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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 25 Sep 2022 at 06:26 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: 2022-09-23

Loeb KR, Le QH, Tang T, et al (2022)

Targeting FOLR1 in high-risk CBF2AT3-GLIS2 Pediatric AML with STRO-002 FOLR1-Antibody-Drug Conjugate.

Blood advances pii:486700 [Epub ahead of print].

RevDate: 2022-09-23

Mugume Y, Ding G, Dueñas ME, et al (2022)

Correction: Mugume et al. Complex Changes in Membrane Lipids Associated with the Modification of Autophagy in Arabidopsis. Metabolites 2022, 12, 190.

Metabolites, 12(9): pii:metabo12090810.

In the original article [...].

RevDate: 2022-09-22

Ochs-Balcom HM, Johnson C, Guertin KA, et al (2022)

Racial differences in the association of body mass index and ovarian cancer risk in the OCWAA Consortium.

British journal of cancer [Epub ahead of print].

BACKGROUND: Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race.

METHODS: We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models.

RESULTS: The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORBMI 30+= 1.62, 95% CI: 1.16, 2.26) and White women with obesity (ORBMI 30+= 1.20, 95% CI: 1.02, 2.42) compared to non-obese. Obesity was associated with higher NHGS risk in White women who never used HT (ORBMI 30+= 1.40, 95% CI: 1.08, 1.82). Higher NHGS ovarian cancer risk was observed for AA women who ever used HT (ORBMI 30+= 2.66, 95% CI: 1.15, 6.13), while in White women, there was an inverse association between recent BMI and risk of EOC and HGS in ever-HT users (EOC ORBMI 30+= 0.81, 95% CI: 0.69, 0.95, HGS ORBMI 30+= 0.73, 95% CI: 0.61, 0.88).

CONCLUSION: Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

RevDate: 2022-09-22

Le Q, Hadland B, Smith JL, et al (2022)

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.

The Journal of clinical investigation pii:157101 [Epub ahead of print].

Fusion oncoproteins are the initiating event in the pathogenesis of many pediatric AML. The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem/progenitor cells (CB HSPCs) in an endothelial cell (EC) co-culture system, that recapitulates the transcriptome, morphology and immunophenotype of C/G AML and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, FOLR1, and demonstrated their pre-clinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.

RevDate: 2022-09-22

Schuster DJ, Karuna S, Brackett C, et al (2022)

Lower SARS-CoV-2 specific humoral immunity in People Living with HIV-1 recovered from non-hospitalized COVID-19.

JCI insight pii:158402 [Epub ahead of print].

People living with HIV-1 (PLWH) exhibit more rapid antibody decline following routine immunization and elevated baseline chronic inflammation than people without HIV-1 (PWOH), indicating potential for diminished humoral immunity during SARS-CoV-2 infection. Conflicting reports have emerged on the ability of PLWH to maintain humoral protection against SARS-CoV-2 co-infection during convalescence. It is unknown if peak COVID-19 severity, along with HIV-1 infection status, associates with the quality and quantity of humoral immunity following recovery. Using a cross-sectional observational cohort from the USA and Peru, adults were enrolled 1-10 weeks post-SARS-CoV-2 infection diagnosis or symptom resolution. Serum antibodies were analyzed for SARS-CoV-2-specific response rates, binding magnitudes, ACE2 receptor blocking and antibody dependent cellular phagocytosis (ADCP). Overall, (1) PLWH exhibited a trend towards decreased magnitude of SARS-CoV-2-specific antibodies, despite modestly increased overall response rates when compared to PWOH, (2) PLWH recovered from symptomatic outpatient COVID-19 had comparatively diminished immune responses, and (3) PLWH lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when comparing asymptomatic to symptomatic outpatient disease.

RevDate: 2022-09-21

Infectious Diseases Clinical Research Consortium (IDCRC) Mentorship Program Writing Group, Scherer EM, Backer M, et al (2022)

The COVID-19 Pandemic Unmasked the Challenges Faced by Early-Stage Faculty in Infectious Diseases: A Call to Action.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6710388 [Epub ahead of print].

The COVID-19 pandemic and associated increase in family care responsibilities resulted in unsustainable personal and professional workloads for Infectious Diseases (ID) faculty on the front lines. This was especially true for early-stage faculty (ESF), many of whom had caregiving responsibilities. In addition, women faculty, underrepresented in medicine and science faculty, and particularly ESF experienced marked declines in research productivity, which significantly impacts career trajectories. When combined with staffing shortages due to an aging workforce and suboptimal recruitment and retention in ID, these work-life imbalances have brought the field to an inflection point. We propose actionable recommendations and call on ID leaders to act to close the gender, racial, and ethnic gaps to improve the recruitment, retention, and advancement of ESF in ID. By investing in systemic change to make the ID workforce more equitable, we can embody the shared ideals of diversity and inclusion and prepare for the next pandemic.

RevDate: 2022-09-21

Hendrikse LD, Haldipur P, Saulnier O, et al (2022)

Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Nature [Epub ahead of print].

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

RevDate: 2022-09-24

Gallagher CS, Mäkinen N, Harris HR, et al (2022)

Author Correction: Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Nature communications, 13(1):5543 pii:10.1038/s41467-022-33222-y.

RevDate: 2022-09-24

Casper C, Corey L, Cohen JI, et al (2022)

KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine.

NPJ vaccines, 7(1):108.

Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered.

RevDate: 2022-09-24
CmpDate: 2022-09-23

Oliva Rapoport VE, Altamirano E, Senador L, et al (2022)

Impact of prolonged isolation on adolescents with drug-susceptible tuberculosis in Lima, Peru: a qualitative study.

BMJ open, 12(9):e063287.

OBJECTIVES: Patients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects.

METHODS: This study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews.

RESULTS: We interviewed 85 participants: 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents' mental health.

CONCLUSION: Prolonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents' rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

RevDate: 2022-09-24
CmpDate: 2022-09-22

Huang BJ, Smith JL, Farrar JE, et al (2022)

Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia.

Nature communications, 13(1):5487.

Relapsed or refractory pediatric acute myeloid leukemia (AML) is associated with poor outcomes and relapse risk prediction approaches have not changed significantly in decades. To build a robust transcriptional risk prediction model for pediatric AML, we perform RNA-sequencing on 1503 primary diagnostic samples. While a 17 gene leukemia stem cell signature (LSC17) is predictive in our aggregated pediatric study population, LSC17 is no longer predictive within established cytogenetic and molecular (cytomolecular) risk groups. Therefore, we identify distinct LSC signatures on the basis of AML cytomolecular subtypes (LSC47) that were more predictive than LSC17. Based on these findings, we build a robust relapse prediction model within a training cohort and then validate it within independent cohorts. Here, we show that LSC47 increases the predictive power of conventional risk stratification and that applying biomarkers in a manner that is informed by cytomolecular profiling outperforms a uniform biomarker approach.

RevDate: 2022-09-19

Mao JJ, Ismaila N, Bao T, et al (2022)

Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology-ASCO Guideline.

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

PURPOSE: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other health care providers on integrative approaches to managing pain in patients with cancer.

METHODS: The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included pain intensity, symptom relief, and adverse events. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations.

RESULTS: The literature search identified 227 relevant studies to inform the evidence base for this guideline.

RECOMMENDATIONS: Among adult patients, acupuncture should be recommended for aromatase inhibitor-related joint pain. Acupuncture or reflexology or acupressure may be recommended for general cancer pain or musculoskeletal pain. Hypnosis may be recommended to patients who experience procedural pain. Massage may be recommended to patients experiencing pain during palliative or hospice care. These recommendations are based on an intermediate level of evidence, benefit outweighing risk, and with moderate strength of recommendation. The quality of evidence for other mind-body interventions or natural products for pain is either low or inconclusive. There is insufficient or inconclusive evidence to make recommendations for pediatric patients. More research is needed to better characterize the role of integrative medicine interventions in the care of patients with cancer.Additional information is available at https://integrativeonc.org/practice-guidelines/guidelines and www.asco.org/survivorship-guidelines.

RevDate: 2022-09-19

Furqan F, Ahn KW, Chen Y, et al (2022)

Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma.

British journal of haematology [Epub ahead of print].

The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.

RevDate: 2022-09-21
CmpDate: 2022-09-20

Luo R, Fong Y, Boeras D, et al (2022)

The clinical effect of point-of-care HIV diagnosis in infants: a systematic review and meta-analysis.

Lancet (London, England), 400(10356):887-895.

BACKGROUND: Timely diagnosis and treatment of HIV is crucial in HIV-exposed infants to prevent the high rates of mortality seen during the first 2 years of life if HIV is untreated. However, challenges with sample transportation, testing, and result delivery to caregivers have led to long delays in treatment initiation. We aimed to compare the clinical effect of point-of-care HIV testing versus laboratory-based testing (standard of care) in HIV-exposed infants.

METHODS: We did a systematic review and meta-analysis and searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus, from Jan 1, 2014, to Aug 31, 2020. Studies were included if they pertained to the use of point-of-care nucleic acid testing for infant HIV diagnosis, had a laboratory-based nucleic acid test as the comparator or standard of care against the index test (same-day point-of-care testing), evaluated clinical outcomes when point-of-care testing was used, and included HIV-exposed infants aged younger than 2 years. Studies were excluded if they did not use a laboratory-based comparator, a nucleic acid test that had been approved by a stringent regulatory authority, or diagnostic-accuracy or performance evaluations (eg, no clinical outcomes included). Reviews, non-research letters, commentaries, and editorials were also excluded. The risk of bias was evaluated using the ROBINS-I framework. Data were extracted from published reports. Data from all studies were analysed using frequency statistics to describe the overall populations evaluated and their results. Key outcomes were time to result delivery and antiretroviral therapy initiation, and proportion of HIV-positive infants initiated on antiretroviral therapy within 60 days after sample collection.

FINDINGS: 164 studies were identified by the search and seven were included in the analysis, comprising 37 377 infants in total across 15 countries, including 25 170 (67%) who had point-of-care HIV testing and 12 207 (33%) who had standard-of-care testing. The certainty of evidence was high. Same-day point-of-care testing led to a significantly shorter time between sample collection and result delivery to caregivers compared with standard-of-care testing (median 0 days [95% CI 0-0] vs 35 days [35-37]). Time from sample collection to antiretroviral therapy initiation in infants found to be HIV-positive was significantly lower with point-of-care testing compared with standard of care (median 0 days [95% CI 0-1] vs 40 days [36-44]). When each study's result was weighted equally, 90·3% (95% CI 76·7-96·5) of HIV-positive infants diagnosed using point-of-care testing had started antiretroviral therapy within 60 days of sample collection, compared with only 51·6% (27·1-75·7) who had standard-of-care testing (odds ratio 8·74 [95% CI 6·6-11·6]; p<0·0001).

INTERPRETATION: Overall, the certainty of the evidence in this analysis was rated as high for the primary outcomes related to result delivery and treatment initiation, with no serious risk of bias, inconsistency, indirectness, or imprecision. In HIV-exposed infants, same-day point-of-care HIV testing was associated with significantly improved time to result delivery, time to antiretroviral therapy initiation, and proportion of HIV-positive infants starting antiretroviral therapy within 60 days compared with standard of care.

FUNDING: The Bill & Melinda Gates Foundation.

RevDate: 2022-09-20
CmpDate: 2022-09-20

Yang SW, Kernic MA, Mueller BA, et al (2022)

Mother's and Father's Serious Mental Illness and Risk of Child Injury in a Taiwanese Birth Cohort.

The Journal of clinical psychiatry, 83(6):.

Objective: Parental serious mental illness (SMI) is associated with childhood injury. This study investigated whether child injury risk differs according to which parent is affected, SMI diagnosis, or timing of SMI onset.

Methods: This cohort study included 1,999,322 singletons born in 2004-2014 identified from the national Taiwanese registries. General estimating equation Poisson models were used to estimate incidence rate ratios (IRRs) of injury events and hospitalizations before the age of 5 years among children according to which parent was affected, SMI diagnosis (schizophrenia [ICD-9-CM codes: 295, 297, 298.3, 298.4, 298.9], bipolar disorder [296.00-296.16, 296.40-296.81, 296.89-296.99, 298.1, 648.4], or major depressive disorder [MDD; 296.20-296.36, 296.82, 298.0]), and timing of diagnosis (before or after childbirth, as a proxy of timing of onset). Data analysis was performed on data obtained from April 20, 2017, to May 6, 2020.

Results: Relative to unexposed children, the IRRs of injury hospitalizations for children with two SMI-affected parents, maternal SMI only, and paternal SMI only were 1.85 (95% CI, 1.38-2.48), 1.58 (95% CI, 1.48-1.68), and 1.34 (95% CI, 1.23-1.46), respectively. The IRRs of injury hospitalizations for maternal schizophrenia, bipolar disorder, and MDD were 2.09 (95% CI, 1.82-2.40), 1.77 (95% CI, 1.56-2.00), and 1.38 (95% CI, 1.26-1.50), respectively. The IRRs for paternal schizophrenia, bipolar disorder, and MDD were 1.39 (95% CI, 1.20-1.60), 1.61 (95% CI, 1.39-1.87), and 1.19 (95% CI, 1.05-1.36), respectively. The magnitude of excess risk was similar for children whose parent(s) experienced SMI diagnosed before and after childbirth.

Conclusions: We found children with two SMI-affected parents or at least one parent with schizophrenia or bipolar disorder to be at greatest risk of severe injury requiring hospitalization. These parents may benefit from extra parenting support and injury prevention coaching.

RevDate: 2022-09-16

Granot-Hershkovitz E, He S, Bressler J, et al (2022)

Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.

METHODS: We tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function.

RESULTS: Six metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar-related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet.

DISCUSSION: Several diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities.

HIGHLIGHTS: Metabolites associated with cognitive function in Puerto Rican adults were recently identified. We demonstrate the generalizability of these associations across diverse race/ethnicities. Most identified metabolites are related to sugars. Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function. Beta-cryptoxanthin and other metabolites highlight the importance of a healthy diet.

