5D43TW009375-05).

RevDate: 2022-05-08

van der Laan L, Zhang W, PB Gilbert (2022)

Nonparametric estimation of the causal effect of a stochastic threshold-based intervention.

Biometrics [Epub ahead of print].

Identifying a biomarker or treatment-dose threshold that marks a specified level of risk is an important problem, especially in clinical trials. In view of this goal, we consider a covariate-adjusted threshold-based interventional estimand, which happens to equal the binary treatment-specific mean estimand from the causal inference literature obtained by dichotomizing the continuous biomarker or treatment as above or below a threshold. The unadjusted version of this estimand was considered in Donovan et al. (2019). Expanding upon Stitelmen et al. (2010), we show that this estimand, under conditions, identifies the expected outcome of a stochastic intervention that sets the treatment dose of all participants above the threshold. We propose a novel nonparametric efficient estimator for the covariate-adjusted threshold-response function for the case of informative outcome missingness, which utilizes machine learning and Targeted Minimum-Loss Estimation (TMLE). We prove the estimator is efficient and characterize its asymptotic distribution and robustness properties. Construction of simultaneous 95% confidence bands for the threshold-specific estimand across a set of thresholds is discussed. In the supplementary information, we discuss how to adjust our estimator when the biomarker is missing-at-random, as occurs in clinical trials with biased sampling designs, using inverse-probability-weighting. Efficiency and bias-reduction of the proposed estimator are assessed in simulations. The methods are employed to estimate neutralizing antibody thresholds for virologically confirmed dengue risk in the CYD14 and CYD15 dengue vaccine trials. This article is protected by copyright. All rights reserved.

RevDate: 2022-05-06

Brahma S, S Henikoff (2022)

CUT&RUN Profiling of the Budding Yeast Epigenome.

Methods in molecular biology (Clifton, N.J.), 2477:129-147.

Mapping the epigenome is key to describe the relationship between chromatin landscapes and the control of DNA-based cellular processes such as transcription. Cleavage under targets and release using nuclease (CUT&RUN) is an in situ chromatin profiling strategy in which controlled cleavage by antibody-targeted Micrococcal Nuclease solubilizes specific protein-DNA complexes for paired-end DNA sequencing. When applied to budding yeast, CUT&RUN profiling yields precise genome-wide maps of histone modifications, histone variants, transcription factors, and ATP-dependent chromatin remodelers, while avoiding cross-linking and solubilization issues associated with the most commonly used chromatin profiling technique Chromatin Immunoprecipitation (ChIP). Furthermore, targeted chromatin complexes cleanly released by CUT&RUN can be used as input for a subsequent native immunoprecipitation step (CUT&RUN.ChIP) to simultaneously map two epitopes in single molecules genome-wide. The intrinsically low background and high resolution of CUT&RUN and CUT&RUN.ChIP allows for identification of transient genomic features such as dynamic nucleosome-remodeling intermediates. Starting from cells, one can perform CUT&RUN or CUT&RUN.ChIP and obtain purified DNA for sequencing library preparation in 2 days.

RevDate: 2022-05-06

Otegbeye F (2022)

Bench at Bedside Models Facilitate CAR-T Cell Supply Chain.

Transplantation and cellular therapy, 28(5):221-222.

RevDate: 2022-05-05

Sofi MH, Tian L, Schutt S, et al (2022)

Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway.

Leukemia [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for various hematologic malignancies, predominantly through potent graft-versus-leukemia (GVL) effect. However, the mortality after allo-HCT is because of relapse of primary malignancy and followed by graft-vs-host-disease (GVHD) as a major cause of transplant-related mortality. Hence, strategies to limit GVHD while preserving the GVL effect are highly desirable. Ceramide, which serves a central role in sphingolipid metabolism, is generated by ceramide synthases (CerS1-6). In this study, we found that genetic or pharmacologic targeting of CerS6 prevented and reversed chronic GVHD (cGVHD). Furthermore, specific inhibition of CerS6 with ST1072 significantly ameliorated acute GVHD (aGVHD) while preserving the GVL effect, which differed from FTY720 that attenuated aGVHD but impaired GVL activity. At the cellular level, blockade of CerS6 restrained donor T cells from migrating into GVHD target organs and preferentially reduced activation of donor CD4 T cells. At the molecular level, CerS6 was required for optimal TCR signaling, CD3/PKCθ co-localization, and subsequent N-RAS activation and ERK signaling, especially on CD4+ T cells. The current study provides rationale and means for targeting CerS6 to control GVHD and leukemia relapse, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.

RevDate: 2022-05-05

Carlson JA, Sallis JF, Jankowska MM, et al (2022)

Neighborhood built environments and Hispanic/Latino adults' physical activity in the U.S.: The Hispanic community health study/study of Latinos community and surrounding areas study.

Preventive medicine pii:S0091-7435(22)00121-9 [Epub ahead of print].

Despite experiencing health inequities, less is known about neighborhood environments and physical activity among Hispanic/Latino adults compared to other populations. We investigated this topic in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanic/Latino adults in the San Diego, California area of the U.S. completed measures of overall moderate-to-vigorous physical activity (MVPA) via accelerometry and domain-specific MVPA via questionnaire at Visits 1 (2008-2011; n = 4086) and 2 (2014-2017; n = 1776), ~6 years apart. 800-m home neighborhood buffers were used to create objective measures of residential, intersection, and retail density, bus/trolley stops, greenness, parks, and recreation area at Visit 1. Regression models tested the association of each neighborhood feature with MVPA at Visit 1 and over 6 years, adjusting for individual characteristics and neighborhood socioeconomic deprivation. At Visit 1, those in neighborhoods with higher vs. lower retail density or recreation area (+1 vs. -1 standard deviation from the mean) engaged in 10% more overall MVPA and 12-22% more active transportation. Those in neighborhoods with higher vs. lower residential density engaged in 22% more active transportation. Those in neighborhoods with higher vs. lower greenness and park count engaged in 14-16% more recreational MVPA. Neighborhood features were unassociated with changes in MVPA over 6 years. Although changes in MVPA over time were similar across neighborhoods, Hispanic/Latino adults living in neighborhoods with design features supportive of walking and recreational activity (e.g., greater residential and retail density, more parks and recreation facilities) were consistently more active. Improving neighborhood environments appears important for supporting physical activity among Hispanic/Latino adults.

RevDate: 2022-05-05

Tian Y, Kim AE, Bien SA, et al (2022)

Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk.

Journal of the National Cancer Institute pii:6581085 [Epub ahead of print].

BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.

METHODS: We conducted a genome-wide gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen-only, and combined estrogen-progestogen therapy with CRC risk, among 28,486 postmenopausal women (11,519 cases and 16,967 controls) from 38 studies, using logistic regression, two-step method, and 2- or 3-degree-of-freedom (d.f.) joint test. A set-based score test was applied for rare genetic variants.

RESULTS: The use of any MHT, estrogen-only and estrogen-progestogen were associated with a reduced CRC risk [odds ratio (OR) with 95% confidence interval (95% CI) of 0.71 (0.64-0.78), 0.65 (0.53-0.79), and 0.73 (0.59-0.90), respectively]. The two-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was significantly reduced in women with the GG genotype [0.68 (0.64-0.72)] but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-d.f. joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing ORs of 0.78 (0.70-0.87) for TT, 0.68 (0.63-0.73) for TC, and 0.66 (0.60-0.74) for CC genotypes. In addition, five genes in rare variant analysis showed suggestive interactions with MHT (two-sided P < 1.2x10-4).

CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

RevDate: 2022-05-05

Flynn KE, Atallah E, Lin L, et al (2022)

Patient- and physician-reported pain after tyrosine kinase inhibitor discontinuation among patients with chronic myeloid leukemia.

Haematologica [Epub ahead of print].