RevDate: 2022-09-17

Shaik I, Gaddam B, Patel A, et al (2022)

Success Rate of Growth Factors for Existing Periapical Lesions in Failed Endodontically Treated Teeth in Adult Population: A Systematic Review and Meta-Analysis.

Journal of pharmacy & bioallied sciences, 14(Suppl 1):S200-S202.

Introduction: In this study, we investigated the success rate of growth factors for existing periapical lesions in failed endodontically treated teeth in an adult population by systematic review and meta-analysis.

Materials and Methods: We conducted an online data search based on preferred reporting items for systematic reviews and meta analyses (PRISMA), from databases PUBMED, MEDLINE, and EMBASE, for the application of various types of growth factors in endodontically failed teeth with periapical lesions in adults. These included the "platelet-rich plasma (PRP) and platelet-rich fibrin (PRF)," blood, etc. The data were meta-analyzed using MetaXL 5.3, and GRADE was used to assess the certainty.

Results: We observed that success of 0.95 was achieved by the end of a year's follow-up with the application of growth factors for periodontal lesions. We also observed that the teeth responded to thermal tests, indicating regeneration; however, studies were with bias and lower sensitivity.

Discussion: \ Similar to regeneration in immature teeth, growth factors also showed greater success in the treatment of periapical lesions in the failed endodontic teeth in adults.

RevDate: 2022-09-19
CmpDate: 2022-09-19

Westbrook TC, Guan X, Rodansky E, et al (2022)

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

Nature communications, 13(1):5345.

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

RevDate: 2022-09-21
CmpDate: 2022-09-16

Sobieszczyk ME, Maaske J, Falsey AR, et al (2022)

Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months.

The Journal of clinical investigation, 132(18):.

BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.

RevDate: 2022-09-15

Chao CR, Chubak J, Beaber EF, et al (2022)

Gaps in the screening process for women diagnosed with cervical cancer in four diverse US health care settings.

Cancer medicine [Epub ahead of print].

BACKGROUND: Potential care gaps in the cervical cancer screening process among women diagnosed with cervical cancer in an era with increased human papillomavirus (HPV) testing have not been extensively evaluated.

METHODS: Women diagnosed with cervical cancer between ages 21 and 65 at four study sites between 2010 and 2014 were included. Screening histories were ascertained from 0.5 to 4 years prior to cervical cancer diagnosis. We identified potential care gaps in the screening history for each woman and classified them into one of three mutually exclusive types: lack of a screening test, screening test failure, and diagnostic/treatment care gap. Distributions of care gaps were tabulated by stage, histology, and study site. Multivariable nominal logistic regression was used to examine the associations between demographic and cancer characteristics and type of care gap.

RESULTS: Of 499 women evaluated, 46% lacked a screening test in the time window examined, 31% experienced a screening test failure, and 22% experienced a diagnostic/treatment care gap. More than half of the women with advanced cancer and squamous cell carcinoma lacked a screening test compared to 31% and 24% of women with localized cancer and adenocarcinoma, respectively. Women aged 21-29 at diagnosis were more likely to experience screening test failure and diagnostic/treatment care gap, while those aged 50-65 were more likely to lack a screening test, compared to women aged 30-39.

CONCLUSIONS: Our findings demonstrate a continuing need to develop interventions targeting unscreened and under-screened women and improve detection and diagnosis of adenocarcinoma in women undergoing cervical cancer screening and diagnostic follow-up.

RevDate: 2022-09-21
CmpDate: 2022-09-16

George DJ, Spigel DR, Gordan LN, et al (2022)

Safety and efficacy of first-line nivolumab plus ipilimumab alternating with nivolumab monotherapy in patients with advanced renal cell carcinoma: the non-randomised, open-label, phase IIIb/IV CheckMate 920 trial.

BMJ open, 12(9):e058396.

OBJECTIVES: The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profile previously observed with this combination in patients with advanced renal cell carcinoma (aRCC).

SETTING: Patients were enrolled from 48 largely community-based sites in the USA.

PARTICIPANTS: 106 patients with previously untreated, predominantly clear cell aRCC received treatment.

INTERVENTIONS: Patients received NIVO 6 mg/kg plus IPI 1 mg/kg on day 1 of the first week of each 8-week cycle; the combination alternated with NIVO 480 mg monotherapy on day 1 of the fifth week of each 8-week cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. The maximum treatment duration was 2 years. The primary endpoint was the incidence of high-grade (grade 3/4 and grade 5) immune-mediated adverse events (IMAEs) within 100 days of the last dose. Select secondary endpoints included time to onset and resolution of high-grade IMAEs, progression-free survival (PFS) and objective response rate (ORR). The incidence of treatment-related adverse events and the overall survival (OS) were the exploratory endpoints.

RESULTS: The most common grade 3/4 IMAEs were diarrhoea/colitis (7.5%) and rash (6.6%) and no grade 5 IMAEs occurred, with a minimum follow-up of 28.5 months. The median PFS was 4.8 (95% CI 3.0 to 8.3) months, the ORR in evaluable patients (n=96) was 34.4% (95% CI 25.0 to 44.8), and the median OS was not reached (95% CI 24.8 months to not estimable).

CONCLUSIONS: While no new safety signals were reported with less frequent, but continual NIVO+IPI dosing in CheckMate 920, the modified regimen was not associated with clinical benefits relative to the approved NIVO+IPI dose. These results support the continued use of the currently approved NIVO+IPI combination dosing schedule for patients with aRCC.

TRIAL REGISTRATION NUMBER: NCT02982954.

RevDate: 2022-09-17

Dioverti V, Boghdadly ZE, Shahid Z, et al (2022)

Revised Guidelines for COVID-19 management in hematopoietic cell transplantation and cellular therapy recipients (August 2022).

RevDate: 2022-09-13

Dalmat RR, Ziebell RA, Kamineni A, et al (2022)

Risk of colorectal cancer and colorectal cancer mortality beginning ten years after a negative colonoscopy, among screen-eligible adults 76-85 years old.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:709189 [Epub ahead of print].

BACKGROUND: Few empirical data are available to inform older adults' decisions about whether to screen or continue screening for colorectal cancer (CRC) based on their prior history of screening, particularly among individuals with a prior negative exam.

METHODS: Using a retrospective cohort of older adults receiving healthcare at three Kaiser Permanente integrated healthcare systems in Northern California (KPNC), Southern California (KPSC), and Washington (KPWA), we estimated the cumulative risk of CRC incidence and mortality among older adults who had a negative colonoscopy ten years earlier, accounting for death from other causes.

RESULTS: Screen-eligible adults aged 76-85 years who had a negative colonoscopy ten years earlier were found to be at a low risk of CRC diagnosis, with a cumulative incidence of 0.39% (95% CI: 0.31-0.48%) at two years that increased to 1.29% (95% CI: 1.02-1.61%) at eight years. Cumulative mortality from CRC was 0.04% (95% CI: 0.02-0.08%) at two years and 0.46% (95% CI: 0.30-0.70%) at eight years.

CONCLUSIONS: These low estimates of cumulative CRC incidence and mortality occurred in the context of much higher risk of death from other causes.

IMPACT: Knowledge of these results could bear on older adults' decision to undergo or not undergo further CRC screening, including choice of modality, should they decide to continue screening.

RevDate: 2022-09-13

Himbert C, Warby CA, Gigic B, et al (2022)

Associations of individual and combined physical activity and body mass index groups with pro-inflammatory biomarkers among colorectal cancer patients.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:709190 [Epub ahead of print].

BACKGROUND: Physical activity and obesity are well-established factors of colorectal cancer (CRC) risk and prognosis. Here, we investigate associations of individual and combined physical activity and BMI groups with pro-inflammatory biomarkers in CRC patients.

METHODS: Self-reported physical activity levels were classified as 'active' (≥8.75 MET-hrs/wk) vs. 'inactive' (<8.75 MET-hrs/wk) in n=579 stage I-IV CRC patients enrolled in the ColoCare Study. BMI [normal weight (≥18.5-<25kg/m2), overweight (≥25-<30kg/m2), and obese (≥30kg/m2)] was abstracted from medical records. Patients were classified into four combinations of physical activity levels and BMI. Biomarkers (CRP, SAA, IL-6, IL-8, and TNF-α) in pre-surgery serum samples were measured using Meso-Scale-Discovery platform. Regression models were used to compute relative percent differences in biomarker levels by physical activity and BMI groups.

RESULTS: 'Inactive' patients had non-statistically significant higher IL-6 levels compared to 'active' patients (+36%, p=0.10). 'Obese' patients had 88% and 17% higher CRP and TNF-α levels compared to 'normal weight' patients (p=0.03 and 0.02, respectively). Highest CRP levels were observed among 'overweight or obese/inactive' compared to 'normal weight/active' patients (p=0.03).

CONCLUSION: We provide evidence of associations between individual and combined physical activity and BMI groups with pro-inflammatory biomarkers. While BMI was identified as the key driver of inflammation, biomarker levels were higher among 'inactive' patients across BMI groups.

IMPACT: This is the largest study in CRC patients investigating associations of energy balance components with inflammatory biomarkers. Our results suggest that physical activity may reduce obesity-induced inflammation in CRC patients and support the design of randomized controlled trials testing this hypothesis.

RevDate: 2022-09-13

Roberts ST, van der Straten A, Rael CT, et al (2022)

Intimate Partner Violence and Engagement in the HIV Care Continuum among Women in Sub-Saharan Africa: A Prospective Cohort Study.

AIDS and behavior [Epub ahead of print].

Research suggests that women's experience of intimate partner violence (IPV) is associated with poor engagement in HIV care and treatment. However, most studies have been cross-sectional and conducted in North America. We examined the association between physical IPV and HIV care outcomes in a prospective cohort study of women living with HIV (WLHIV) in Malawi, South Africa, Uganda, and Zimbabwe. At enrollment, 15% of the 351 participants self-reported physical IPV. IPV experience was not associated with time to first engagement in HIV care or the proportion virally suppressed after 6 months on ART. Women reporting physical IPV were less likely to initiate ART within 6 months of becoming eligible (adjusted RR 0.74, 95% CI 0.53-1.03). IPV screening is critical to identify survivors and link them to appropriate services. However, addressing IPV may not increase engagement in HIV care or viral load suppression among WLHIV in sub-Saharan Africa.

RevDate: 2022-09-15

Rosconi F, Rudmann E, Li J, et al (2022)

A bacterial pan-genome makes gene essentiality strain-dependent and evolvable.

Nature microbiology [Epub ahead of print].

Many bacterial species are represented by a pan-genome, whose genetic repertoire far outstrips that of any single bacterial genome. Here we investigate how a bacterial pan-genome might influence gene essentiality and whether essential genes that are initially critical for the survival of an organism can evolve to become non-essential. By using Transposon insertion sequencing (Tn-seq), whole-genome sequencing and RNA-seq on a set of 36 clinical Streptococcus pneumoniae strains representative of >68% of the species' pan-genome, we identify a species-wide 'essentialome' that can be subdivided into universal, core strain-specific and accessory essential genes. By employing 'forced-evolution experiments', we show that specific genetic changes allow bacteria to bypass essentiality. Moreover, by untangling several genetic mechanisms, we show that gene essentiality can be highly influenced by and/or be dependent on: (1) the composition of the accessory genome, (2) the accumulation of toxic intermediates, (3) functional redundancy, (4) efficient recycling of critical metabolites and (5) pathway rewiring. While this functional characterization underscores the evolvability potential of many essential genes, we also show that genes with differential essentiality remain important antimicrobial drug target candidates, as their inactivation almost always has a severe fitness cost in vivo.

RevDate: 2022-09-12

Etra AM, Capellini A, Alousi AM, et al (2022)

Effective treatment of low risk acute GVHD with itacitinib monotherapy.

Blood pii:486577 [Epub ahead of print].

The standard primary treatment for acute graft vs host disease (GVHD) requires prolonged, high dose systemic corticosteroids (SCS) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/day (responders could receive a second 28-day cycle) and compared their outcomes to 140 contemporaneous, matched control patients treated with SCS. More patients responded to itacitinib within 7 days (81% vs 66%, p=0.02) and response rates at day 28 were very high for both groups (89% vs 86%, p=0.67) with few symptomatic flares (11% vs 12%, p=0.88). Fewer itacitinib treated patients developed a serious infection within 90 days (27% vs 42%, p=0.04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, p=0.02). No other grade ≥3 adverse events occurred in >10% of itacitinib treated patients. There were no significant differences between groups at 1-year for non-relapse mortality (4% vs 11%, p=0.21), relapse (18% vs 21%, p=0.64), chronic GVHD (28% vs 33%, p=0.33) or survival (88% vs 80%, p=0.11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD that deserves further investigation.

RevDate: 2022-09-24

Walter M, Chen IP, Vallejo-Gracia A, et al (2022)

SIRT5 is a proviral factor that interacts with SARS-CoV-2 Nsp14 protein.

PLoS pathogens, 18(9):e1010811.

SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response, independently of the Mitochondrial Antiviral Signaling Protein MAVS. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.

RevDate: 2022-09-12

Tapsoba JD, Cover J, Obong'o C, et al (2022)

Continued attendance in a PrEP program despite low adherence and non-protective drug levels among adolescent girls and young women in Kenya: Results from a prospective cohort study.

PLoS medicine, 19(9):e1004097 pii:PMEDICINE-D-22-00813 [Epub ahead of print].

BACKGROUND: In sub-Saharan Africa (SSA), adolescent girls and young women (AGYW) ages 15 to 24 years represent <10% of the population yet account for 1 in 5 new HIV infections. Although oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) can be highly effective, low persistence in PrEP programs and poor adherence have limited its ability to reduce HIV incidence among women.