For patients with optimally treated chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitor (TKI) therapy can lead to treatment-free remission (TFR). In previous trials, TKI discontinuation has been associated with increased musculoskeletal pain in some patients ("withdrawal syndrome"), based on physician-reported adverse events (AEs). Patient-reported pain has not been described. The Life After Stopping TKIs study was a 14-site prospective, nonrandomized clinical trial of TKI discontinuation. We defined increased pain after discontinuation as: (1) a physician-reported pain AE, (2) a 2-level increase in self-reported musculoskeletal pain (4-level single item), or (3) initiation of a medication for pain. We plotted the trajectory of patient-reported pain over time using a piecewise mixed-effects ordinal logistic model. Within 3 months of discontinuation, 35/172 patients (20.3%) had a physician-reported pain AE, 22/172 (12.8%) had an increase in self-reported pain, and 18/154 (11.7%) initiated a pain medication. Agreement among these measures was limited; overall, 60/172 patients (34.9%) had increased pain. Three patients (1.7%) restarted a TKI because of pain. The modelpredicted trajectory showed an increase in pain in the first 3 months followed by a decrease, returning to baseline levels by 6 months and further decreasing after that. This trajectory was similar among patients who did and did not restart TKI, suggesting that resuming a TKI for withdrawal syndrome may be necessary for some, but other approaches to manage pain should be tried so that patients can remain in TFR when possible.

RevDate: 2022-05-05

Luyten YA, Hausman DE, Young JC, et al (2022)

Identification and characterization of the WYL BrxR protein and its gene as separable regulatory elements of a BREX phage restriction system.

Nucleic acids research pii:6576551 [Epub ahead of print].

Bacteriophage exclusion ('BREX') phage restriction systems are found in a wide range of bacteria. Various BREX systems encode unique combinations of proteins that usually include a site-specific methyltransferase; none appear to contain a nuclease. Here we describe the identification and characterization of a Type I BREX system from Acinetobacter and the effect of deleting each BREX ORF on growth, methylation, and restriction. We identified a previously uncharacterized gene in the BREX operon that is dispensable for methylation but involved in restriction. Biochemical and crystallographic analyses of this factor, which we term BrxR ('BREX Regulator'), demonstrate that it forms a homodimer and specifically binds a DNA target site upstream of its transcription start site. Deletion of the BrxR gene causes cell toxicity, reduces restriction, and significantly increases the expression of BrxC. In contrast, the introduction of a premature stop codon into the BrxR gene, or a point mutation blocking its DNA binding ability, has little effect on restriction, implying that the BrxR coding sequence and BrxR protein play independent functional roles. We speculate that elements within the BrxR coding sequence are involved in cis regulation of anti-phage activity, while the BrxR protein itself plays an additional regulatory role, perhaps during horizontal transfer.

RevDate: 2022-05-04

Mac Kain A, Maarifi G, Aicher SM, et al (2022)

Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen.

Nature communications, 13(1):2442.

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

RevDate: 2022-05-04

Gray MD, Feng J, Weidle CE, et al (2022)

Characterization of a vaccine-elicited human antibody with sequence homology to VRC01-class antibodies that binds the C1C2 gp120 domain.

Science advances, 8(18):eabm3948.

Broadly HIV-1-neutralizing VRC01-class antibodies bind the CD4-binding site of Env and contain VH1-2*02-derived heavy chains paired with light chains expressing five-amino acid-long CDRL3s. Their unmutated germline forms do not recognize HIV-1 Env, and their lack of elicitation in human clinical trials could be due to the absence of activation of the corresponding naïve B cells by the vaccine immunogens. To address this point, we examined Env-specific B cell receptor sequences from participants in the HVTN 100 clinical trial. Of all the sequences analyzed, only one displayed homology to VRC01-class antibodies, but the corresponding antibody (FH1) recognized the C1C2 gp120 domain. For FH1 to switch epitope recognition to the CD4-binding site, alterations in the CDRH3 and CDRL3 were necessary. Only germ line-targeting Env immunogens efficiently activated VRC01 B cells, even in the presence of FH1 B cells. Our findings support the use of these immunogens to activate VRC01 B cells in humans.

RevDate: 2022-05-04

Fajgenbaum DC, Pierson SK, Kanhai K, et al (2022)

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry.

British journal of haematology [Epub ahead of print].

Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched-control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non-fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.

RevDate: 2022-05-04

De Biasi S, Guida A, Lo Tartaro D, et al (2022)

Redistribution of CD8+ T cell subsets in metastatic renal cell carcinoma patients treated with anti-PD-1 therapy.

Cytometry. Part A : the journal of the International Society for Analytical Cytology [Epub ahead of print].

Renal-cell carcinoma (RCC) is responsible for the majority of tumors arising from the kidney parenchyma. Although a progressive improvement in median overall survival has been observed after the introduction of anti-PD-1 therapy, many patients do not benefit from this treatment. Therefore, we have investigated T cell dynamics to find immune modification induced by anti-PD-1 therapy. Here, we show that, after therapy, RCC patients (5 responders and 14 nonresponders) are characterized by a redistribution of different subsets across the memory T cell compartment.

RevDate: 2022-04-30
CmpDate: 2022-04-28

Chrisman SPD, Bollinger BJ, Mendoza JA, et al (2022)

Mobile Subthreshold Exercise Program (MSTEP) for concussion: study protocol for a randomized controlled trial.

Trials, 23(1):355.

BACKGROUND: Subthreshold exercise, defined as aerobic exercise below the level that causes symptoms, has been utilized as a treatment for youth with persistent postconcussive symptoms (PPCS), but there is currently little evidence to guide use. In addition, prior studies of exercise for PPCS have all required multiple in-person visits. We developed a virtual approach for delivering subthreshold exercise to youth with PPCS called the Mobile Subthreshold Exercise Program (MSTEP), and we have now been funded to conduct a large national randomized controlled trial (RCT) to test its efficacy for reducing concussive symptoms and improving health-related quality of life.

METHODS: This investigation is an RCT comparing MSTEP to an active control. We will recruit 200 adolescents 11-18 years old with postconcussive symptoms persisting for at least 1 week but less than 1 year. Youth will be randomized to receive either 6 weeks of subthreshold exercise (MSTEP) or a stretching condition (control). Youth and parents will complete surveys of concussive symptoms at baseline, weekly during the intervention, and at 3 and 6 months. The primary outcomes will be trajectory of concussive symptoms and health-related quality of life over the 6 months of the study. Secondary outcomes will include depression, anxiety, and sleep quality. We will also assess potential mediators of treatment effects including moderate-vigorous physical activity and fear avoidance of concussive symptoms.

DISCUSSION: This multisite RCT of MSTEP will provide vital information regarding the efficacy of a virtually delivered subthreshold exercise program for youth with PPCS, and insight regarding potential mediators of treatment effects, including objectively measured physical activity and fear avoidance of concussive symptoms.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04688255. Registered on December 29, 2020.

RevDate: 2022-04-29
CmpDate: 2022-04-21

Lee HJ, Song KH, Oh SJ, et al (2022)

Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes.

Nature communications, 13(1):2127.

Immunotherapy has emerged as a powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be targeted by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop combination strategies. Here, using the transcriptome data of patients, and immune-refractory tumor models, we identify TCTP as an immune-resistance factor that correlates with clinical outcome of anti-PD-L1 therapy and confers immune-refractory phenotypes, decreased T cell trafficking to the tumor and resistance to cytotoxic T lymphocyte-mediated tumor cell killing. Mechanistically, TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, treatment with dihydroartenimsinin, the most effective agent impending the TCTP-mediated-refractoriness, synergizes with T cell-mediated therapy to control immune-refractory tumors. Thus, our findings suggest a role of TCTP in promoting immune-refractoriness, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.

RevDate: 2022-05-03

Huang L, Rosen JD, Sun Q, et al (2022)

TOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data.

American journal of human genetics pii:S0002-9297(22)00154-9 [Epub ahead of print].

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Here, we present TOP-LD, an online tool to explore LD inferred with high-coverage (∼30×) WGS data from 15,578 individuals in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. TOP-LD provides a significant upgrade compared to current LD tools, as the TOPMed WGS data provide a more comprehensive representation of genetic variation than the 1000 Genomes data, particularly for rare variants and in the specific populations that we analyzed. For example, TOP-LD encompasses LD information for 150.3, 62.2, and 36.7 million variants for European, African, and East Asian ancestral samples, respectively, offering 2.6- to 9.1-fold increase in variant coverage compared to HaploReg 4.0 or LDlink. In addition, TOP-LD includes tens of thousands of structural variants (SVs). We demonstrate the value of TOP-LD in fine-mapping at the GGT1 locus associated with gamma glutamyltransferase in the African ancestry participants in UK Biobank. Beyond fine-mapping, TOP-LD can facilitate a wide range of applications that are based on summary statistics and estimates of LD. TOP-LD is freely available online.

RevDate: 2022-05-03

Bender Ignacio RA, Long J, Saha A, et al (2022)

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition.

PloS one, 17(5):e0267729 pii:PONE-D-21-33120.

BACKGROUND: Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.

METHODS: We conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition.

RESULTS: Among 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV.

CONCLUSIONS: LTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

RevDate: 2022-05-03

Roychoudhury P, Luo S, Hayashibara K, et al (2022)

Identification of Omicron-Delta Coinfections Using PCR-Based Genotyping.

RevDate: 2022-05-02

Zhang R, Shen S, Wei Y, et al (2022)

A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(22)00215-5 [Epub ahead of print].

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G×G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G×G interaction study on European NSCLC risk via a series of analyses. First, we used BiForce to evaluate and rank over 58 billion G×G interactions from 340,958 SNPs. Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.

RESULTS: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, P = 6.57×10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, P = 2.43×10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, P = 2.84×10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, P = 2.70×10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, P = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, P = 5.23×10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, P = 0.006). The interaction empowered polygenetic risk score (iPRS) that integrated classical polygenetic risk score and G×G information score was remarkable in lung cancer risk stratification.

CONCLUSIONS: Significant G×G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

RevDate: 2022-05-02

Mulenga H, Fiore-Gartland A, Mendelsohn SC, et al (2022)

Evaluation of a transcriptomic signature of tuberculosis risk in combination with an interferon gamma release assay: A diagnostic test accuracy study.

EClinicalMedicine, 47:101396 pii:S2589-5370(22)00126-2.

Background: We evaluated the diagnostic and prognostic performance of a transcriptomic signature of tuberculosis (TB) risk (RISK11) and QuantiFERON-TB Gold-plus (QFTPlus) as combination biomarkers of TB risk.

Methods: Healthy South Africans who were HIV-negative aged 18-60 years with baseline RISK11 and QFTPlus results were evaluated in a prospective cohort study conducted between Sept 20, 2016 and Dec 20, 2019. Prevalence and incidence-rate ratios were used to evaluate risk of TB. Positive (LR+) and negative (LR-) likelihood ratios were used to compare individual tests versus Both-Positive (RISK11+/QFTPlus+) and Either-Positive (RISK11+ or QFTPlus+) combinations.

Findings: Among 2912 participants, prevalent TB in RISK11+/QFTPlus+ participants was 13·3-fold (95% CI 4·2-42·7) higher than RISK11-/QFTPlus-; 2·4-fold (95% CI 1·2-4·8) higher than RISK11+/QFTPlus-; and 4·5-fold (95% CI 2·5-8·0) higher than RISK11-/QFTPlus+ participants. Risk of incident TB in RISK11+/QFTPlus+ participants was 8·3-fold (95% CI 2·5-27·0) higher than RISK11-/QFTPlus-; 2·5-fold (95% CI 1·0-6·6) higher than RISK11+/QFTPlus-; and 2·1-fold (95% CI 1·2-3·4) higher than RISK11-/QFTPlus+ participants, respectively. Compared to QFTPlus, the Both-Positive test combination increased diagnostic LR+ from 1·3 (95% CI 1·2-1·5) to 4·7 (95% CI 3·2-7·0), and prognostic LR+ from 1·4 (95% CI 1·2-1·5) to 2·8 (95% CI 1·5-5·1), but did not improve upon RISK11 alone. Compared with RISK11, the Either-Positive test combination decreased diagnostic LR- from 0·7 (95% CI 0·6-0·9) to 0·3 (95% CI 0·2-0·6), and prognostic LR- from 0·9 (95% CI 0·8-1·0) to 0·3 (0·1-0·7), but did not improve upon QFTPlus alone.