METHODS AND FINDINGS: A total of 336 AGYW participating in the PEPFAR-funded DREAMS PrEP program in western Kenya were enrolled into a study of PrEP use conducted between 6/2019 to 1/2020. AGYW, which used daily oral TDF/FTC, completed interviews and provided dried blood spots (DBS) for measurement of tenofovir-diphosphate (TFV-DP) concentrations at enrollment and 3 months later, and 176/302 (58.3%, 95% confidence interval [95% CI 52.3 to 63.8]) met our definition of PrEP persistence: having expressed intention to use PrEP and attended both the second interview and an interim refill visit. Among AGYW with DBS taken at the second interview, only 9/197 (4.6%, [95% CI 1.6 to 7.5]) had protective TFV-DP levels (≥700 fmol/punch) and 163/197 (82.7%, [95% CI 77.5 to 88]) had levels consistent with no recent PrEP use (<10 fmol/punch). Perception of being at moderate-to-high risk for HIV if not taking PrEP was associated with persistence (adjusted odds ratio, 10.17 [95% CI 5.14 to 20.13], p < 0.001) in a model accounting for county of residence and variables that had p-value <0.1 in unadjusted analysis (age, being in school, initiated PrEP 2 to 3 months before the first interview, still active in DREAMS, having children, having multiple sex partners, partner aware of PrEP use, partner very supportive of PrEP use, partner has other partners, AGYW believes that a partner puts her at risk, male condom use, injectable contraceptive use, and implant contraceptive use). Among AGYW who reported continuing PrEP, >90% indicated they were using PrEP to prevent HIV, although almost all had non-protective TFV-DP levels. Limitations included short study duration and inclusion of only DREAMS participants.

CONCLUSIONS: Many AGYW persisted in the PrEP program without taking PrEP frequently enough to receive benefit. Notably, AGYW who persisted had a higher self-perceived risk of HIV infection. These AGYW may be optimal candidates for long-acting PrEP.

RevDate: 2022-09-17

Gonzalez MA, Bhatti AM, Fitzpatrick K, et al (2022)

Humoral and Cellular Responses to SARS-CoV-2 Vaccines Before and After Chimeric Antigen Receptor-Modified T Cell Therapy.

Blood advances pii:486572 [Epub ahead of print].

RevDate: 2022-09-12

Hoff MN, Xiang QS, Cross NM, et al (2022)

Motion resilience of the balanced steady-state free precession geometric solution.

Magnetic resonance in medicine [Epub ahead of print].

PURPOSE: Many MRI sequences are sensitive to motion and its associated artifacts. The linearized geometric solution (LGS), a balanced steady-state free precession (bSSFP) off-resonance signal demodulation technique, is evaluated with respect to motion artifact resilience.

THEORY AND METHODS: The mechanism and extent of LGS motion artifact resilience is examined in simulated, flow phantom, and in vivo clinical imaging. Motion artifact correction capabilities are decoupled from susceptibility artifact correction when feasible to permit controlled analysis of motion artifact correction when comparing the LGS with standard and phase-cycle-averaged (complex sum) bSSFP imaging.

RESULTS: Simulations reveal that the LGS demonstrates motion artifact reduction capabilities similar to standard clinical bSSFP imaging techniques, with slightly greater resilience in high SNR regions and for shorter-duration motion. Flow phantom experiments assert that the LGS reduces shorter-duration motion artifact error by ∼24%-65% relative to the complex sum, whereas reconstructions exhibit similar error reduction for constant motion. In vivo analysis demonstrates that in the internal auditory canal/orbits, the LGS was deemed to have less artifact in 24%/49% and similar artifact in 76%/51% of radiological assessments relative to the complex sum, and the LGS had less artifact in 97%/81% and similar artifact in 3%/16% of assessments relative to standard bSSFP. Only 2 of 63 assessments deemed the LGS inferior to either complex sum or standard bSSFP in terms of artifact reduction.

CONCLUSION: The LGS provides sufficient bSSFP motion artifact resilience to permit robust elimination of susceptibility artifacts, inspiring its use in a wide variety of applications.

RevDate: 2022-09-15
CmpDate: 2022-09-13

Noto A, Suffiotti M, Joo V, et al (2022)

The deficiency in Th2-like Tfh cells affects the maturation and quality of HIV-specific B cell response in viremic infection.

Frontiers in immunology, 13:960120.

Optimal T follicular helper (Tfh) cells function is important to promote the development of germinal centers and maturation of high affinity antigen-specific B cells. We have found that the expression of CXCR3 defines distinct Tfh subsets: CXCR3+ Th1-like Tfh cells mainly producing single IFN-γ and dual IL-21/IFN-γ and CXCR3- Th2-like Tfh cells mainly producing single IL-4 and dual IL-21/IL-4 cytokines. CXCR3- Th2-like Tfhs are significantly reduced during ongoing HIV replication. While the percentage of Th2-like Tfh cells correlates with that of total and cycling HIV-specific B cells, the percentage of CXCR3+ Th1-like Tfhs correlates with HIV-specific B cells expressing T-bet and CXCR3. Of note, only IL-4 and IL-21 cytokines boosted efficient maturation of HIV-specific B cells while IFN-γ induced expression of T-bet and CXCR3 in B cells. Interestingly, total and HIV-specific CXCR3+ B cells showed lower rate of somatic hypermutation, as compared to CXCR3- B cells. Therefore, the imbalance in Th2/Th1-like Tfhs affects B cell responses in viremic HIV infection.

RevDate: 2022-09-22

Velloza J, Donnell D, Hosek S, et al (2022)

Alignment of PrEP adherence with periods of HIV risk among adolescent girls and young women in South Africa and Zimbabwe: a secondary analysis of the HPTN 082 randomised controlled trial.

The lancet. HIV pii:S2352-3018(22)00195-3 [Epub ahead of print].

BACKGROUND: Adolescent girls and young women in southern and eastern Africa have adherence challenges with daily oral HIV pre-exposure prophylaxis (PrEP). High adherence is most important during periods of HIV risk (prevention-effective adherence). We aimed to describe HIV risk behaviour and to understand patterns in PrEP adherence during periods of risk among adolescent girls and young women from sub-Saharan Africa.

METHODS: We did a secondary analysis of the HPTN 082 trial, an open-label, interventional, randomised controlled trial of sexually active adolescent girls and young women (aged 16-25 years) testing negative for HIV in Johannesburg and Cape Town, South Africa, and in Harare, Zimbabwe. The primary outcomes were high cumulative PrEP adherence, dichotomised as intracellular tenofovir diphosphate concentrations of at least 700 fmol/punch in dried blood spots at weeks 13, 26, and 52, and high recent PrEP adherence, dichotomised as plasma tenofovir concentrations of at least 40 ng/mL at weeks 13, 26, and 52, among participants who accepted PrEP. We collected data on sexual behaviour every 3 months. We categorised visits into a binary variable of any HIV risk based on condomless sex, more than one sexual partner, primary partner's HIV status and antiretroviral use, transactional sex, drug or alcohol use around sexual activity, and laboratory-diagnosed STIs. We used generalised estimating equations to evaluate associations between HIV risk (reflecting behaviour during the previous 3 months) and high cumulative and recent adherence to PrEP and any PrEP use (quantifiable drug concentrations). The trial is registered with ClinicalTrials.gov, NCT02732730.

FINDINGS: Between Oct 12, 2016, and Oct 25, 2018, 451 women were recruited, and 427 participants (median age 21·0 years [IQR 19·0-22·0]) were eligible for inclusion in this analysis. The proportion of participants reporting at least one HIV risk factor decreased significantly over follow-up, from 364 (85%) participants at enrolment, 226 (60%) at week 13, and 243 (65%) at week 26, to 224 (61%) at week 52 (p<0·0001). Any HIV risk was significantly associated with high PrEP adherence, measured by both tenofovir diphosphate concentrations of at least 700 fmol/punch (adjusted relative risk 1·57 [95% CI 1·09-2·25]; p=0·014) and plasma tenofovir concentrations of at least 40 ng/mL (1·36 [1·11-1·65]; p=0·0025). Any HIV risk was also associated with quantifiable concentrations of tenofovir diphosphate (1·15 [1·03-1·29]; p=0·013) and tenofovir (1·27 [1·09-1·49]; p=0·0022). We observed significant dose-response relationships between number of HIV risk factors and PrEP drug concentrations.

INTERPRETATION: The association between any HIV risk and high PrEP adherence suggests that adolescent girls and young women were able to use PrEP during periods of risk, an indicator of prevention-effective PrEP adherence. Our findings support a shift in the PrEP framework to acknowledge prevention-effective adherence practices, which might improve PrEP delivery and adherence support for adolescent girls and young women in HIV-endemic settings.

FUNDING: US National Institutes of Health.

RevDate: 2022-09-10

Jones SMW, Gaffney A, JM Unger (2022)

Common methods of determining meaningful change in clinical practice: implications for precision patient-reported outcomes.

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

PURPOSE: Patient-reported outcomes (PROs) are used in clinical practice for several purposes, including to monitor whether a treatment is working or whether a patient is experiencing adverse events from treatment. This study surveyed oncology providers (OP) and mental health providers (MHP) to determine how clinicians from different disciplines determine individual-level meaningful change on PROs. Understanding how clinicians determine change on PROs could help inform methods for individualizing meaningful change definitions, an approach we have dubbed "Precision PROs".

METHODS: Three hundred and forty-seven providers utilizing PROs completed an online survey about PRO use to monitor patients in clinical practice. A question on methods used to determine individual-level meaningful change on PROs was developed with input from clinicians. Multivariate logistic regression analyses were used to assess whether specific methods were associated with clinician characteristics.

RESULTS: The most commonly reported method was comparing the previous score to the current score (65%). Other methods included examining the numerical scores without a visual aid (59%), considering other factors affecting scores (42%), comparing scores to norms (31%) and using a graph of scores (29%). Provider age was negatively associated with odds of using a graph (OR = 0.95, 95% CI 0.91, 1.0) but no other method. Provider gender, hours per week in clinical practice and years in practice were not associated with odds of using a specific method.

CONCLUSIONS: Most providers determined individual-level meaningful change without a visual aid and used only the previous score and current score, the minimum number (2 scores) to determine change. Consistent with current practice, future research on methods of determining within-individual meaningful change for clinical use should focus on methods requiring two rather than three or more scores. When attempting to personalize within-individual change definitions (Precision PROs), methods examining a baseline and single follow-up may be most useful for clinical practice.

RevDate: 2022-09-20
CmpDate: 2022-09-13

Schattgen SA, Hazelton WD, Thomas PG, et al (2022)

Multimodal T Cell Analysis with CoNGA.

Methods in molecular biology (Clifton, N.J.), 2574:367-388.

Advances in single-cell technologies have made it possible to simultaneously quantify gene expression and immune receptor sequence across thousands of individual T or B cells in a single experiment. Data from such experiments are advancing our understanding of the relationship between adaptive immune receptor sequence and transcriptional profile. We recently reported a software tool, CoNGA, specifically developed to detect correlation between receptor sequence and transcriptional profile. Here we describe in detail how CoNGA can be applied to analyze a large and diverse T cell dataset featuring multiple donors and batch annotations. Our workflow illustrates new analysis modes for the detection of TCR sequence convergence into similarity clusters and of matches to literature-derived TCR databases, as well as processing of gamma-delta T cells.

RevDate: 2022-09-20
CmpDate: 2022-09-13

Mayer-Blackwell K, Fiore-Gartland A, PG Thomas (2022)

Flexible Distance-Based TCR Analysis in Python with tcrdist3.

Methods in molecular biology (Clifton, N.J.), 2574:309-366.

Paired- and single-chain T cell receptor (TCR) sequencing are now commonly used techniques for interrogating adaptive immune responses. TCRs targeting the same epitope frequently share motifs consisting of critical contact residues. Here we illustrate the key features of tcrdist3, a new Python package for distance-based TCR analysis through a series of three interactive examples. In the first example, we illustrate how tcrdist3 can integrate sequence similarity networks, gene-usage plots, and background-adjusted CDR3 logos to identify TCR sequence features conferring antigen specificity among sets of peptide-MHC-multimer sorted receptors. In the second example, we show how the TCRjoin feature in tcrdist3 can be used to flexibly query receptor sequences of interest against bulk repertoires or libraries of previously annotated TCRs based on matching of similar sequences. In the third example, we show how the TCRdist metric can be leveraged to identify candidate polyclonal receptors under antigenic selection in bulk repertoires based on sequence neighbor enrichment testing, a statistical approach similar to TCRNET and ALICE algorithms, but with added flexibility in how the neighborhood can be defined.

RevDate: 2022-09-10

Wong E, Franceschini N, Tinker LF, et al (2022)

Continuity of care among postmenopausal women with cardiometabolic diseases in the United States early during the COVID-19 pandemic: Findings from the Women's Health Initiative.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6695368 [Epub ahead of print].

BACKGROUND: In response to the COVID-19 pandemic, public health measures, including stay-at-home orders, were widely instituted in the United States (US) by March 2020. However, few studies have evaluated the impact of these measures on continuity of care among older adults living with chronic diseases.

METHODS: Beginning in June 2020, participants of the national Women's Health Initiative (WHI) (N=64,061) were surveyed on the impact of the pandemic on various aspects of their health and well-being since March 2020, including access to care appointments, medications, and caregivers. Responses received by November 2020 (response rate=77.6%) were tabulated and stratified by prevalent chronic diseases, including hypertension, type 2 diabetes, and cardiovascular disease (CVD).

RESULTS: Among 49,695 respondents (mean age=83.6 years), 70.2% had a history of hypertension, 21.8% had diabetes, and 18.9% had CVD. Half of respondents reported being very concerned about the pandemic and 24.5% decided against seeking medical care to avoid COVID-19 exposure. A quarter reported difficulties with getting routine care and 45.5% had in-person appointments converted to telemedicine formats; many reported cancelled (27.8%) or rescheduled (37.7%) appointments. Among those taking prescribed medication (88.0%), 9.7% reported changing their method of obtaining medications. Those living with and without chronic diseases generally reported similar changes in care and medication access.

CONCLUSIONS: Early in the pandemic, many older women avoided medical care or adapted to new ways of receiving care and medications. Therefore, optimizing alternative services, like telemedicine, should be prioritized to ensure that older women continue to receive quality care during public health emergencies.

RevDate: 2022-09-09

Kong X, Wu X, Wang B, et al (2022)

Trafficking between clonally related peripheral T helper cells and tissue-resident T helper cells in chronic GVHD.

Blood pii:486566 [Epub ahead of print].

Chronic graft versus host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. Here, we show that in cGVHD patients, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B cell differentiation and production of IgG via IL-21. Tph cell expansion was also observed in murine model of cGVHD. This Tph expansion in the blood is associated with the expansion of pathogenic tissue-resident T helper (Trh) cells that form lymphoid aggregates surrounded by collagen in GVHD target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T cell receptor α and β repertoires. Deficiency of IL-21R, BCL6, or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and chronic GVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.

RevDate: 2022-09-09

Schenk JM, Till C, Neuhouser ML, et al (2022)

Differential Biopsy Patterns Influence Associations Between Multivitamin Use and Prostate Cancer Risk in the Selenium and Vitamin E Cancer Prevention Trial.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:709163 [Epub ahead of print].

BACKGROUND: Multivitamin use is a common health behavior but there is conflicting evidence from prospective studies about whether this behavior increases or decreases prostate cancer (PCa) risk.

METHODS: Associations of multivitamin (MVI) use and PCa risk were evaluated using data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cox proportional hazards models estimated associations of MVI use with risk of total, low- and high-grade PCa. Longitudinal data were used to evaluate screening and biopsy patterns. To account for differential biopsy patterns, the probability of PCa was estimated for men with a positive screening value but no biopsy. Incidence Density Ratios were used to approximate hazards ratios, and associations of MVI use with predicted PCa risk were compared to observed.

RESULTS: Analyses of data from observed biopsies suggest a respective 19% (95% CI 10-28%) and 21% (12-31%) higher risk of high-grade PCa for current and long-term MVI use, compared to no use. Current and long-term MVI use was associated with a shorter time to first on-study biopsy, indicating the potential for detection bias. After accounting for differential acceptance of biopsy, associations of MVI use with PCa were attenuated and not statistically significant.

CONCLUSIONS: In SELECT, biopsy acceptance patterns differed by MVI use. Estimates of associations of MVI use with PCa risk based on observed biopsy data may be biased by differential acceptance of biopsy.

IMPACT: Differential biopsy ascertainment may impact associations of risk factors and PCa. Detailed screening and biopsy data can be used to analytically minimize such bias.

RevDate: 2022-09-09

Phipps W, Adams SV, Mooka P, et al (2022)

A prospective study of HIV-associated and hiv-negative kaposi sarcoma in Uganda: identifying factors associated with poor outcomes.

AIDS (London, England) pii:00002030-990000000-00107 [Epub ahead of print].

OBJECTIVE: Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV+KS) and endemic (HIV-negative; HIV-KS) KS patients in Uganda to identify factors associated with survival and response.

METHODS: Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over one year to assess overall survival (OS) and treatment response.

RESULTS: 200 participants were enrolled; 166 (83%) had HIV+KS, and 176 (88%) were poor-risk tumor (T1) stage. 1-year OS was 64% (95%CI 57%-71%), with the hazard of death nearly three-fold higher for HIV+KS (HR=2.93; p = 0.023). Among HIV+KS, abnormal chest x-ray (HR = 2.81; p = 0.007), lower CD4 T-cell count (HR =0.68 per 100 cells/μL; p = 0.027), higher HIV viral load (HR=2.22 per log10 copies/mL; p = 0.026), and higher plasma KSHV copy number (HR =1.79 per log10 copies/mL; p = 0.028) were associated with increased mortality. Among HIV-KS, factors associated with mortality included Karnofsky score <70 (HR =9.17; p = 0.045), abnormal chest x-ray (HR=8.41; p = 0.025), and higher plasma KSHV copy number (HR =6.21 per log10 copies/mL; p < 0.001).

CONCLUSIONS: Although survival rates were better for HIV-KS than HIV+KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

RevDate: 2022-09-09

Chung E, Magedson A, Emanuels A, et al (2022)

SARS-CoV-2 Screening Testing in Schools: A Comparison of School- vs Home-Based Collection Methods.

Journal of the Pediatric Infectious Diseases Society pii:6694752 [Epub ahead of print].

RevDate: 2022-09-09

Dicanio M, Giaccherini M, Clay-Gilmour A, et al (2022)

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

International journal of cancer [Epub ahead of print].

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and non-cancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28,684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P<5x10-8) with their respective trait. The selected SNPs were analyzed in 2,434 MM cases and 3,446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1,955 MM cases and 1,549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147,282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR=1.22, 95%CI 1.13-1.32, P=4.81x10-7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus. This article is protected by copyright. All rights reserved.

RevDate: 2022-09-13

Vykoukal J, Fahrmann JF, Patel N, et al (2022)

Contributions of Circulating microRNAs for Early Detection of Lung Cancer.

Cancers, 14(17):.

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) consisting of the precursor form of surfactant protein B (Pro-SFTPB), cancer antigen 125 (CA125), carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1) was additionally assessed. Of the 30 miRNAs evaluated, five (miR-320a-3p, miR-210-3p, miR-92a-3p, miR-21-5p, and miR-140-3p) were statistically significantly (Wilcoxon rank sum test p < 0.05) elevated in case sera compared to controls, with individual AUCs ranging from 0.57-0.62. Compared to the 4MP alone, the combination of 3-miRNAs + 4MP improved sensitivity at 95% specificity by 19.1% ((95% CI of difference 0.0-28.6); two-sided p: 0.006). Our findings demonstrate utility for miRNAs for early detection of lung cancer in combination with a four-protein marker panel.

RevDate: 2022-09-13

Eastment MC, Long JE, Wanje G, et al (2022)

Qualitative evaluation of the Systems Analysis and Improvement Approach as a strategy to increase HIV testing in family planning clinics using the Consolidated Framework for Implementation Research and the Implementation Outcomes Framework.

Implementation science communications, 3(1):97.

BACKGROUND: Significant gaps remain in HIV testing and counseling (HTC) in family planning (FP) clinics. To address these gaps, our group tested an implementation strategy called the Systems Analysis and Improvement Approach (SAIA), an evidenced-based multi-component implementation strategy focused on improving entire care cascades. In a cluster randomized trial of 24 FP clinics in Mombasa County, Kenya, SAIA led to a significant increase in HTC in intervention clinics compared to control clinics. The objective of this manuscript was to evaluate SAIA using the Consolidated Framework for Implementation Research (CFIR) and assess the Implementation Outcomes Framework outcomes of acceptability, appropriateness, and feasibility.

METHODS: This qualitative assessment was nested within the cluster-randomized trial. Data collection included questionnaires to assess modifiable and non-modifiable health system factors related to HTC and in-depth interviews to query clinic norms, priorities, communication strategies, and readiness for change. The primary outcomes of interest were feasibility, appropriateness, and acceptability of SAIA. Data on inner setting and structural characteristics of FP clinics were collected to inform how context may impact outcomes. All interviews were recorded and analyzed using a rapid assessment approach.

RESULTS: Of the 12 intervention clinics, 6 (50%) were public facilities. Availability of resources varied by clinic. Most clinics had a positive implementation climate, engaged leadership, and access to resources and information. While not all clinics identified HTC as a clinic priority, most reported a strong culture of embracing change and recognition of the importance of HIV testing within FP clinics. Interviews highlighted very high acceptability, appropriateness, and feasibility of SAIA. The implementation strategy was not complicated and fit well into existing clinic processes. In particular, staff appreciated that SAIA allowed clinic staff to generate contextually relevant solutions that they implemented.

CONCLUSIONS: SAIA was implemented in FP clinics of varying sizes, capacity, and management support and was found to be acceptable, appropriate, and feasible. The agency that clinic staff felt in proposing and implementing their own solutions was likely part of SAIA's success. We anticipate this will continue to be a mechanism of SAIA's success when it is scaled up to more clinics in future trials.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT02994355) registered 16 December 2016.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Brown DW, Zhou W, Wang Y, et al (2022)

Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis.

Nature communications, 13(1):5284.

Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Gerds AT, Gotlib J, Ali H, et al (2022)

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(9):1033-1062.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

RevDate: 2022-09-08

Smith CJ, Sinnott-Armstrong N, Cichońska A, et al (2022)

Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation.

eLife, 11: pii:79348 [Epub ahead of print].

Pleiotropy and genetic correlation are widespread features in GWAS, but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.

RevDate: 2022-09-21
CmpDate: 2022-09-09

Weymar GHJ, Bar-On Y, Oliveira TY, et al (2022)

Distinct gene expression by expanded clones of quiescent memory CD4+ T cells harboring intact latent HIV-1 proviruses.

Cell reports, 40(10):111311.

Antiretroviral therapy controls, but does not cure, HIV-1 infection due to a reservoir of rare CD4+ T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here, we report a strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single-cell transcriptomic analysis of 1,050 CD4+ T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis reveals that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, granzymes A and K, cystatin F, LYAR, and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4+ T cell population, opening possibilities for eradication.

RevDate: 2022-09-09
CmpDate: 2022-09-09

Zhao LP, Lybrand TP, Gilbert P, et al (2022)

Application of Statistical Learning to Identify Omicron Mutations in SARS-CoV-2 Viral Genome Sequence Data From Populations in Africa and the United States.

JAMA network open, 5(9):e2230293 pii:2795987.

Importance: With timely collection of SARS-CoV-2 viral genome sequences, it is important to apply efficient data analytics to detect emerging variants at the earliest time.

Objective: To evaluate the application of a statistical learning strategy (SLS) to improve early detection of novel SARS-CoV-2 variants using viral sequence data from global surveillance.

This case series applied an SLS to viral genomic sequence data collected from 63 686 individuals in Africa and 531 827 individuals in the United States with SARS-CoV-2. Data were collected from January 1, 2020, to December 28, 2021.

Main Outcomes and Measures: The outcome was an indicator of Omicron variant derived from viral sequences. Centering on a temporally collected outcome, the SLS used the generalized additive model to estimate locally averaged Omicron caseload percentages (OCPs) over time to characterize Omicron expansion and to estimate when OCP exceeded 10%, 25%, 50%, and 75% of the caseload. Additionally, an unsupervised learning technique was applied to visualize Omicron expansions, and temporal and spatial distributions of Omicron cases were investigated.

Results: In total, there were 2698 cases of Omicron in Africa and 12 141 in the United States. The SLS found that Omicron was detectable in South Africa as early as December 31, 2020. With 10% OCP as a threshold, it may have been possible to declare Omicron a variant of concern as early as November 4, 2021, in South Africa. In the United States, the application of SLS suggested that the first case was detectable on November 21, 2021.

Conclusions and Relevance: The application of SLS demonstrates how the Omicron variant may have emerged and expanded in Africa and the United States. Earlier detection could help the global effort in disease prevention and control. To optimize early detection, efficient data analytics, such as SLS, could assist in the rapid identification of new variants as soon as they emerge, with or without lineages designated, using viral sequence data from global surveillance.

RevDate: 2022-09-07

Schumacher BT, Di C, Bellettiere J, et al (2022)

Validation, Recalibration, and Predictive Accuracy of Published V˙O2max Prediction Equations for Adults Ages 50 - 96.

Medicine and science in sports and exercise pii:00005768-990000000-00112 [Epub ahead of print].

PURPOSE: Maximal oxygen uptake (V˙O2max) is the criterion measure of cardiorespiratory fitness (CRF). Lower CRF is a strong predictor of poor health outcomes, including all-cause mortality. Since V˙O2max testing is resource intensive, several non-exercise based V˙O2max prediction equations have been published. We assess these equations' ability to predict measured V˙O2max, recalibrate these equations, and quantify the association of measured and predicted V˙O2max with all-cause mortality.

METHODS: Baltimore Longitudinal Study of Aging participants with valid V˙O2max tests were included (n = 1,080). Using published V˙O2max prediction equations, we calculated predicted V˙O2max and present performance metrics before and after recalibration (deriving new regression estimates by regressing measured V˙O2max on BLSA covariates). Cox proportional hazards models were fit to quantify associations of measured, predicted, and recalibration-predicted values of V˙O2max with mortality.

RESULTS: Mean age and V˙O2max were 69.0 ± 10.4 years and 21.6 ± 5.9 mL·kg-1·min-1, respectively. The prediction equations yielded root mean squared error values ranging from 4.2-20.4 mL·kg-1·min-1. After recalibration, these values decreased to 3.9-4.2 mL·kg-1·min-1. Adjusting for all covariates, all-cause mortality risk was 66% lower for the highest quartile of measured V˙O2max relative to the lowest. Predicted V˙O2max variables yielded similar estimates in unadjusted models but were not robust to adjustment.

CONCLUSIONS: Measured V˙O2max is an extremely strong predictor of all-cause mortality. Several published V˙O2max prediction equations yielded: (1) reasonable performance metrics relative to measured V˙O2max,especially when recalibrated, (2) all-cause mortality hazard ratios similar to those of measured V˙O2max, especially when recalibrated, yet (3) were not robust to adjustment for basic demographic covariates likely because these were used in the equation for predicted V˙O2max.

RevDate: 2022-09-07

Steineck A, Lau N, Fladeboe KM, et al (2022)

Seeking virtual support: Digital technology use in adolescent and young adults with advanced cancer.

Pediatric blood & cancer [Epub ahead of print].

BACKGROUND: A cancer diagnosis, especially advanced cancer, interferes with adolescent/young adult (AYA) peer relationships. AYAs increasingly use digital technologies (i.e., social media, video games) as a social instrument; little is known about the role of digital technologies in the AYA cancer experience. The objective of this analysis was to describe the use and impact of digital technologies among AYAs with advanced cancer.

PROCEDURE: As part of the "Exploring the Concept of a 'Good Death'" study, semi-structured interviews were conducted with 32 English-speaking AYAs (14-25 years) with advanced cancer (relapsed/refractory disease, estimated survival <50%). Interviews were audio recorded, deidentified, and transcribed verbatim. Questions focused on communication and sources of psychosocial support. Directed content analysis was used for codebook creation. Three reviewers completed transcript coding and reconciled discrepancies. Thematic analysis identified hierarchical themes. The present analysis focused on the specific theme of "digital technologies as a support mechanism."

RESULTS: When asked about sources of support, social media and multiplayer online games were most often recognized by AYAs. Three themes emerged regarding the role of digital technologies: distraction, maintaining existing peer support, and connecting with peers with cancer. Two AYAs acknowledged negative consequences of social media.

CONCLUSIONS: AYAs with advanced cancer cite digital technologies as a mechanism for maintaining and seeking peer support. Digital technologies may be leveraged to provide psychosocial support for AYAs with advanced cancer.

RevDate: 2022-09-07

Güner G, Aßfalg M, Zhao K, et al (2022)

Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.

EMBO molecular medicine [Epub ahead of print].

Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ-secretase in tumor cells reduced sFn14 secretion, increased full-length Fn14 at the cell surface, and enhanced TWEAK ligand-stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ-Secretase-dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ-secretase inhibitor prior to chimeric antigen receptor (CAR)-T-cell treatment. Taken together, our study demonstrates a novel function for γ-secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ-secretase activity in vivo.

RevDate: 2022-09-10
CmpDate: 2022-09-08

Weil AA, Luiten KG, Casto AM, et al (2022)

Genomic surveillance of SARS-CoV-2 Omicron variants on a university campus.

Nature communications, 13(1):5240.

Novel variants continue to emerge in the SARS-CoV-2 pandemic. University testing programs may provide timely epidemiologic and genomic surveillance data to inform public health responses. We conducted testing from September 2021 to February 2022 in a university population under vaccination and indoor mask mandates. A total of 3,048 of 24,393 individuals tested positive for SARS-CoV-2 by RT-PCR; whole genome sequencing identified 209 Delta and 1,730 Omicron genomes of the 1,939 total sequenced. Compared to Delta, Omicron had a shorter median serial interval between genetically identical, symptomatic infections within households (2 versus 6 days, P = 0.021). Omicron also demonstrated a greater peak reproductive number (2.4 versus 1.8), and a 1.07 (95% confidence interval: 0.58, 1.57; P < 0.0001) higher mean cycle threshold value. Despite near universal vaccination and stringent mitigation measures, Omicron rapidly displaced the Delta variant to become the predominant viral strain and led to a surge in cases in a university population.

RevDate: 2022-09-06

Mirembe BG, Cabrera MV, van der Straten A, et al (2022)

Correlates of Dapivirine Vaginal Ring Acceptance among Women Participating in an Open Label Extension Trial.

AIDS and behavior [Epub ahead of print].

MTN-025/HOPE was an open-label trial of the dapivirine vaginal ring conducted in four African countries between 2016 and 2018. Women were first offered one ring monthly (at baseline, months 1 and 2), thereafter, transitioned to a more applicable real-world dispensation schedule, - 3 rings quarterly (at months 3, 6 and 9). Logistic regression analysis was used to assess correlates of ring acceptance at baseline and through follow-up. A total of 1456 women (median age 31 years) enrolled, 1342 (92.2%) accepted the ring at baseline and 1163 (79.9%) accepted the ring(s) at all visits. Changing ring dispensation from a monthly to a quarterly schedule had no negative effect on acceptance. Having a primary partner and him knowing about the ring being offered in HOPE, use of long-acting contraception (implants, injections, IUDs) or sterilization were associated with ring acceptance, along with prior strong intention to use the ring in the future. Efforts should consider these factors when rolling out the ring for HIV prevention.

RevDate: 2022-09-17

Adams SJ, Madtes DK, Burbridge B, et al (2022)

Clinical Impact and Generalizability of a Computer-Assisted Diagnostic Tool to Risk-Stratify Lung Nodules With CT.

Journal of the American College of Radiology : JACR pii:S1546-1440(22)00630-5 [Epub ahead of print].

OBJECTIVE: To evaluate whether an imaging classifier for radiology practice can improve lung nodule classification and follow-up.

METHODS: A machine learning classifier was developed and trained using imaging data from the National Lung Screening Trial (NSLT) to produce a malignancy risk score (malignancy Similarity Index [mSI]) for individual lung nodules. In addition to NLST cohorts, external cohorts were developed from a tertiary referral lung cancer screening program data set, and an external nonscreening data set of all nodules detected on CT. Performance of the mSI combined with Lung-RADS was compared with Lung-RADS alone and the Mayo and Brock risk calculators.

RESULTS: We analyzed 963 subjects and 1,331 nodules across these cohorts. The mSi was comparable in accuracy (area under the curve = 0.89) to existing clinical risk models (area under the curve = 0.86-0.88) and independently predictive in the NLST cohort of 704 nodules. When compared with Lung-RADS, the mSi significantly increased sensitivity across all cohorts (25%-117%), with significant increases in specificity in the screening cohorts (17%-33%). When used in conjunction with Lung-RADS, use of mSI would result in earlier diagnoses and reduced follow-up across cohorts, including the potential for early diagnosis in 42% of malignant NLST nodules from prior-year CT scans.

CONCLUSION: A computer-assisted diagnosis software improved risk classification from chest CTs of screening and incidentally detected lung nodules compared with Lung-RADS. mSI added predictive value independent of existing radiological and clinical variables. These results suggest the generalizability and potential clinical impact of a tool that is straightforward to implement in practice.

RevDate: 2022-09-02

Lee BY, Ordovás JM, Parks EJ, et al (2022)

Research gaps and opportunities in precision nutrition: an NIH workshop report.

The American journal of clinical nutrition pii:6687804 [Epub ahead of print].

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On January 11-12, 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The Workshop proceeded in three parts: Part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer's disease, and cancer. Part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health. Part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches, and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

RevDate: 2022-09-02

Ramsey SD, Friedberg JW, Cox JV, et al (2022)

Economic Analysis of Screening, Diagnostic, and Treatment Technologies for Cancer: Reflections and a Roadmap for Prospective Authors.

RevDate: 2022-09-02

Ramsey SD, Friedberg JW, Cox JV, et al (2022)

Economic Analysis of Screening, Diagnostic, and Treatment Technologies for Cancer: Reflections and a Roadmap for Prospective Authors.

RevDate: 2022-09-10

Hanscom BS, Donnell DJ, Fleming TR, et al (2022)

Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

Clinical trials (London, England) [Epub ahead of print].

BACKGROUND/AIMS: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy.

METHODS: Here we describe some unique aspects of the trial's design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring.

RESULTS: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control.

CONCLUSIONS: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small-as will often be the case-nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

RevDate: 2022-09-20
CmpDate: 2022-09-08

Rodems TS, Heninger E, Stahlfeld CN, et al (2022)

Reversible epigenetic alterations regulate class I HLA loss in prostate cancer.

Communications biology, 5(1):897.

Downregulation of HLA class I (HLA-I) impairs immune recognition and surveillance in prostate cancer and may underlie the ineffectiveness of checkpoint blockade. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Here, we conducted a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Loss of HLA-I gene expression was associated with repressive chromatin states including DNA methylation, histone H3 tri-methylation at lysine 27, and reduced chromatin accessibility. Pharmacological DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition decreased DNA methylation and increased H3 lysine 27 acetylation and resulted in re-expression of HLA-I on the surface of tumor cells. Re-expression of HLA-I on LNCaP cells by DNMT and HDAC inhibition increased activation of co-cultured prostate specific membrane antigen (PSMA)27-38-specific CD8+ T-cells. HLA-I expression is epigenetically regulated by functionally reversible DNA methylation and chromatin modifications in human prostate cancer. Methylated HLA-I was detected in HLA-Ilow circulating tumor cells (CTCs), which may serve as a minimally invasive biomarker for identifying patients who would benefit from epigenetic targeted therapies.

RevDate: 2022-09-16
CmpDate: 2022-09-16

Chen T, Wei X, Courret C, et al (2022)

The nanoCUT&RUN technique visualizes telomeric chromatin in Drosophila.

PLoS genetics, 18(9):e1010351.

Advances in genomic technology led to a more focused pattern for the distribution of chromosomal proteins and a better understanding of their functions. The recent development of the CUT&RUN technique marks one of the important such advances. Here we develop a modified CUT&RUN technique that we termed nanoCUT&RUN, in which a high affinity nanobody to GFP is used to bring micrococcal nuclease to the binding sites of GFP-tagged chromatin proteins. Subsequent activation of the nuclease cleaves the chromatin, and sequencing of released DNA identifies binding sites. We show that nanoCUT&RUN efficiently produces high quality data for the TRL transcription factor in Drosophila embryos, and distinguishes binding sites specific between two TRL isoforms. We further show that nanoCUT&RUN dissects the distributions of the HipHop and HOAP telomere capping proteins, and uncovers unexpected binding of telomeric proteins at centromeres. nanoCUT&RUN can be readily applied to any system in which a chromatin protein of interest, or its isoforms, carries the GFP tag.

RevDate: 2022-09-12
CmpDate: 2022-09-08

Su T, Duran GE, Kwang AC, et al (2022)

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome.

Oncoimmunology, 11(1):2115197.

The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment using single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole-exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.

RevDate: 2022-09-13

Calder T, Tong T, Hu DJ, et al (2022)

Leveraging lessons learned from the COVID-19 pandemic for HIV.

Communications medicine, 2:110.

The rapid development of COVID-19 vaccines and their deployment in less than a year is an unprecedented scientific, medical, and public health achievement. This rapid development leveraged knowledge from decades of HIV/AIDS research and advances. However, the search for an HIV vaccine that would contribute to a durable end to the HIV pandemic remains elusive. Here, we draw from the US government experience and highlight lessons learned from COVID-19 vaccine development, which include the importance of public-private partnerships, equitable inclusion of populations impacted by the infectious pathogen, and continued investment in basic research. We summarize key considerations for an accelerated and re-energized framework for developing a safe and efficacious HIV vaccine.

RevDate: 2022-09-08
CmpDate: 2022-09-08

Vallejo J, Saigusa R, Gulati R, et al (2022)

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells.

BMC biology, 20(1):193.

BACKGROUND: Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single-cell (sc)RNA sequencing (scRNA-seq) in PBMCs.

RESULTS: Among 31 participants in the Women's Interagency HIV Study (WIHS), we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs (tool for visualizing high-dimensional data) and Louvain clustering, we identified 50 subsets among CD4+ T, CD8+ T, B, NK cells, and monocytes. This resolution was superior to flow cytometry, mass cytometry, or scRNA-seq without antibodies. Combined protein and transcript scRNA-seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportions. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease.

CONCLUSIONS: In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

RevDate: 2022-09-24

Harding C, Larsen BB, Gryseels S, et al (2022)

Discovery of three cycloviruses in fecal samples from silver-haired bats (Lasionycteris noctivagans) in Arizona (USA).

Archives of virology [Epub ahead of print].

Bats harbour a diverse array of viruses, some of which are zoonotic, and are one of the most speciose groups of mammals on earth. As part of an ongoing bat-associated viral diversity research project, we identified three cycloviruses (family Circoviridae) in fecal samples of silver-haired bats (Lasionycteris noctivagans) caught in Cave Creek Canyon of Arizona (USA). Two of the three identified genomes represent two new species in the genus Cyclovirus. Cycloviruses have been found in a wide range of environments and hosts; however, little is known about their biology. These new genomes of cycloviruses are the first from silver-haired bats, adding to the broader knowledge of cyclovirus diversity. With continuing studies, it is likely that additional viruses of the family Circoviridae will be identified in Arizona bat populations.

RevDate: 2022-09-22
CmpDate: 2022-09-08

Bosch DE, Yeh MM, Salipante SJ, et al (2022)

Isolated MLH1 Loss by Immunohistochemistry Because of Benign Germline MLH1 Polymorphisms.

JCO precision oncology, 6:e2200227.

PURPOSE: Mismatch repair (MMR) immunohistochemistry (IHC) is frequently used to inform prognosis, select (immuno-)therapy, and identify patients for heritable cancer syndrome testing. However, false-negative and false-positive MMR IHC interpretations have been described.

MATERIALS AND METHODS: Following identification of discordant MMR IHC and DNA-based microsatellite instability testing in a patient with colorectal carcinoma, we retrospectively reviewed institutional archives to identify patient samples with similar discrepancies.

RESULTS: We report a patient with metastatic colorectal carcinoma who initially received immunotherapy on the basis of apparent isolated loss of MLH1 by IHC; notably, MLH1 promoter hypermethylation was negative. Subsequent evaluation of neoplastic tissue on a DNA-based targeted next-generation sequencing panel demonstrated microsatellite stability, low tumor mutational burden, and a benign MLH1 variant, MLH1 p.V384D, accompanied by loss of heterozygosity. The constellation of findings and repeat MLH1 IHC demonstrating retained expression using a different antibody-clone, supported reclassification of the neoplasm as MMR-proficient. Immunotherapy was discontinued, and cytotoxic chemotherapy was initiated. This index case of apparent discordance between MMR IHC and DNA-based microsatellite instability prompted a retrospective review of institutional archives to identify patient samples with similar discrepancies. Further evaluation of neoplasms harboring MLH1 p.V384D with loss of heterozygosity revealed systematic antibody-dependent interference. The review also identified a second IHC-interference candidate, MLH1 p.A441T.

CONCLUSION: This study confirms that rare germline polymorphisms can result in incorrect IHC results, potentially affecting selection of optimal therapy and the decision to pursue germline testing. This case further highlights the need for expert molecular pathologic review and communication between clinical and molecular oncology teams.

RevDate: 2022-09-02

Peng K, Deng N, Meng Y, et al (2022)

Alpha-Momorcharin Inhibits Proinflammatory Cytokine Expression by M1 Macrophages but Not Anti-Inflammatory Cytokine Expression by M2 Macrophages.

Journal of inflammation research, 15:4853-4872.

Background: Alpha-momorcharin (α-MMC) is a natural medicine derived from bitter melon and has been found to exert immunomodulatory effects. Our previous study indicated that α-MMC can regulate cytokine release from monocytes, but it remains unknown about its regulatory effect on different types of cytokines, such as inflammatory cytokines or anti-inflammatory cytokines.

Methods: LPS-induced M1-type macrophages model and IL-4-induced M2-type macrophages model were established, and the expression of proinflammatory cytokines and anti-inflammatory cytokines were assessed by ELISA after α-MMC was administered. Then, a LPS-induced acute pneumonia mouse model was established, the proinflammatory cytokines levels and inflammatory lesions in lung tissues were examined by ELISA or H&E staining. Furthermore, omics screening analysis and Western blotting verification were performed on TLR4 and JAK1-STAT6 signalling pathway-related proteins to elucidate the regulatory mechanism of α-MMC in those M1 macrophages and M2 macrophages.

Results: At a noncytotoxic dose of 0.3 μg/mL, α-MMC significantly inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, MIP-1α and MCP-1, by M1 macrophages in a time-dependent manner, but α-MMC did not inhibit the IL-4-induced synthesis of anti-inflammatory cytokines, such as IL-10, IL-1RA, EGF, VEGF, TGF-β and CCL22, by M2 macrophages. Moreover, α-MMC also inhibited inflammatory cytokine expression in an LPS-induced acute pneumonia mouse model and alleviated inflammation in lung tissues. Furthermore, omics screening and Western blotting analysis confirmed that α-MMC inhibited TAK1/p-TAK1 and subsequently blocked the downstream MAPK and NF-κB pathways, thus inhibiting the LPS-induced inflammatory cytokine expression.

Conclusion: Our results reveal that α-MMC inhibits proinflammatory cytokine expression by M1 macrophages but not anti-inflammatory cytokine expression by M2 macrophages. The efficacy of α-MMC in selectively inhibiting proinflammatory cytokine expression renders it particularly suitable for the treatment of severe inflammation and autoimmune diseases characterized by cytokine storms.

RevDate: 2022-08-30

Chen YY, Chen GC, Abittan N, et al (2022)

Healthy dietary patterns and risk of cardiovascular disease in US Hispanics/Latinos: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

The American journal of clinical nutrition pii:6679288 [Epub ahead of print].

BACKGROUND: Multiple dietary patterns haven been recommended by 2015-2020 Dietary Guidelines for Americans for the prevention of cardiovascular disease (CVD). The adherence to these patterns and its relationship with risk of CVD remain unclear in the US Hispanic/Latino population.

OBJECTIVES: We aimed to evaluate three healthy eating patterns measured by three dietary pattern scores (the Alternate Mediterranean diet (aMED), the Healthy Eating Index (HEI)-2015, and the healthful Plant-based Diet Index (hPDI)) across different Hispanic/Latino backgrounds and generations. We further examined the associations of these dietary scores with incident CVD in US Hispanics/Latinos.

METHODS: We included 10,293 adult participants of US Hispanics/Latinos of six backgrounds (Mexican, Puerto Rican, Cuban, Dominican, Central American and South American), free of CVD or cancer at baseline, in the Hispanic Community Health Study/Study of Latinos. Dietary pattern scores were derived at the baseline visit using two 24-hour dietary recalls. The primary outcome was the major incident CVD (n = 232), comprised of coronary heart disease and stroke, during an average 6-year follow-up.

RESULTS: Mean levels of all three dietary scores were significantly different across 6 Hispanic/Latino background groups (all P < 0.001), with highest (i.e., healthiest) in those of Mexican background and lowest in those of Puerto Rican background. Compared to non-mainland-US-born Hispanics/Latinos, mainland-US-born Hispanics/Latinos had significantly lower dietary scores (P < 0.001). Differences in dietary scores between mainland-US-born and non-mainland-US-born Hispanics/Latinos were majorly driven by differences in dietary intakes of healthy plant-based foods. After adjusting for multiple covariates, significantly lower risk ratios (95% CI) of CVD were observed for one standard deviation increment of the dietary scores, with 0.74 (0.60,0.91) for aMED, 0.80 (0.63,1.00) for HEI-2015, and 0.74 (0.60,0.93) for hPDI.

CONCLUSIONS: Although adherence to healthy eating patterns varies by Hispanic/Latino backgrounds and generations, greater adherence to these eating patterns is associated with lower risk of CVD across diverse US Hispanics/Latinos.

RevDate: 2022-09-07

Rahal HK, Tabibian JH, Issaka RB, et al (2022)

Diversity, Equity, and Inclusion in Gastroenterology and Hepatology: A Survey of Where We Stand.

The American journal of gastroenterology pii:00000434-990000000-00492 [Epub ahead of print].

This paper has been temporarily removed by the publisher, Wolters-Kluwer, due to a publication embargo. We regret any confusion this may have caused. This paper will be published once production is complete.

RevDate: 2022-08-30

Neuhouser ML, Pettinger M, Tinker LF, et al (2022)

Associations of Biomarker-Calibrated HEI-2010 Scores With Chronic Disease Risk and Their Dependency On Energy Intake and Body Mass Index in Postmenopausal Women.

The Journal of nutrition pii:6679107 [Epub ahead of print].

BACKGROUND: Prior studies examined associations between Healthy Eating Index (HEI) and chronic disease risk based on self-reported diet without measurement error correction.

OBJECTIVES: Our objective was to test associations between biomarker-calibration of food frequency questionnaire (FFQ)-derived HEI-2010 with incident cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) among Women's Health Initiative (WHI) participants. WHI is registered at clinicaltrials.gov: NCT00000611.

METHODS: Data were derived from WHI postmenopausal women (n = 100,374) aged 50-79 y at enrollment (1993-1998) at 40 US clinical centers, linked to nutritional biomarker substudies and outcomes over subsequent decades of follow-up. Baseline or year 1 FFQ-derived HEI-2010 scores were calibrated with nutritional biomarkers and participant characteristics [e.g., body mass index (BMI)] for systematic measurement error correction. Calibrated data were then used in hazard ratio (HR) models examining associations with incidence of CVD (total, subtypes, mortality), cancer (total, subtypes, mortality), and T2D in WHI participants with approximately two decades of follow-up. Models were multivariable-adjusted with further adjustment for BMI and doubly-labeled water (DLW)-calibrated energy.

RESULTS: Multivariable adjusted HRs modeled a 20% increment in HEI-2010 score in relation to outcomes. HRs were modest using uncalibrated HEI-2010 scores (HRs = 0.91-1.09). Using biomarker calibrated HEI-2010, 20% increments in scores yielded multivariable-adjusted HRs (95%CIs) of: 0.75 (0.60-0.93): coronary heart disease; 0.75, (0.61.-0.91): myocardial infarction; 0.96 (0.92-1.01): stroke; 0.88 (0.75-1.02): CVD mortality; 0.81 (0.70-0.94): colorectal cancer; 0.81 (0.74-0.88): breast cancer; 0.79 (0.73-0.87): cancer mortality; and 0.45 (0.36-0.55): T2D. Except for cancer mortality and T2D incidence, results became null when adjusted for DLW-calibrated energy intake and BMI.

CONCLUSIONS: Biomarker calibration of FFQ-derived HEI-2010 was associated with lower CVD and cancer incidence and mortality and lower T2D incidence in postmenopausal women. Attenuation after adjustment with BMI and DLW-calibrated energy suggest that energy intake and/or obesity are strong drivers of diet-related chronic disease risk in postmenopausal women.

RevDate: 2022-08-29

Mohty M, R Storb (2022)

'Standing on the Shoulders of the Giants': Dr Rainer Storb.

Clinical hematology international pii:10.1007/s44228-022-00018-2 [Epub ahead of print].

RevDate: 2022-08-29

Tafazzoli A, Ramsey SD, Shaul A, et al (2022)

The Potential Value-Based Price of a Multi-Cancer Early Detection Genomic Blood Test to Complement Current Single Cancer Screening in the USA.

PharmacoEconomics [Epub ahead of print].

BACKGROUND: Multi-cancer early detection (MCED) testing could increase detection of cancer at early stages, when survival outcomes are better and treatment costs are lower, but is expected to increase screening costs. This study modeled an MCED test for 19 solid cancers in a US population and estimated the potential value-based price (the maximum price to meet a given willingness to pay) of the MCED test plus current single cancer screening (usual care) compared to usual care alone from a third-party payer perspective over a lifetime horizon.

METHODS: A hybrid cohort-level state-transition and decision-tree model was developed to estimate the clinical and economic outcomes of annual MCED testing between age 50 and 79 years. The impact on time and stage of diagnosis was computed using an interception modeling approach, with the consequences of cancer modeled based on stage at diagnosis. The model parameters were mainly sourced from the literature, including a published case-control study to inform MCED test performance. All costs were inflated to 2021 US dollars.

RESULTS: Multi-cancer early detection testing shifted cancer diagnoses to earlier stages, with a 53% reduction in stage IV cancer diagnoses, resulting in longer overall survival compared with usual care. Addition of MCED decreased per cancer treatment costs by $5421 and resulted in a gain of 0.13 and 0.38 quality-adjusted life-years across all individuals in the screening program and those diagnosed with cancer, respectively. At a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained, the potential value-based price of an MCED test was estimated at $1196. The projected survival of individuals diagnosed with cancer and the number of cancers detected at an earlier stage by MCED had the greatest impact on outcomes.

CONCLUSIONS: An MCED test with high specificity would potentially improve long-term health outcomes and reduce cancer treatment costs, resulting in a value-based price of $1196 at a $100,000/quality-adjusted life-year willingness-to-pay threshold.

RevDate: 2022-08-29

Sowalsky AG, Plymate SR, Haffner MC, et al (2022)

Re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation Therapy. Eur Urol 2021;79:879-86 AR-V7 is Rare in Hormone-sensitive Prostate Cancer: AR-V7 is Rare in Hormone-sensitive Prostate Cancer.

RevDate: 2022-08-29

Gregory PF, Angus J, Brothers AW, et al (2022)

Risk Factors for Development of Pneumatosis Intestinalis After Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Case-Control Study.

Transplantation and cellular therapy pii:S2666-6367(22)01592-5 [Epub ahead of print].

BACKGROUND: The significance of pneumatosis intestinalis (PI) in pediatric patients following hematopoietic stem cell transplantation (HSCT) is poorly understood. A knowledge gap remains with respect to the etiology, risk factors and evidence-based treatment of these patients. As a result, management is frequently based on each center's clinical practice without standardization across treatment centers.

PURPOSE: In this single-center trial, we aimed to validate both previously proposed as well as additional risk factors for development of PI and to examine our management and outcomes for these patients.

METHODS: We performed a retrospective case-control study examining risk factors for the development of PI in pediatric HSCT patients at a single tertiary referral children's hospital. We used univariate and multivariable conditional logistic regression analysis to explore differences in pharmacologic and other transplant-specific risk factors.

RESULTS: Between 2012 and 2019, PI was diagnosed in two hundred twelve patients at our pediatric hospital, of which forty-two were HSCT recipients. The majority of patients (88%; n=37 of 42) with PI were diagnosed by X-ray. Eighteen (43%) patients were asymptomatic and diagnosed incidentally after imaging was obtained for standard post-transplantation surveillance or other nonrelated indications. All patients with PI were hospitalized and placed on strict bowel rest while receiving parenteral nutrition (PN) and antibiotics. Recurrence of PI occurred in four patients (10%) following their initial diagnosis. Increased doses of steroid exposure within 30 days of PI diagnosis (OR 5.7; 95% CI 2.1 to 15.3; p=0.0006), presence of grade 2 to 4 gastrointestinal graft-vs-host disease (GVHD) (OR 5.3; 95% CI 1.0 to 28.1; p=0.05), and receipt of greater than 50% of total daily nutrition by nasogastric tube feeds (OR 22.0; 95% CI 1.3 to 370.2; p=0.03) were found to be independent risk factors for development of PI. Intensity of the conditioning regimen, exposure to total-body irradiation, stem cell source, donor type, HLA matching, use of mycophenolate mofetil, and presence of bacterial or viral infection at the time of PI diagnosis were not demonstrably associated with development of PI in our study.

CONCLUSION: We conclude that development of asymptomatic PI is a benign condition following HSCT and the risk for PI increases in patients with gastrointestinal GVHD, those receiving steroid therapy, and patients relying on supplemental nasogastric tube feeds for at least half of their total daily nutrition.

RevDate: 2022-09-10

Turcotte LM, Whitton JA, Leisenring WM, et al (2022)

Chronic Conditions, Late Mortality and Health Status After Childhood AML: A Childhood Cancer Survivor Study Report.

Blood pii:486440 [Epub ahead of print].

Five-year survival following childhood acute myeloid leukemia (AML) has increased due to improvements in treatment and supportive care. The impact of these changes on long-term health outcomes is unknown. To address this, cumulative incidence of late mortality and grades 3-5 chronic health conditions (CHCs) standardized mortality ratios (SMR) were estimated among five-year AML survivors from the Childhood Cancer Survivor Study diagnosed 1970-1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT]; chemotherapy with cranial radiation [chemo+CRT]; chemotherapy only [chemo-only]) and decade of diagnosis. Self-reported health status was compared across treatments, decade of diagnosis, and with siblings. Among 856 survivors (median diagnosis age 7.1 years; median age at last follow-up 29.4 years) the 20-year late mortality cumulative incidence was highest after HCT (13.9%, 95%CI 10.0-17.8%; chemo+CRT 7.6%, 95%CI 2.2-13.1%; chemo-only 5.1%, 95%CI 2.8-7.4%). Mortality cumulative incidence decreased for survivors of HCT diagnosed in the 1990s (8.5%, 95%CI 4.1-12.8%) compared with the 1970s (38.9%, 95%CI 16.4-61.4%), as did SMRs. Most survivors did not experience any grade 3-5 CHC after 20 years (HCT, 45.8%; chemo+CRT 23.7%; chemo-only 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; p=0.02), mirroring a reduction in total body irradiation use. Self-reported health status was good to excellent for 88.2% of survivors, regardless of treatment; however, this was lower than siblings (94.8%; p<0.0001). Although HCT is associated with greater long-term morbidity and mortality compared with chemotherapy-based treatment, these gaps have narrowed and all treatment groups report favorable health status.

RevDate: 2022-09-18

Irajizad E, Han CY, Celestino J, et al (2022)

A blood-based metabolite panel for distinguishing ovarian cancer from benign pelvic masses.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:708818 [Epub ahead of print].

PURPOSE: To assess the contributions of circulating metabolites for improving upon the performance of the Risk of Ovarian Malignancy Algorithm (ROMA) for risk prediction of ovarian cancer (OvCa) among women with ovarian cysts.

EXPERIMENTAL DESIGN: Metabolomic profiling was performed on an initial set of sera from 101 serous and non-serous OvCa cases and 134 individuals with benign pelvic masses (BPM). Using a deep learning model, a panel consisting of seven cancer-related metabolites (diacetylspermine, diacetylspermidine, N-(3-acetamidopropyl)pyrrolidin-2-one, N-acetylneuraminate, N-acetyl-mannosamine, N-acetyl-lactosamine, and hydroxyisobutyric acid) was developed for distinguishing early-stage OvCa from BPM. The performance of the metabolite panel was evaluated in an independent set of sera from 118 OvCa cases and 56 subjects with BPM. The contributions of the panel for improving upon the performance of ROMA was further assessed.

RESULTS: A 7-marker metabolite panel (7MetP) developed in the Training Set yielded an AUC of 0.86 (95% CI: 0.76-0.95) for early-stage OvCa in the independent Test Set. The 7MetP+ROMA model had an AUC of 0.93 (95% CI: 0.84-0.98) for early-stage OvCa in the Test Set, which was improved compared to ROMA alone (0.91 (95% CI: 0.84-0.98); likelihood ratio test p-value:.03). In the entire specimen set, the combined 7MetP+ROMA model yielded a higher positive predictive value (0.68 vs 0.52; 1-sided p<.001) with improved specificity (0.89 vs 0.78; 1-sided p<.001) for early-stage OvCa compared to ROMA alone.

CONCLUSIONS: A blood-based metabolite panel was developed that demonstrates independent predictive ability and complements ROMA for distinguishing early-stage OvCa from benign disease to better inform clinical decision making.

RevDate: 2022-08-30

Clarke SL, Parham M, Lankester J, et al (2022)

Broad clinical manifestations of polygenic risk for coronary artery disease in the Women's Health Initiative.

Communications medicine, 2:108.

Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.

Methods: We measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women's Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes.

Results: Polygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal.

Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

RevDate: 2022-08-30

Ellis SD, Vaidya R, Unger JM, et al (2022)

Access to urologists for participation in research: An analysis of NCI's Community Oncology Research Program landscape survey.

Contemporary clinical trials communications, 29:100981.

Purpose: Urological cancer clinical trials face accrual challenges, which may stem from structural barriers within cancer programs. We sought to describe the extent to which urology cancer care providers are available within community cancer research programs and explore the role of oncology practice group ownership in their access to urology practices to participate in research.

Materials and methods: We conducted secondary analysis of organizational survey data collected in 2017 among National Cancer Institute Community Oncology Research Program practice groups. We used logistic regression to assess the association of self-reported access to urologists to participate in research and oncology practice group ownership type: independent, payor-provider, health-system, or public ownership.

Results: Of the 209 community oncology practice groups in the analysis sample, 133 (63.6%) had access to urologists for research participation. Ownership was not statistically significantly associated with access to urology practices after controlling for other covariates (p = 0.4). Instead, having a hospital outpatient clinic (p = 0.008) and identifying as a safety-net hospital (p = 0.035) were both positively significantly associated with access to urologists to participate in research.

Conclusions: Two-thirds of community cancer research groups have access to urology. Oncology ownership status was not associated with access to urologists for research. Research groups may need support to increase their capacity to engage non-oncology cancer care providers in research.

RevDate: 2022-09-06

Iketani S, Hong SJ, Sheng J, et al (2022)

Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites.

Cell host & microbe [Epub ahead of print].

The SARS-CoV-2 3CL protease (3CLpro) is an attractive therapeutic target, as it is essential to the virus and highly conserved among coronaviruses. However, our current understanding of its tolerance to mutations is limited. Here, we develop a yeast-based deep mutational scanning approach to systematically profile the activity of all possible single mutants of the 3CLpro and validate a subset of our results within authentic viruses. We reveal that the 3CLpro is highly malleable and is capable of tolerating mutations throughout the protein. Yet, we also identify specific residues that appear immutable, suggesting that these may be targets for future 3CLpro inhibitors. Finally, we utilize our screening as a basis to identify E166V as a resistance-conferring mutation against the clinically used 3CLpro inhibitor, nirmatrelvir. Collectively, the functional map presented herein may serve as a guide to better understand the biological properties of the 3CLpro and for drug development against coronaviruses.

RevDate: 2022-08-26

Phuong A, Marquardt JP, O'Malley R, et al (2022)

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

Urologic oncology pii:S1078-1439(22)00275-7 [Epub ahead of print].

OBJECTIVES: To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events.

MATERIALS AND METHODS: This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles.

RESULTS: 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs.

CONCLUSIONS: In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Prentice RL, Howard BV, Van Horn L, et al (2021)

Reply to WC Willett and D Ludwig.

The American journal of clinical nutrition, 114(6):2120-2122.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Yarborough S, Fitzpatrick A, Schwartz SM, et al (2022)

Evaluation of cognitive function in the Dog Aging Project: associations with baseline canine characteristics.

Scientific reports, 12(1):13316.

Canine cognitive dysfunction (CCD) is a neurodegenerative disease in aging dogs. It has been described previously in relatively small cohorts of dogs using multiple different rating scales. This study aimed to use a minimally modified CCD rating scale developed by previous researchers to describe the prevalence of CCD more thoroughly in a large, nationwide cohort of companion dogs participating in the Dog Aging Project (DAP) (n = 15,019). Associations between various canine characteristics, predicted lifespan quartiles, and CCD were examined using univariable and multivariable logistic regression models and receiver operating curve (ROC) analysis. When controlling for all other characteristics, the odds of CCD increased 52% with each additional year of age. Among dogs of the same age, health status, breed type, and sterilization status, odds of CCD were 6.47 times higher in dogs who were not active compared to those who were very active. When controlling for age, breed type, activity level, and other comorbidities, dogs with a history of neurological, eye, or ear disorders had higher odds of CCD. Lifespan quartile analysis showed excellent discriminating ability between CCD positive and negative dogs. Weight-based lifespan quartile estimation could therefore serve as a tool to inform CCD screening by veterinarians.

RevDate: 2022-08-25

Li C, Georgakopoulou A, Newby GA, et al (2022)

In vivo base editing by a single intravenous vector injection for treatment of hemoglobinopathies.

JCI insight pii:162939 [Epub ahead of print].

Individuals with beta-thalassemia or Sickle Cell Disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% HbF appear to be symptom-free. Here, we used a non-integrating HDAd5/35++ vector expressing a highly efficient and accurate version of an adenine base editor (ABE8e) to install, in vivo, a -113A>G HPFH mutation in the gamma-globin promoters in "healthy" CD46/β-YAC mice carrying the human β-globin locus. Our in vivo hematopoietic stem cell (HSC) editing/selection strategy involves only subcutaneous and intravenous injections and does not require myeloablation and HSC transplantation. In vivo HSC base editing in CD46/β-YAC mice resulted in >60% -113A>G conversion with 30% γ-globin of human beta globin expressed in 70% of erythrocytes. Importantly, no off-target editing at sites predicted by CIRCLE-Seq or in silico was detected. Furthermore, no critical alterations in the transcriptome of in vivo edited mice were found by RNA-seq. In vitro, in HSCs from beta-thalassemia and Sickle Cell Disease patients, transduction with the base editor vector mediated efficient -113 A>G conversion and reactivation of γ-globin expression with subsequent phenotypic correction of erythroid cells. Because our in vivo base editing strategy is safe and technically simple, it has the potential for clinical application in developing countries where hemoglobinopathies are prevalent.

RevDate: 2022-08-25

Gust J, Rawlings-Rhea SD, Wilson AL, et al (2022)

GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients.

Blood advances pii:486403 [Epub ahead of print].

There is a need for biomarkers to predict and measure the severity of immune effector cell associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS, and that increases of GFAP and NfL levels during treatment reflect ICANS severity. We measured CSF GFAP (cGFAP) and NfL (cNfL) as well as serum NfL (sNfL) levels in pretreatment and day 7-10 post CAR T samples in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL increased during grade≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. sNfL levels did not increase during ICANS. Pre-lymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline levels of cGFAP were associated with history of transplant, patients with prior CNS radiation had higher cNfL levels, and elevated baseline levels of sNfLwere associated with a history of peripheral neuropathy. cGFAP and cNfL may be useful biomarkers to measure the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL and sNfL likely reflect the cumulative injury to the central and peripheral nervous system from prior treatment. However, levels of any of the three biomarkers prior to CAR T cell infusion did not predict ICANS risk.

RevDate: 2022-09-20

Holmberg LA, Linenberger M, L Connelly-Smith (2022)

Successful Mobilization of Autologous Hematopoietic Peripheral Blood Stem Cells after Salvage Chemotherapy in Patients with Low CD34 Blood Cell Counts.

Transplantation and cellular therapy pii:S2666-6367(22)01558-5 [Epub ahead of print].

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

RevDate: 2022-08-26
CmpDate: 2022-08-26

Murphy SC, Vaughan AM, Kublin JG, et al (2022)

A genetically engineered Plasmodium falciparum parasite vaccine provides protection from controlled human malaria infection.

Science translational medicine, 14(659):eabn9709.

Genetically engineered live Plasmodium falciparum sporozoites constitute a potential platform for creating consistently attenuated, genetically defined, whole-parasite vaccines against malaria through targeted gene deletions. Such genetically attenuated parasites (GAPs) do not require attenuation by irradiation or concomitant drug treatment. We previously developed a P. falciparum (Pf) GAP with deletions in P52, P36, and SAP1 genes (PfGAP3KO) and demonstrated its safety and immunogenicity in humans. Here, we further assessed safety, tolerability, and immunogenicity of the PfGAP3KO vaccine and tested its efficacy against controlled human malaria infection (CHMI) in malaria-naïve subjects. The vaccine was delivered by three (n = 6) or five (n = 8) immunizations with ~200 PfGAP3KO-infected mosquito bites per immunization. PfGAP3KO was safe and well tolerated with no breakthrough P. falciparum blood stage infections. Vaccine-related adverse events were predominately localized urticaria related to the numerous mosquito bites administered per vaccination. CHMI via bites with mosquitoes carrying fully infectious Pf NF54 parasites was carried out 1 month after the last immunization. Half of the study participants who received either three or five PfGAP3KO immunizations remained P. falciparum blood stage negative, as shown by a lack of detection of Plasmodium 18S rRNA in the blood for 28 days after CHMI. Six protected study participants received a second CHMI 6 months later, and one remained completely protected. Thus, the PfGAP3KO vaccine was safe and immunogenic and was capable of inducing protection against sporozoite infection. These results warrant further evaluation of PfGAP3KO vaccine efficacy in dose-range finding trials with an injectable formulation.

RevDate: 2022-08-31
CmpDate: 2022-08-25

Lu D, Sapkota Y, Valdimarsdóttir UA, et al (2022)

Genome-wide association study of posttraumatic stress disorder among childhood cancer survivors: results from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Translational psychiatry, 12(1):342.

Genetic influence shapes who develops posttraumatic stress disorder (PTSD) after traumatic events. However, the genetic variants identified for PTSD may in fact be associated with traumatic exposures (e.g., interpersonal violence), which appear heritable as well. Childhood cancer survivors (CCS) are at risk for PTSD, but genetic influences affecting cancer are unlikely to overlap with those affecting PTSD. This offers a unique opportunity to identify variants specific to PTSD risk. In a genome-wide association study (GWAS), 3984 5-year survivors of childhood cancer of European-ancestry from the Childhood Cancer Survivor Study (CCSS) were evaluated for discovery and 1467 survivors from the St. Jude Lifetime (SJLIFE) cohort for replication. Childhood cancer-related PTSD symptoms were assessed using the Posttraumatic Stress Diagnostic Scale in CCSS. GWAS was performed in CCSS using logistic regression and lead markers were replicated/meta-analyzed using SJLIFE. Cross-associations of identified loci were examined between CCS and the general population. PTSD criteria were met for 671 participants in CCSS and 161 in SJLIFE. Locus 10q26.3 was significantly associated with PTSD (rs34713356, functionally mapped to ECHS1, P = 1.36 × 10-8, OR 1.57), and was replicated in SJLIFE (P = 0.047, OR 1.37). Variants in locus 6q24.3-q25.1 reached marginal significance (rs9390543, SASH1, P = 3.56 × 10-6, OR 0.75) in CCSS and significance when meta-analyzing with SJLIFE (P = 2.02 × 10-8, OR 0.75). Both loci were exclusively associated with PTSD in CCS rather than PTSD/stress-related disorders in general population (P-for-heterogeneity < 5 × 10-6). Our CCS findings support the role of genetic variation in PTSD development and may provide implications for understanding PTSD heterogeneity.

RevDate: 2022-08-26

Chow EJ, Casto AM, Rogers JH, et al (2022)

The clinical and genomic epidemiology of seasonal human coronaviruses in congregate homeless shelter settings: A repeated cross-sectional study.

Lancet Regional Health. Americas, 15:100348.

Background: The circulation of respiratory viruses poses a significant health risk among those residing in congregate settings. Data are limited on seasonal human coronavirus (HCoV) infections in homeless shelter settings.

Methods: We analysed data from a clinical trial and SARS-CoV-2 surveillance study at 23 homeless shelter sites in King County, Washington between October 2019-May 2021. Eligible participants were shelter residents aged ≥3 months with acute respiratory illness. We collected enrolment data and nasal samples for respiratory virus testing using multiplex RT-PCR platform including HCoV. Beginning April 1, 2020, eligibility expanded to shelter residents and staff regardless of symptoms. HCoV species was determined by RT-PCR with species-specific primers, OpenArray assay or genomic sequencing for samples with an OpenArray relative cycle threshold <22.

Findings: Of the 14,464 samples from 3281 participants between October 2019-May 2021, 107 were positive for HCoV from 90 participants (median age 40 years, range: 0·9-81 years, 38% female). HCoV-HKU1 was the most common species identified before and after community-wide mitigation. No HCoV-positive samples were identified between May 2020-December 2020. Adults aged ≥50 years had the highest detection of HCoV (11%) among virus-positive samples among all age-groups. Species and sequence data showed diversity between and within HCoV species over the study period.

Interpretation: HCoV infections occurred in all congregate homeless shelter site age-groups with the greatest proportion among those aged ≥50 years. Species and sequencing data highlight the complexity of HCoV epidemiology within and between shelters sites.

Funding: Gates Ventures, Centers for Disease Control and Prevention, National Institute of Health.

RevDate: 2022-08-22

Gregg JR, Kim J, Logothetis C, et al (2022)

Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer.

European urology oncology pii:S2588-9311(22)00138-9 [Epub ahead of print].

BACKGROUND: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized.

OBJECTIVE: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer.

Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up.

Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype.

RESULTS AND LIMITATIONS: High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p > 0.05). Limitations include the nominal statistical significance and residual confounding.

CONCLUSIONS: Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (*1F/*1F) genotype, a finding that will require further replication.

PATIENT SUMMARY: It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why.

RevDate: 2022-09-23

Sun J, Mossa-Basha M, Canton G, et al (2022)

Characterization of non-stenotic plaques in intracranial arteries with multi-contrast, multi-planar vessel wall image analysis.

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 31(10):106719.

OBJECTIVES: Non-stenotic plaques have been observed in intracranial arteries but are less understood compared to those in coronary and carotid arteries. We sought to compare plaque distribution and morphology between stenotic and non-stenotic intracranial plaques with MR vessel wall imaging (VWI) and quantitative image analysis.

MATERIALS AND METHODS: Twenty-four patients with intracranial arterial stenosis or luminal irregularity on clinical imaging were scanned with a multi-contrast VWI protocol. Plaques were detected as focal wall thickening on co-registered multiplanar reformats of multi-contrast VWI, with assessment of the location and morphology. TOF-MRA was independently reviewed for any appreciable stenosis using the WAISD criteria.

RESULTS: Across 504 arterial segments, a total of 80 plaques were detected, including 23 (29%) with stenosis on TOF-MRA, 56 (70%) without, and 1 (1%) not covered by TOF-MRA. Plaques involving the ICA were more likely to be non-stenotic than those involving other segments (80% versus 55%, p = 0.030) whereas the basilar artery (40%) and PCA (33%) had the lowest proportions of non-stenotic plaques. Maximum wall thickness, indicative of plaque burden, correlated poorly with degree of stenosis (p = 0.10) and overlapped substantially between stenotic and non-stenotic plaques (1.9 [1.5, 2.4] versus 2.0 [1.5, 2.2] mm, p = 0.074).

CONCLUSIONS: Intracranial plaques without appreciable stenosis on TOF-MRA represent a large proportion of lesions throughout arterial segments but disproportionately affect the ICA. Morphological characterization of plaques with and without stenosis shows that luminal stenosis is a poor indicator of the underlying burden of intracranial atherosclerosis.

RevDate: 2022-08-29
CmpDate: 2022-08-24

Bauermeister JA, Tingler RC, Ho K, et al (2022)

Acceptability of PC-1005 Gel Administered Rectally to HIV-1 Seronegative Adults at Three Different Volume Levels (MTN-037).

AIDS education and prevention : official publication of the International Society for AIDS Education, 34(4):257-271.

Multipurpose prevention technologies (MPT) have been increasingly researched for their dual-purpose preventative properties against HIV and other STIs. The acceptability of PC-1005, a topical MPT candidate, was explored among men and women participating in the MTN-037 Phase I trial at two U.S. sites (Pittsburgh, PA, and Birmingham, AL). We triangulated quantitative and qualitative assessments of the acceptability of three volumes (4 mL, 16 mL, 32 mL) of PC-1005 administered rectally (N = 12; 6 males, 6 females). Participants rated overall gel acceptability on a scale of 1-10, with a median of 7.17 (SD = 2.04) and had positive feelings about all three dose volumes, citing them to be very comfortable or comfortable (dose 1 = 91.7%; dose 2 = 91.7%; dose 3 = 83.3%). High acceptability of and comfort with all three dose volumes shows promise for PC-1005 as an MPT to prevent HIV and STIs, warranting future clinical development.

RevDate: 2022-08-23

Heffron R, Muwonge TR, Thomas KK, et al (2022)

PrEP uptake and HIV viral suppression when PrEP is integrated into Ugandan ART clinics for HIV-negative members of HIV-serodifferent couples: A stepped wedge cluster randomized trial.

EClinicalMedicine, 52:101611.

Background: Global scale-up of HIV pre-exposure prophylaxis (PrEP) includes services to HIV-negative people in partnerships with people living with HIV (serodifferent couples). Data are needed on HIV outcomes, including uptake and adherence to PrEP and antiretroviral treatment (ART), to describe the impact of integrating PrEP into an existing HIV program.

Methods: Using a stepped-wedge cluster randomized trial design, we launched PrEP delivery for HIV-negative members of serodifferent couples in Uganda by integrating PrEP into existing ART programs for people living with HIV. The program provided PrEP training for ART providers, ongoing technical assistance, and a provisional supply chain mechanism for PrEP medication. Primary data on PrEP initiation, PrEP refills, ART initiation, and HIV viremia at 6 months (measured at 42-270 days) were collected through data abstraction of medical records from HIV-serodifferent couples sequentially enrolling at the ART clinics. Modified Poisson regression models, controlling for time and cluster, compared viral suppression (<1000 copies/ml) before and after launch of the PrEP program. This trial was registered at ClinicalTrials.gov, NCT03586128.

Findings: From June 1, 2018-December 15, 2020, 1,381 HIV-serodifferent couples were enrolled across 12 ART clinics in Kampala and Wakiso, Uganda, including 730 enrolled before and 651 after the launch of PrEP delivery. During the baseline period, 99.4% of partners living with HIV initiated ART and 85.0% were virally suppressed at 6 months. Among HIV-negative partners enrolled after PrEP launched, 81.0% (527/651) initiated PrEP within 90 days of enrolling; among these 527, 11.2% sought a refill 6 months later. In our powered intent-to-treat analysis, 82.1% and 76.7% of partners living with HIV were virally suppressed, respectively, which was not a statistically significant difference (RR=0.94, 95% CI: 0.82-1.07) and was stable across sensitivity analyses.

Interpretation: Integration of PrEP into ART clinics reached a high proportion of people in HIV-serodifferent relationships and did not improve the already high frequency of HIV viral suppression among partners living with HIV.

Funding: National Institute of Mental Health (R01MH110296).

RevDate: 2022-08-24

Saigusa R, Roy P, Freuchet A, et al (2022)

Single cell transcriptomics and TCR reconstruction reveal CD4 T cell response to MHC-II-restricted APOB epitope in human cardiovascular disease.

Nature cardiovascular research, 1(5):462-475.

Atherosclerosis is accompanied by a CD4 T cell response to apolipoprotein B (APOB). Major Histocompatibility Complex (MHC)-II tetramers can be used to isolate antigen-specific CD4 T cells by flow sorting. Here, we produce, validate and use an MHC-II tetramer, DRB1*07:01 APOB-p18, to sort APOB-p18-specific cells from peripheral blood mononuclear cell samples from 8 DRB1*07:01+ women with and without subclinical cardiovascular disease (sCVD). Single cell RNA sequencing showed that transcriptomes of tetramer+ cells were between regulatory and memory T cells in healthy women and moved closer to memory T cells in women with sCVD. TCR sequencing of tetramer+ cells showed clonal expansion and V and J segment usage similar to those found in regulatory T cells. These findings suggest that APOB-specific regulatory T cells may switch to a more memory-like phenotype in women with atherosclerosis. Mouse studies showed that such switched cells promote atherosclerosis.

RevDate: 2022-09-03

Liese AD, Neuhouser M, CJ Boushey (2022)

Comparisons of Four Diet Quality Indexes to Define Single Meal Healthfulness.

RevDate: 2022-09-11

Pai RK, Banerjee I, Shivji S, et al (2022)

Quantitative Pathologic Analysis of Digitized Images of Colorectal Carcinoma Improves Prediction of Recurrence-Free Survival.

Gastroenterology pii:S0016-5085(22)00951-9 [Epub ahead of print].

BACKGROUND AND AIMS: To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis.

METHODS: A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938).

RESULTS: There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs.

CONCLUSIONS: QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.

RevDate: 2022-08-19

Park HA, Edelmann D, Canzian F, et al (2022)

Predictive polygenic score for outcome after first-line oxaliplatin-based chemotherapy in colorectal cancer patients using supervised principal component analysis.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:708158 [Epub ahead of print].

BACKGROUND: Associations between candidate germline genetic variants and treatment outcome of oxaliplatin, a drug commonly used for colorectal cancer patients, have been reported but not robustly established. This study aimed to construct polygenic hazard scores (PHSs) as predictive markers for oxaliplatin treatment outcome by using a supervised principal component approach (PCA).

METHODS: Genome-wide association analysis for overall survival, including interaction terms (SNP*treatment type) was carried out using two phase III trials, 3,098 resected stage III colon cancer (rCC) patients of NCCTG N0147 and 506 metastatic colorectal cancer (mCRC) patients of NCCTG N9741, separately. SNPs showing interaction with genome-wide significance (P<5×10-8) were selected for PCA to derive a PHS. PHS interaction with treatment was included in Cox regression models to predict outcome. Replication of prediction models was performed in an independent cohort, DACHS.

RESULTS: The two PHSs based on the first two principal components of selected SNPs (15SNPs for rCC and 13SNPs for mCRC) were used to construct interaction terms with treatment type and included in models adjusted for clinical covariables. However, in the DACHS study, the addition of the two PHS terms to clinical models did not improve the prediction error in either rCC or mCRC patients. PHS interaction were also not replicated.

CONCLUSION: The PHSs derived using principal components efficiently combined multiple predictive SNPs for estimating likelihood of benefit from oxaliplatin versus other treatment but could not be replicated.

IMPACT: These results highlight the potential but also challenges in generating evidence for a predictive polygenic score for oxaliplatin efficacy.

RevDate: 2022-08-19

Kirkey DC, Loeb A, Castro S, et al (2022)

Therapeutic targeting PRAME with mTCRCAR T cells in acute myeloid leukemia.

Blood advances pii:486322 [Epub ahead of print].

Preferentially Expressed Antigen in Melanoma (PRAME) , a cancer testes antigen provides an ideal target for immunotherapy in AML. We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a CAR construct encoding a targeting domain based on T cell receptor (TCR) mimic antibodies that targets the peptide:HLA complex. We used the antibody sequence from a previously designed antibody, Pr20, a TCR mimic antibody that recognizes PRAME ALY peptide in complex with HLA-A*02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary AML patient samples and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to the appropriate controls, PRAME mTCRCAR T cells demonstrate target specific and HLA-mediated in vitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared to unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with IFN-γ, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

RevDate: 2022-09-06
CmpDate: 2022-08-22

Yuan AE, W Shou (2022)

Data-driven causal analysis of observational biological time series.

eLife, 11:.

Complex systems are challenging to understand, especially when they defy manipulative experiments for practical or ethical reasons. Several fields have developed parallel approaches to infer causal relations from observational time series. Yet, these methods are easy to misunderstand and often controversial. Here, we provide an accessible and critical review of three statistical causal discovery approaches (pairwise correlation, Granger causality, and state space reconstruction), using examples inspired by ecological processes. For each approach, we ask what it tests for, what causal statement it might imply, and when it could lead us astray. We devise new ways of visualizing key concepts, describe some novel pathologies of existing methods, and point out how so-called 'model-free' causality tests are not assumption-free. We hope that our synthesis will facilitate thoughtful application of methods, promote communication across different fields, and encourage explicit statements of assumptions. A video walkthrough is available (Video 1 or https://youtu.be/AIV0ttQrjK8).

RevDate: 2022-08-20

Peters BA, Santoro N, Kaplan RC, et al (2022)

Spotlight on the Gut Microbiome in Menopause: Current Insights.

International journal of women's health, 14:1059-1072.

The gut microbiome is an important contributor to human health, shaped by many endogenous and exogenous factors. The gut microbiome displays sexual dimorphism, suggesting influence of sex hormones, and also has been shown to change with aging. Yet, little is known regarding the influence of menopause - a pivotal event of reproductive aging in women - on the gut microbiome. Here, we summarize what is known regarding the interrelationships of female sex hormones and the gut microbiome, and review the available literature on menopause, female sex hormones, and the gut microbiome in humans. Taken together, research suggests that menopause is associated with lower gut microbiome diversity and a shift toward greater similarity to the male gut microbiome, however more research is needed in large study populations to identify replicable patterns in taxa impacted by menopause. Many gaps in knowledge remain, including the role the gut microbiome may play in menopause-related disease risks, and whether menopausal hormone therapy modifies menopause-related change in the gut microbiome. Given the modifiable nature of the gut microbiome, better understanding of its role in menopause-related health will be critical to identify novel opportunities for improvement of peri- and post-menopausal health and well-being.

RevDate: 2022-09-06
CmpDate: 2022-08-26

Yuan M, Tu B, Li H, et al (2022)

Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.

Nature cancer, 3(8):945-960.

Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

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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.

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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 )