Interpretation: Combining two tests such as RISK11 and QFTPlus, with discordant individual performance characteristics does not improve overall discriminatory performance, relative to the individual tests.

Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.

RevDate: 2022-05-02

Marcelin JR, Pettifor A, Janes H, et al (2022)

COVID-19 Vaccines and SARS-CoV-2 Transmission in the Era of New Variants: A Review and Perspective.

Open forum infectious diseases, 9(5):ofac124 pii:ofac124.

Coronavirus disease 2019 (COVID-19) vaccines have yielded definitive prevention and major reductions in morbidity and mortality from severe acute respiratory syndrome coronavirus 2 infection, even in the context of emerging and persistent variants of concern. Newer variants have revealed less vaccine protection against infection and attenuation of vaccine effects on transmission. COVID-19 vaccines still likely reduce transmission compared with not being vaccinated at all, even with variants of concern; however, determining the magnitude of transmission reduction is constrained by the challenges of performing these studies, requiring accurate linkage of infections to vaccine status and timing thereof, particularly within households. In this review, we synthesize the currently available data on the impact of COVID-19 vaccines on infection, serious illness, and transmission; we also identify the challenges and opportunities associated with policy development based on this data.

RevDate: 2022-05-02

Reding KW, Simon MS, RK Cheng (2022)

Toward a More Precise Understanding of Obesity and Cancer and Cardiovascular Disease Risk.

JACC. CardioOncology, 4(1):82-84 pii:S2666-0873(22)00117-X.

RevDate: 2022-05-02

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

Lifestyle and Cardiovascular Risk Factors Associated With Heart Failure Subtypes in Postmenopausal Breast Cancer Survivors.

JACC. CardioOncology, 4(1):53-65 pii:S2666-0873(22)00110-7.

Background: Breast cancer (BC) survivors experience an increased burden of long-term comorbidities, including heart failure (HF). However, there is limited understanding of the risk for the development of HF subtypes, such as HF with preserved ejection fraction (HFpEF), in BC survivors.

Objectives: This study sought to estimate the incidence of HFpEF and HF with reduced ejection fraction (HFrEF) in postmenopausal BC survivors and to identify lifestyle and cardiovascular risk factors associated with HF subtypes.

Methods: Within the Women's Health Initiative, participants with an adjudicated diagnosis of invasive BC were followed to determine the incidence of hospitalized HF, for which adjudication procedures determined left ventricular ejection fraction. We calculated cumulative incidences of HF, HFpEF, and HFrEF. We estimated HRs for risk factors in relation to HF, HFpEF, and HFrEF using Cox proportional hazards survival models.

Results: In 2,272 BC survivors (28.6% Black and 64.9% White), the cumulative incidences of hospitalized HFpEF and HFrEF were 6.68% and 3.96%, respectively, over a median of 7.2 years (IQR: 3.6-12.3 years). For HFpEF, prior myocardial infarction (HR: 2.83; 95% CI: 1.28-6.28), greater waist circumference (HR: 1.99; 95% CI: 1.14-3.49), and smoking history (HR: 1.65; 95% CI: 1.01-2.67) were the strongest risk factors in multivariable models. With the exception of waist circumference, similar patterns were observed for HFrEF, although none were significant. In relation to those without HF, the risk of overall mortality in BC survivors with hospitalized HFpEF was 5.65 (95% CI: 4.11-7.76), and in those with hospitalized HFrEF, it was 3.77 (95% CI: 2.51-5.66).

Conclusions: In this population of older, racially diverse BC survivors, the incidence of HFpEF, as defined by HF hospitalizations, was higher than HFrEF. HF was also associated with an increased mortality risk. Risk factors for HF were largely similar to the general population with the exception of prior myocardial infarction for HFpEF. Notably, both waist circumference and smoking represent potentially modifiable factors.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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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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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )