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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 08 Feb 2023 at 01:44 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: ( fhcrc[Affiliation] OR "fred hutchinson"[Affiliation] OR "Fred Hutchinson Cancer Research"[Affiliation] OR "Fred Hutch"[affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2023-02-06

Montoya VR, Ready TM, Felton A, et al (2023)

A Virus-Packageable CRISPR System Identifies Host Dependency Factors Co-Opted by Multiple HIV-1 Strains.

mBio [Epub ahead of print].

At each stage of the HIV life cycle, host cellular proteins are hijacked by the virus to establish and enhance infection. We adapted the virus packageable HIV-CRISPR screening technology at a genome-wide scale to comprehensively identify host factors that affect HIV replication in a human T cell line. Using a smaller, targeted HIV Dependency Factor (HIVDEP) sublibrary, we then performed screens across HIV strains representing different clades and with different biological properties to define which T cell host factors are important across multiple HIV strains. Nearly 90% of the genes selected across various host pathways validated in subsequent assays as bona fide host dependency factors, including numerous proteins not previously reported to play roles in HIV biology, such as UBE2M, MBNL1, FBXW7, PELP1, SLC39A7, and others. Our ranked list of screen hits across diverse HIV-1 strains form a resource of HIV dependency factors for future investigation of host proteins involved in HIV biology. IMPORTANCE With a small genome of ~9.2 kb that encodes 14 major proteins, HIV must hijack host cellular machinery to successfully establish infection. These host proteins necessary for HIV replication are called "dependency factors." Whole-genome, and then targeted screens were done to try to comprehensively identify all dependency factors acting throughout the HIV replication cycle. Many host processes were identified and validated as critical for HIV replication across multiple HIV strains.

RevDate: 2023-02-07

Ha TV, Hoffman IF, Miller WC, et al (2022)

Association between drug use and ART use among people living with HIV who inject drugs in Vietnam, Ukraine and Indonesia: results from HPTN 074.

Journal of substance use, 27(6):648-657.

BACKGROUND AND OBJECTIVE: Drug use type and frequency may affect Anti-Retroviral Therapy (ART) uptake for HIV-infected people who inject drugs (PWID). This paper assesses the association between self-reported baseline drug use and ART among HIV-infected PWID in Indonesia, Ukraine and Vietnam.

METHODS: Data on self-reported baseline drug use and ART among HIV-infected PWID at the 26- and 52-week follow-ups were extracted from the HIV Prevention Trials Network (HPTN) 074, a randomized, controlled vanguard study to facilitate HIV treatment for PWID in Indonesia, Ukraine, and Vietnam. Multivariable logistic regression models were fit by study site and the whole HPTN 074 sample, using a 0.5 type I error rate.

RESULTS: The response rate were 83.3% and 77.0% at 26[th] and 52[th] weeks. At 26-week, baseline use of over one non-opiate/non-stimulant drug was associated with lower odds of ART use among Indonesian participants (OR = 0.21, 95%CI: 0.05-0.82); and baseline injecting drugs for over 20 days in the previous month was associated with lower odds of ART use among all HPTN 074 sample (OR = 0.59, 95% CI: 0.36-0.97).

CONCLUSION: The association of a specific drug use pattern with later ART uptake implies the importance of medication-assisted treatment to enhance ART uptake and adherence among participants.

RevDate: 2023-02-06

Velloza J, Roche SD, Owidi EJ, et al (2023)

Provider perspectives on service delivery modifications to maintain access to HIV pre-exposure prophylaxis during the COVID-19 pandemic: qualitative results from a PrEP implementation project in Kenya.

Journal of the International AIDS Society, 26(2):e26055.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) is an essential prevention strategy being scaled up for priority populations in Kenya, including for HIV serodiscordant couples. The COVID-19 pandemic posed challenges to PrEP rollout. We conducted a qualitative study of PrEP providers to understand how clinics adjusted PrEP delivery during the COVID-19 pandemic.

METHODS: Since 2017, the Partners Scale-Up Project has integrated PrEP into 25 HIV clinics in Central and Western Kenya. We conducted qualitative interviews with 40 purposively sampled clinic personnel. We interviewed personnel once during the first pandemic wave (May-Aug 2020) and again after some decline in COVID-19 rates (Nov-Jan 2021). We analysed data using inductive memo-writing and summarized data by themes along the PrEP delivery cascade, guided by the Framework for Reporting Adaptation and Modifications (FRAME).

RESULTS: We interviewed 27 clinical officers, five nurses, four health records and information officers, and four counsellors from Central (n = 20) and Western (n = 20) Kenya. About half (n = 19) were female, with a median age of 32 (IQR: 29-34) and 2.3 years of experience delivering PrEP (IQR: 2-3). All participants reported clinic changes in PrEP demand creation and service delivery during the pandemic. Modifications occurred during PrEP implementation and sustainment phases, were partly reactive to the pandemic and also facilitated by interim Ministry of Health guidance on PrEP delivery during COVID, and were made by PrEP delivery teams, clients and clinic managers. Commonly reported modifications included dispensing multiple-month PrEP refills, intensifying phone-based client engagement and collaborating with other HIV clinics to ensure that clients with prolonged stays in other regions could continue to access PrEP. Some clinics also adopted practices to streamline visits, such as within clinical-room PrEP dispensing, pre-packing PrEP and task-shifting. Most providers liked these changes and hoped they would continue after the pandemic subsides.

CONCLUSIONS: COVID-19 served as a catalyst for PrEP delivery innovations in Kenya. HIV clinics successfully and rapidly adapted their PrEP demand creation, refill and retention strategies to promote PrEP uptake and effective use. These modified implementation strategies highlight opportunities to streamline the delivery of PrEP, as well as other HIV and chronic care services, and strengthen engagement with populations post-pandemic.

RevDate: 2023-02-03

Miller CP, Shokri F, Akilesh S, et al (2023)

Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma.

Applied immunohistochemistry & molecular morphology : AIMM pii:00129039-990000000-00078 [Epub ahead of print].

5T4 (trophoblast glycoprotein encoded by TPBG) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of 5T4 by emerging receptor-engineered cellular immunotherapies has been hampered by the lack of validated 5T4-specific reagents for immunohistochemistry (IHC). We tested 4 commercially available monoclonal antibodies (mAbs) for the detection of 5T4 in formalin-fixed, paraffin-embedded RCC and normal tissues. Using parental and TPBG-edited A498 cells, 3 mAbs showed 5T4 specificity. Further analyses focused on 2 mAbs with the most robust staining (MBS1750093, Ab134162). IHC on tissue microarrays incorporating 263 renal tumors showed high staining concordance of these 2 mAbs ranging from 0.80 in chromophobe RCC to 0.89 in advanced clear cell RCC (ccRCC). MBS1750093, the most sensitive, exhibited 2+/3+ staining in papillary RCC (92.2%) > advanced ccRCC (60.0%) > chromophobe RCC (43.6%) > localized ccRCC (39.6%) > oncocytoma (22.7%). RNA in situ hybridization also revealed high levels of TPBG RNA were present most frequently in papillary and advanced ccRCC. In advanced ccRCC, there was a trend towards higher 5T4 expression and regional or distant metastases. Normal organ controls showed no or weak staining with the exception of focal moderate staining in kidney glomeruli and distal tubules by IHC. These data identify mAbs suitable for detecting 5T4 in formalin-fixed, paraffin-embedded tissues and demonstrate both interpatient and histologic subtype heterogeneity. Our validated 5T4 IHC protocol will facilitate biomarker studies and support the therapeutic targeting of 5T4.

RevDate: 2023-02-03

Shouse G, Kaempf A, Gordon MJ, et al (2023)

A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B cell lymphoma.

Blood advances pii:494303 [Epub ahead of print].

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥3) in the respiratory, upper gastrointestinal, hepatic, or renal system - herein termed "Severe4" - had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC (hazards ratio [HR]=2.15 and 1.94, respectively; p<0.001) and in an independent single-center validation cohort (VC) (n=218; HR=1.85, p=0.003; HR=1.70, p=0.019, respectively). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC (odds ratio [OR]=2.43, p=0.042), while maintaining this trend in the VC (OR=2.05, p=0.114). Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.

RevDate: 2023-02-03

Kampouri E, O Manuel (2023)

Preemptive therapy versus universal prophylaxis: Time for reconciliation?.

RevDate: 2023-02-05

Henpita C, Vyas R, Healy CL, et al (2023)

Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy.

Aging cell [Epub ahead of print].

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1[-/D] mice). Ckmm-Cre[+/-] ;Ercc1[-/fl] mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre[+/-] ;Ercc1[-/fl] mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre[+/-] ;Ercc1[-/fl] mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre[+/-] ;Ercc1[-/fl] and Ercc1[-/D] mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.

RevDate: 2023-02-03

Marcoux C, Marin D, Ramdial J, et al (2023)

Younger Haploidentical Donor Versus Older Matched Unrelated Donor for Patients With AML/MDS.

American journal of hematology [Epub ahead of print].

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n = 494) or older (>35 years) MUDs (n = 1005). Patients in the haploidentical and MUD groups received post-transplant cyclophosphamide (PTCy) and conventional graft-versus-host-disease (GVHD) prophylaxis, respectively. In multivariate analysis, use of younger haploidentical donors was associated with improved overall survival (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69-0.95, p = 0.01) and lower rates of grade II-IV acute GVHD (HR 0.64, 95%CI 0.53-0.77, p < 0.001), grade III-IV acute GVHD (HR 0.37, 95%CI 0.25-0.53, p < 0.001), and chronic GVHD (HR 0.49, 95%CI 0.40-0.60, p < 0.001). Relapse rates were similar among those who received myeloablative conditioning but were higher in patients of the younger haploidentical group who received reduced intensity conditioning (HR 1.49, 95%CI 1.18-1.88, p = 0.001). The younger haploidentical group had significantly lower non-relapse mortality ≥3 months post-HCT (HR 0.59, 95%CI 0.38-0.90, p = 0.02). Our data support the use of younger haploidentical donors with PTCy over older MUDs with conventional prophylaxis in patients with MDS or AML. Further studies on the importance of donor age in haploidentical and MUD HCT with PTCy prophylaxis are warranted. This article is protected by copyright. All rights reserved.

RevDate: 2023-02-03

Li W, Li R, Yan Q, et al (2023)

Conditional concordance-assisted learning under matched case-control design for combining biomarkers for population screening.

Statistics in medicine [Epub ahead of print].

Incorporating promising biomarkers into cancer screening practices for early-detection is increasingly appealing because of the unsatisfactory performance of current cancer screening strategies. The matched case-control design is commonly adopted in biomarker development studies to evaluate the discriminative power of biomarker candidates, with an intention to eliminate confounding effects. Data from matched case-control studies have been routinely analyzed by the conditional logistic regression, although the assumed logit link between biomarker combinations and disease risk may not always hold. We propose a conditional concordance-assisted learning method, which is distribution-free, for identifying an optimal combination of biomarkers to discriminate cases and controls. We are particularly interested in combinations with a clinically and practically meaningful specificity to prevent disease-free subjects from unnecessary and possibly intrusive diagnostic procedures, which is a top priority for cancer population screening. We establish asymptotic properties for the derived combination and confirm its favorable finite sample performance in simulations. We apply the proposed method to the prostate cancer data from the carotene and retinol efficacy trial (CARET).

RevDate: 2023-02-02

Hu X, Wu X, Berry K, et al (2023)

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nature cell biology [Epub ahead of print].

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

RevDate: 2023-02-02

Mitchell K, Sprowls SA, Arora S, et al (2023)

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Genes & development pii:gad.349803.122 [Epub ahead of print].

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

RevDate: 2023-02-02

Nip Y, Bennett SR, Smith AA, et al (2023)

Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.

Human molecular genetics pii:7024679 [Epub ahead of print].

Human DUX4 and its mouse ortholog Dux are normally expressed in the early embryo-the 4-cell or 2-cell cleavage stage embryo, respectively-and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas FSHD-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program, and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a preclinical model for FSHD. In this study, we identify the porcine DUXC mRNA expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.

RevDate: 2023-02-02

Jiao B, Fredricks DN, Srinivasan S, et al (2023)

Economic Evaluation of a Point-of-Care Test for Bacterial Vaginosis among Women with Vaginal Symptoms.

Sexually transmitted diseases pii:00007435-990000000-00143 [Epub ahead of print].

BACKGROUND: There is an unmet need for a clinical diagnostic technology to detect bacterial vaginosis (BV) rapidly and accurately. Novel point-of-care (POC) tests have the potential to fulfill this gap. Our objective was to determine the cost-effectiveness of a hypothetical clinician-administered POC test for diagnosing BV in the United States.

METHODS: We developed a state-transition microsimulation model to evaluate the cost-effectiveness of using the POC test versus usual care among women of reproductive age with vaginal symptoms. We adopted a healthcare sector perspective that included relevant healthcare costs and a societal perspective that further incorporated productivity costs. Model parameters were empirically estimated based on commercial insurance claims data or derived from published literature. The primary model outcome was incremental cost-effectiveness ratio (ICER). We started with analyzing a hypothetical POC test with a sensitivity and specificity of 0.9 and a cost of $40, followed by extensive sensitivity analyses.

RESULTS: Using the hypothetical POC test to diagnose BV increased costs by $16 and quality-adjusted life year (QALYs) by 0.0005 per person compared with the usual care, leading to an ICER of $31,108 per QALY gained. When also capturing the productivity costs, the POC test resulted in an average cost savings of $57. The sensitivity analyses showed that the POC test's sensitivity was more influential on its cost-effectiveness than specificity.

CONCLUSIONS: Using the POC test to diagnose BV is likely to be cost-effective relative to usual care, especially with a high sensitivity or a substantial positive effect on productivity.

RevDate: 2023-02-03

Goldman JD, Wang K, Röltgen K, et al (2020)

Reinfection with SARS-CoV-2 and Failure of Humoral Immunity: a case report.

medRxiv : the preprint server for health sciences.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G. With antibody and B cell analytics, we show correlates of adaptive immunity, including a differential response to D614G. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

RevDate: 2023-02-02

Del Vecchio NJ, Beaber EF, Garcia MP, et al (2023)

Provider- and Facility-Level Variation in Pre-Cancerous Cervical Biopsy Diagnoses.

Journal of lower genital tract disease pii:00128360-990000000-00038 [Epub ahead of print].

OBJECTIVES: Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities.

METHODS: We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation.

RESULTS: A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36).

CONCLUSIONS: Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.

RevDate: 2023-02-02

Chlebowski RT, AK Aragaki (2023)

The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context.

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

IMPORTANCE AND OBJECTIVE: The menopausal hormone therapy (MHT) association with breast cancer has been controversial for more than 40 years. Most recently, findings from cohort studies have been discordant compared with those from the Women's Health Initiative (WHI) randomized trials. In cohort studies, both estrogen therapy and estrogen plus progestin were associated with higher breast cancer incidence. In contrast, in the WHI randomized trials, findings for estrogen plus progestin are concordant with cohort study reports, whereas estrogen therapy significantly reduced breast cancer incidence. In addition, concerns have been raised regarding the WHI findings from both trials. In this report, we briefly summarize findings for MHT on breast cancer from cohort studies and the WHI randomized trials. The report focus is addressing, point-by-point, concerns raised regarding the WHI findings.

METHODS: For cohort studies, we relied on the latest findings from (1) the meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer and (2) the Million Women's Study. To identify commentaries and editorials, "Menopause" and "Climacteric" were searched from 2002 to present; PubMed and Google Scholar were searched for commentaries, editorials, and breast cancer, MHT, estrogen, conjugated equine estrogen, estradiol, "hormone replacement therapy," and "HRT."

DISCUSSION AND CONCLUSIONS: Thirty commentaries challenging WHI findings were identified. All were reviewed, and issues needing response were identified. Findings from the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study were summarized and compared with finding in the two WHI randomized trials evaluating estrogen therapy and estrogen plus progestin. Based on the randomized clinical trials, estrogen therapy, for women with prior hysterectomy, decreases breast cancer incidence and mortality. In contrast, estrogen plus progestin increases breast cancer incidence, which persists through two decades. Women considering estrogen plus progestin use for vasomotor symptoms should understand the breast cancer risk.

RevDate: 2023-02-02

Zewdie K, Pickles M, Floyd S, et al (2023)

Uptake of medical male circumcision with household-based testing, and the association of traditional male circumcision and HIV infection.

AIDS (London, England) pii:00002030-990000000-00176 [Epub ahead of print].

OBJECTIVES: Voluntary medical male circumcision (VMMC) is an important component of combination HIV prevention. Inclusion of traditionally circumcised HIV negative men in VMMC uptake campaigns may be important if traditional male circumcision is less protective against HIV acquisition than VMMC.

METHODS: We used data from the HPTN 071 (PopART) study. This cluster-randomized trial assessed the impact of a combination prevention package on population-level HIV incidence in 21 study communities in Zambia and South Africa.We evaluated uptake of VMMC, using a two-stage analysis approach and used discrete-time survival analysis to evaluate the association between the types of male circumcision and HIV incidence.

RESULTS: 10,803 HIV-negative men with self-reported circumcision status were included in this study. At baseline, 56% reported being uncircumcised, 26% traditionally circumcised and 18% were medically circumcised. During the PopART intervention, 11% of uncircumcised men reported uptake of medical male circumcision. We found no significant difference in the uptake of VMMC in communities receiving the PopART intervention package and standard of care (adj rate ratio=1·10 (95% CI 0·82, 1·50, P = 0·48)). The rate of HIV acquisition for medically circumcised men was 70% lower than for those who were uncircumcised adjHR=0·30 (95% CI 0·16 to 0·55; p < 0·0001). There was no difference in rate of HIV acquisition for traditionally circumcised men compared to those uncircumcised adjHR= 0·84 (95% CI 0·54, 1·31; P = 0·45).

CONCLUSIONS: Household-based delivery of HIV testing followed by referral for medical male circumcision did not result in substantial VMMC uptake. Traditional circumcision is not associated with lower risk of HIV acquisition.

RevDate: 2023-02-02

Radich JP, Wall M, Branford S, et al (2023)

Molecular response in newly diagnosed chronic-phase chronic myeloid leukemia: prediction modeling and pathway analysis.

Haematologica [Epub ahead of print].

Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: Why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase 3 randomized trial, dichotomizing cases into good responders (BCR::ABL1 ≤10% International Scale by 3 and 6 months and ≤0.1% by 12 months) and poor responders (failure to meet these criteria). Predictive models based on gene expression demonstrated the best performance (area under the curve [SD], 0.76 [0.07]). All of the top 20 pathways overexpressed in good responders involved immune regulation, a finding validated in an independent data set. This study emphasizes the importance of pretreatment adaptive immune response in treatment efficacy and suggests biological pathways that can be targeted to improve response.

RevDate: 2023-02-01

Neary J, Fish CS, Cassidy NA, et al (2023)

Predictors of intact HIV DNA levels among children in Kenya.

AIDS (London, England) pii:00002030-990000000-00198 [Epub ahead of print].

OBJECTIVE: We determined predictors of both intact (estimate of replication-competent) and total (intact and defective) HIV DNA in the reservoir among children with HIV.

DESIGN: HIV DNA in the reservoir was quantified longitudinally in children who initiated antiretroviral therapy (ART) at <1 year of age using a novel cross-subtype intact proviral DNA assay that measures both intact and total proviruses. Quantitative PCR was used to measure pre-ART cytomegalovirus (CMV) viral load. Linear mixed effects models were used to determine predictors of intact and total HIV DNA levels (log10copies/million).

RESULTS: Among 65 children, median age at ART initiation was 5 months and median follow-up was 5.2 years; 86% of children had CMV viremia pre-ART. Lower pre-ART CD4 percent (adjusted relative risk [aRR]: 0.87, 95% confidence intervals [95%CI]: 0.79-0.97; p = 0.009) and higher HIV RNA (aRR: 1.21, 95%CI: 1.06-1.39; p = 0.004) predicted higher levels of total HIV DNA during ART. Pre-ART CD4 percent (aRR: 0.76, 95%CI: 0.65-0.89; p<0.001), CMV viral load (aRR: 1.16, 95%CI: 1.01-1.34; p = 0,041), and first line protease inhibitor-based regimens compared to non-nucleoside reverse transcriptase-based regimens (aRR: 1.36, 95%CI: 1.04-1.77; p = 0,025) predicted higher levels of intact HIV DNA.

CONCLUSION: Pre-ART immunosuppression, first-line ART regimen, and CMV viral load may influence establishment and sustainment of intact HIV DNA in the reservoir.

RevDate: 2023-02-02
CmpDate: 2023-02-02

Wen T, Liao D, Wellenius GA, et al (2023)

Short-term Air Pollution Levels and Blood Pressure in Older Women.

Epidemiology (Cambridge, Mass.), 34(2):271-281.

BACKGROUND: Evidence of associations between daily variation in air pollution and blood pressure (BP) is varied and few prior longitudinal studies adjusted for calendar time.

METHODS: We studied 143,658 postmenopausal women 50 to 79 years of age from the Women's Health Initiative (1993-2005). We estimated daily atmospheric particulate matter (PM) (in three size fractions: PM2.5, PM2.5-10, and PM10) and nitrogen dioxide (NO2) concentrations at participants' residential addresses using validated lognormal kriging models. We used linear mixed-effects models to estimate the association between air pollution concentrations and repeated measures of systolic and diastolic BP (SBP, DBP) adjusting for confounders and calendar time.

RESULTS: Short-term PM2.5 and NO2 were each positively associated with DBP {0.10 mmHg [95% confidence interval (CI): 0.04, 0.15]; 0.13 mmHg (95% CI: 0.09, 0.18), respectively} for interquartile range changes in lag 3-5 day PM2.5 and NO2. Short-term NO2 was negatively associated with SBP [-0.21 mmHg (95%CI: -0.30, -0.13)]. In two-pollutant models, the NO2-DBP association was slightly stronger, but for PM2.5 was attenuated to null, compared with single-pollutant models. Associations between short-term NO2 and DBP were more pronounced among those with higher body mass index, lower neighborhood socioeconomic position, and diabetes. When long-term (annual) and lag 3-5 day PM2.5 were in the same model, associations with long-term PM2.5 were stronger than for lag 3-5 day.

CONCLUSIONS: We observed that short-term PM2.5 and NO2 levels were associated with increased DBP, although two-pollutant model results suggest NO2 was more likely responsible for observed associations. Long-term PM2.5 effects were larger than short-term.

RevDate: 2023-02-02

Reynolds KM, Lin BM, Armstrong ND, et al (2022)

Circulating Metabolites Associated with Albuminuria in a Hispanic/Latino Population.

Clinical journal of the American Society of Nephrology : CJASN [Epub ahead of print].

BACKGROUND: Albuminuria is associated with metabolic abnormalities, but these relationships are not well understood. We studied the association of metabolites with albuminuria in Hispanic/Latino people, a population with high risk for metabolic disease.

METHODS: We used data from 3736 participants from the Hispanic Community Health Study/Study of Latinos, of which 16% had diabetes and 9% had an increased urine albumin-to-creatinine ratio (UACR). Metabolites were quantified in fasting serum through nontargeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Spot UACR was inverse normally transformed and tested for the association with each metabolite or combined, correlated metabolites, in covariate-adjusted models that accounted for the study design. In total, 132 metabolites were available for replication in the Hypertension Genetic Epidemiology Network study (n =300), and 29 metabolites were available for replication in the Malmö Offspring Study (n =999).

RESULTS: Among 640 named metabolites, we identified 148 metabolites significantly associated with UACR, including 18 novel associations that replicated in independent samples. These metabolites showed enrichment for D-glutamine and D-glutamate metabolism and arginine biosynthesis, pathways previously reported for diabetes and insulin resistance. In correlated metabolite analyses, we identified two modules significantly associated with UACR, including a module composed of lipid metabolites related to the biosynthesis of unsaturated fatty acids and alpha linolenic acid and linoleic acid metabolism.

CONCLUSIONS: Our study identified associations of albuminuria with metabolites involved in glucose dysregulation, and essential fatty acids and precursors of arachidonic acid in Hispanic/Latino population.

RevDate: 2023-02-01

Totiger TM, Chaudhry S, Musi E, et al (2023)

Protein biomarkers for response to XPO1 inhibition in haematologic malignancies.

Journal of cellular and molecular medicine [Epub ahead of print].

XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumour and haematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes, not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using haematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision-making in the personalized treatment of cancer patients undergoing treatment with selinexor.

RevDate: 2023-02-01

McQuoid J, Durazo A, Mooney E, et al (2023)

Tobacco cessation and prevention interventions for sexual and/or gender minority-identified people and the theories that underpin them: A scoping review.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:7017659 [Epub ahead of print].

INTRODUCTION: This scoping review takes stock of the social and behavior change theories that have underpinned tobacco interventions tailored to sexual and/or gender minority (SGM) people and reflects on the need to target contextually-based drivers of SGM tobacco use inequities.

METHODS: Data sources were Medline (Ovid), Scopus, PubMed, Google Scholar (01/01/1946 - 10/27/2022). Peer-reviewed publications in English from anywhere in the world describing SGM-tailored tobacco cessation and/or prevention interventions were independently identified by a librarian and screened by the first and third authors. 367 articles were extracted; an additional 2 were found by hand searching. 369 articles were assessed for eligibility. Exclusion criteria were: not an intervention, review article, not SGM-tailored or tobacco-focused. We documented intervention name, intervention components, theoretical frameworks cited in reference to intervention design and/or implementation, and evaluation outcomes. All authors provided input on theoretical framework categorization.

RESULTS: We identified 22 publications corresponding to 15 unique interventions. Individual-level behavior change theories (i.e., those focusing on within-person behavior change processes) were the most prominent. Among these, the Transtheoretical Model was the most frequently utilized, while Social Inoculation Theory, Theory of Reasoned Action, and Theory of Psychological Reactance were also employed. A minority of interventions referenced frameworks that more explicitly engaged with SGM people's social contexts, namely, Theory of Diffusion of Innovations and Minority Stress Model.

CONCLUSIONS: Future SGM-tailored tobacco interventions should leverage both the strengths of individual-level behavior change theories and those of frameworks that understand tobacco use inequities as indivisible from place, context, and policy.

IMPLICATIONS: This scoping review describes the theoretical underpinnings of sexual and/or gender minority (SGM)-tailored tobacco interventions published in the peer-review literature in English. It reflects on the need for greater utilization of social and behavior change theoretical frameworks that can engage with unique drivers of SGM tobacco use and barriers to cessation.

RevDate: 2023-01-31

Kurniansyah N, Wallace DA, Zhang Y, et al (2023)

An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling.

Communications biology, 6(1):125 pii:10.1038/s42003-023-04520-y.

Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Women's Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health Study/Study of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.

RevDate: 2023-02-01

Boila LD, Ghosh S, Bandyopadhyay SK, et al (2023)

KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition.

Leukemia [Epub ahead of print].

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. Epigenetic deregulation contributes to AML pathogenesis. KDM6 proteins are histone-3-lysine-27-demethylases that play context-dependent roles in AML. We inform that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. Mechanistically, KDM6 expression is regulated by genotoxic stress, with deficiency of KDM6A-(UTX) and KDM6B-(JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations are implicated in chemoresistance, although a significant percentage of relapsed-AML has upregulated KDM6A. Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, BCL2A1 associates with venetoclax resistance, and KDM6A loss was accompanied with a downregulated BCL2A1. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.

RevDate: 2023-01-31

Manselle MK, Ries RE, Hylkema T, et al (2023)

Functional consequence and therapeutic targeting of cryptic ALK fusions in monosomy 7 acute myeloid leukemia.

Pediatric blood & cancer [Epub ahead of print].

Acute myeloid leukemia (AML) patients have a wide array of cytogenetic and molecular aberrations, which can influence response to therapy. Monosomy 7 is a rare subset within pediatric AML (prevalence of <2%) that is highly associated with poor outcomes. Fusions involving the anaplastic tyrosine kinase (ALK) gene were exclusively identified in 14.3% of this high-risk cohort, while absent across all other AML. Given the dismal outcomes of monosomy 7, we evaluated the use of crizotinib, an FDA-approved tyrosine kinase inhibitor, used to treat patients with ALK fusions. Our findings suggest that crizotinib may serve as a novel therapy for these patients.

RevDate: 2023-01-31

Yagishita Y, Joshi T, Kensler TW, et al (2023)

Transcriptional Regulation of Math1 by Aryl Hydrocarbon Receptor: Effect on Math1[+] Progenitor Cells in Mouse Small Intestine.

Molecular and cellular biology, 43(1):43-63.

The physiological roles of aryl hydrocarbon receptor (AhR) in the small intestine have been revealed as immunomodulatory and barrier functions. However, its contributions to cell fate regulation are incompletely understood. The Notch-activated signaling cascade is a central component of intestinal cell fate determinations. The lateral inhibitory mechanism governed by Notch directs cell fates toward distinct cell lineages (i.e., absorptive and secretory cell lineages) through its downstream effector, mouse atonal homolog 1 (MATH1). An investigation employing cell lines and intestinal crypt cells revealed that AhR regulates Math1 expression in a xenobiotic response element (XRE)-dependent manner. The AhR-Math1 axis was further addressed using intestinal organoids, where AhR-Math1 and HES1-Math1 axes appeared to coexist within the underlying Math1 transcriptional machinery. When the HES1-Math1 axis was pharmacologically suppressed, β-naphthoflavone-mediated AhR activation increased the number of goblet and Math1[+] progenitor cells in the organoids. The same pharmacological dissection of the AhR-Math1 axis was applied in vivo, demonstrating an enhanced number of Math1[+] progenitor cells in the small intestine following AhR activation. We report here that AhR-Math1 is a direct transcriptional axis with effects on Math1[+] progenitor cells in the small intestine, highlighting a novel molecular basis for fine-tuning Notch-mediated cell fate regulation.

RevDate: 2023-01-31

Tagliamento M, Gennari A, Lambertini M, et al (2023)

Pandemic Phase-Adjusted Analysis of COVID-19 Outcomes Reveals Reduced Intrinsic Vulnerability and Substantial Vaccine Protection From Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Breast Cancer.

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

PURPOSE: Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice.

METHODS: We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR28) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis.

RESULTS: By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls.

CONCLUSION: Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.

RevDate: 2023-01-31

Cable J, Balachandran S, Daley-Bauer LP, et al (2023)

Viral immunity: Basic mechanisms and therapeutic applications-a Keystone Symposia report.

Annals of the New York Academy of Sciences [Epub ahead of print].

Viruses infect millions of people each year. Both endemic viruses circulating throughout the population as well as novel epidemic and pandemic viruses pose ongoing threats to global public health. Developing more effective tools to address viruses requires not only in-depth knowledge of the virus itself but also of our immune system's response to infection. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Viral Immunity: Basic Mechanisms and Therapeutic Applications." This report presents concise summaries from several of the symposium presenters.

RevDate: 2023-01-30

Joachim GE, Bohnert KM, As-Sanie S, et al (2023)

Cannabis smoking, tobacco cigarette smoking, and adenomyosis risk.

Fertility and sterility pii:S0015-0282(23)00071-7 [Epub ahead of print].

OBJECTIVE: To investigate cannabis smoking and tobacco cigarette smoking in relation to adenomyosis risk.

DESIGN: We used data from a case-control study of adenomyosis conducted among enrollees ages 18-59 years of an integrated healthcare system in Washington State. The case-control study employed two control groups given the challenge of selecting non-cases when cases are diagnosed by hysterectomy.

SUBJECTS: Cases (n=386) were enrollees with incident, pathology-confirmed adenomyosis diagnosed between April 1, 2001, and March 31, 2006. The two control groups comprised hysterectomy controls (n=233) with pathology-confirmed absence of adenomyosis and population controls (n=323) with an intact uterus randomly selected from the healthcare system population and frequency-matched to cases on age.

EXPOSURE: Detailed data on cannabis and tobacco cigarette smoking history were ascertained through in-person structured interviews, allowing estimation of joint-years of cannabis smoking and pack-years of tobacco cigarette smoking.

MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between cannabis smoking, tobacco cigarette smoking, and adenomyosis were estimated using multivariable unconditional logistic regression. Analyses were adjusted for age, reference year, menarche age, education, and pack-years of cigarette smoking (or joint-years of cannabis smoking).

RESULTS: No association was observed between cannabis smoking history and adenomyosis risk. However, we did observe the suggestion of an association between ever tobacco cigarette smoking and adenomyosis risk, comparing cases to hysterectomy controls (OR 1.3, 95% CI: 0.9-1.9) and population controls (OR 1.2 95% CI: 0.8-1.8). Our data suggested a 50% increased odds of adenomyosis with >15 pack-years of smoking (vs. never smoking), comparing cases to hysterectomy controls (OR 1.5, 95% CI: 0.9-2.6, Ptrend=0.135). The suggestion of a 40% increased adenomyosis odds was observed with smoking >5-15 pack-years (vs. never smoking), comparing cases to population controls (OR 1.4, 95% CI: 0.8-2.4, Ptrend=0.136).

CONCLUSION: In the first study of cannabis smoking and adenomyosis risk, no association was observed. However, our data suggested an increased odds of adenomyosis with history of tobacco cigarette smoking. Further research is warranted to replicate our results given the substantial morbidity with adenomyosis and frequency of cigarette smoking and recreational and medical cannabis use.

RevDate: 2023-01-30

Rubenstein JH, Burns JA, Arasim ME, et al (2023)

Yield of Repeat Endoscopy for Barrett's Esophagus after Normal Index Endoscopy.

The American journal of gastroenterology pii:00000434-990000000-00667 [Epub ahead of print].

OBJECTIVE: Guidelines suggest one time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at increased risk for esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals following a normal index EGD.

DESIGN: We conducted a national retrospective analysis within the United States Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC or esophagogastric junction adenocarcinoma (EGJAC), and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC.

RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years following an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of those, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC following the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. Longer duration between EGDs was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years = 1.31; 95% confidence interval [CI] = 1.19, 1.44), particularly among those who were younger at the time of the index EGD (ages 19-29: aOR = 3.92; 95% CI = 1.24, 12.4; ages 60-69: aOR = 1.19; 95% CI = 1.01, 1.40).

CONCLUSION: The yield of repeat EGD for BE/EAC/EGJAC appears to increase with time following a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

RevDate: 2023-01-30

Devasia TP, Mariotto AB, Nyame YA, et al (2023)

Estimating the Number of Men Living with Metastatic Prostate Cancer in the United States.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:716270 [Epub ahead of print].

BACKGROUND: Metastatic prostate cancer (MPC) includes metastases detected at diagnosis (de novo) and those occurring after diagnosis with early-stage disease (recurrent). Cancer registries collect data only on de novo MPC, providing a partial picture of the burden of MPC. We use cancer registry data to estimate the number of men living with MPC in the US including both de novo and recurrent cases.

METHODS: We apply a back-calculation method to estimate MPC incidence and prevalence from US prostate cancer (PC) mortality and de novo MPC relative survival for cases diagnosed between 2000-2017 in 18 Surveillance, Epidemiology, and End Results registries. We hold overall PC mortality and MPC survival constant for future prevalence projections.

RESULTS: On January 1, 2018, we estimated 120,400 US men living with MPC (45% de novo, 55% recurrent). The age-adjusted prevalence in 2018 for Black men was over double that of White men (137.1 vs. 62.2 per 100,000 men). By 2030, 192,500 men are expected to be living with MPC, with the increase being driven by population growth projections.

CONCLUSIONS: The number of men living with MPC in the US exceeds 100,000 and represents a small fraction of the >3 million men living with a prior diagnosis of PC.

IMPACT: Relatively similar fractions of de novo and recurrent MPC among prevalent cases highlight opportunities for early detection and management of localized disease in reducing the MPC burden. Changes in diagnostic technologies could lead to greater growth in MPC cases in the US than projected.

RevDate: 2023-01-30

Lee S, Lee C, Won Nam J, et al (2023)

Street environments and crime around low-income and minority schools: Adopting an environmental audit tool to assess crime prevention through environmental design (CPTED).

Landscape and urban planning, 232:.

Crime prevention through environmental design (CPTED) suggests an association between micro-scale environmental conditions and crime, but little empirical research exists on the detailed street-level environmental features associated with crime near low-income and minority schools. This study focuses on the neighborhoods around 14 elementary schools serving lower income populations in Seattle, WA to assess if the distribution of crime incidences (2013-2017) is linked with the street-level environmental features that reflect CPTED principles. We used a total of 40 audit variables that were included in the four domains derived from the broken windows theory and CPTED principles: natural surveillance (e.g., number of windows, balconies, and a sense of surveillance), territoriality (e.g., crime watch signs, trees), image/maintenance (e.g., graffiti and a sense of maintenance/cleanness), and geographical juxtaposition (e.g., bus stops, presence of arterial). We found that multiple crime types had significant associations with CPTED components at the street level. Among the CPTED domains, two image/maintenance features (i.e., maintenance of streets and visual quality of buildings) and two geographical juxtaposition features (i.e., being adjacent to multi-family housing and bus stops) were consistently associated with both violent and property crime. The findings suggest that local efforts to improve maintenance of streets and visual quality of buildings and broader planning efforts to control specific land uses near schools are important to improve safety in marginalized neighborhoods near schools that tend to be more vulnerable to crime. Our research on micro-scale environmental determinants of crime can also serve as promising targets for CPTED research and initiatives.

RevDate: 2023-01-29

Montgomery B, EA Mostaghel (2023)

Neoadjuvant Therapy Prior to Prostatectomy: Is the Glass Half Full?.

RevDate: 2023-01-29

Makrakis D, Wright JL, Roudier MP, et al (2022)

A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

Clinical genitourinary cancer pii:S1558-7673(22)00261-0 [Epub ahead of print].

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade.

PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target.

RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME.

CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

RevDate: 2023-01-29

Bossarte RM, Ross EL, Liu H, et al (2023)

Development of a model to predict combined antidepressant medication and psychotherapy treatment response for depression among veterans.

Journal of affective disorders pii:S0165-0327(23)00101-5 [Epub ahead of print].

BACKGROUND: Although research shows that more depressed patients respond to combined antidepressants (ADM) and psychotherapy than either alone, many patients do not respond even to combined treatment. A reliable prediction model for this could help treatment decision-making. We attempted to create such a model using machine learning methods among patients in the US Veterans Health Administration (VHA).

METHODS: A 2018-2020 national sample of VHA patients beginning combined depression treatment completed self-report assessments at baseline and 3 months (n = 658). A learning model was developed using baseline self-report, administrative, and geospatial data to predict 3-month treatment response defined by reductions in the Quick Inventory of Depression Symptomatology Self-Report and/or in the Sheehan Disability Scale. The model was developed in a 70 % training sample and tested in the remaining 30 % test sample.

RESULTS: 30.0 % of patients responded to treatment. The prediction model had a test sample AUC-ROC of 0.657. A strong gradient was found in probability of treatment response from 52.7 % in the highest predicted quintile to 14.4 % in the lowest predicted quintile. The most important predictors were episode characteristics (symptoms, comorbidities, history), personality/psychological resilience, recent stressors, and treatment characteristics.

LIMITATIONS: Restrictions in sample definition, a low recruitment rate, and reliance on patient self-report rather than clinician assessments to determine treatment response limited the generalizability of results.

CONCLUSIONS: A machine learning model could help depressed patients and providers predict likely response to combined ADM-psychotherapy. Parallel information about potential harms and costs of alternative treatments would be needed, though, to inform optimal treatment selection.

RevDate: 2023-01-28

Luen SJ, Viale G, Nik-Zainal S, et al (2023)

Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(23)00047-9 [Epub ahead of print].

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained.

PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the SOFT clinical trial to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1,276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival (OS).

RESULTS: Younger women (<40 years, N=359) compared with older women (≥40 years, N=917) had significantly higher frequencies of mutations in GATA3 (19%vs16%) and CN-amplifications (47%vs26%), but significantly lower frequencies of mutations in PIK3CA (32%vs47%), CDH1 (3%vs9%), and MAP3K1 (7%vs12%). Additionally, significantly higher frequencies of features suggestive of HRD (27%vs21%), and a higher proportion of PIK3CA mutations with concurrent CN-amplifications (23%vs11%).Genomic features suggestive of HRD, PIK3CA mutations with CN-amplifications, and CN-amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% ≥40 years. Poor prognostic features (N=584[46%]) vs none (N=692[54%]) had an 8-year DRFI of 84%vs94% and OS of 88%vs96%. Younger women (<40) had the poorest outcomes: 8-year DRFI 74%vs85% and OS of 80%vs93% respectively.

CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2-EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

RevDate: 2023-01-28

Peters BA, Burk RD, Kaplan RC, et al (2023)

The Gut Microbiome, Microbial Metabolites, and Cardiovascular Disease in People Living with HIV.

Current HIV/AIDS reports [Epub ahead of print].

PURPOSE OF REVIEW: To synthesize recent evidence relating the gut microbiome and microbial metabolites to cardiovascular disease (CVD) in people living with HIV (PLWH).

RECENT FINDINGS: A few cross-sectional studies have reported on the gut microbiome and cardiovascular outcomes in the context of HIV, with no consistent patterns emerging. The largest such study found that gut Fusobacterium was associated with carotid artery plaque. More studies have evaluated microbial metabolite trimethylamine N-oxide with CVD risk in PLWH, but results were inconsistent, with recent prospective analyses showing null effects. Studies of other microbial metabolites are scarce. Microbial translocation biomarkers (e.g., lipopolysaccharide binding protein) have been related to incident CVD in PLWH. Microbial translocation may increase CVD risk in PLWH, but there is insufficient and/or inconsistent evidence regarding specific microbial species and microbial metabolites associated with cardiovascular outcomes in PLWH. Further research is needed in large prospective studies integrating the gut microbiome, microbial translocation, and microbial metabolites with cardiovascular outcomes in PLWH.

RevDate: 2023-01-29

Schoettler ML, Carreras E, Cho B, et al (2022)

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

RevDate: 2023-01-28

Azizoğlu A, Loureiro C, Venetz J, et al (2023)

Autorepression-Based Conditional Gene Expression System in Yeast for Variation-Suppressed Control of Protein Dosage.

Current protocols, 3(1):e647.

Conditional control of gene expression allows an experimenter to investigate many aspects of a gene's function. In the model organism Saccharomyces cerevisiae, a number of methods to control gene expression are widely practiced, including induction by metabolites, small molecules, and even light. However, all current methods suffer from at least one of a set of drawbacks, including need for specialized growth conditions, leaky expression, or requirement of specialized equipment. Here we describe protocols using two transformations to construct strains that carry a new controller in which all these drawbacks are overcome. In these strains, the expression of a controlled gene of interest is repressed by the bacterial repressor TetR and induced by anhydrotetracycline. TetR also regulates its own expression, creating an autorepression loop. This autorepression allows tight control of gene expression and protein dosage with low cell-to-cell variation in expression. A second repressor, TetR-Tup1, prevents any leaky expression. We also present a protocol showing a particular workhorse application of such strains to generate synchronized cell populations. We turn off expression of the cell cycle regulator CDC20 completely, arresting the cell population, and then we turn it back on so that the synchronized cells resume cell cycle progression. This control system can be applied to any endogenous or exogenous gene for precise expression. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Generating a parent WTC846 strain Basic Protocol 2: Generating a WTC846 strain with controlled expression of the targeted gene Alternate Protocol: CRISPR-mediated promoter replacement Basic Protocol 3: Cell cycle synchronization/arrest and release using the WTC846- K3 ::CDC20 strain.

RevDate: 2023-01-28

Ugai T, Haruki K, Harrison TA, et al (2023)

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

The American journal of gastroenterology pii:00000434-990000000-00638 [Epub ahead of print].

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management.

METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases.

RESULTS: The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors (P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend.

DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

RevDate: 2023-01-27

Vieyra G, Hankinson SE, Oulhote Y, et al (2023)

Association between urinary phthalate biomarker concentrations and adiposity among postmenopausal women.

Environmental research pii:S0013-9351(23)00148-2 [Epub ahead of print].

BACKGROUND: Obesity is a leading risk factor for chronic diseases, potentially related to excess abdominal adiposity. Phthalates are environmental chemicals that have been suggested to act as obesogens, driving obesity risk. For the associations between phthalates and adiposity, prior studies have focused primarily on body mass index. We hypothesize that more refined measures of adiposity and fat distribution may provide greater insights into these associations given the role of central adiposity in chronic disease risk.

OBJECTIVES: To evaluate associations between urinary phthalate biomarkers and both visceral and subcutaneous adipose tissue (VAT and SAT) among postmenopausal women enrolled in the Women's Health Initiative (WHI).

METHODS: We included 1125 WHI participants with available, coincident measurements of urinary phthalate biomarkers (baseline, year 3) and VAT and SAT (baseline, year 3, year 6). VAT and SAT measurements were estimated from DXA scans. Multilevel mixed-effects models estimated the prospective associations between urinary phthalate biomarkers at baseline and VAT and SAT three years later.

RESULTS: In multivariable adjusted models, we observed positive associations between some phthalate biomarkers, including the sum of di-isobutyl phthalate (ΣDiBP) biomarkers, MCNP, and DEHP, with VAT three years later. For example, we observed positive associations between concentrations of ΣDiBP and VAT (Q4 vs Q1 β = 7.15, 95% CI -1.76-16.06; Q3 vs Q1 β = 10.94, 95% CI 3.55-18.33). Associations were generally attenuated but remained significant after additional adjustment for SAT. MBzP was positively associated with SAT. Other phthalate biomarkers investigated (MEP, MCOP, MCPP, ΣDBP) were not significantly associated with VAT or SAT.

DISCUSSION: Based on robust measures of adiposity, this study provides supportive evidence that higher urinary concentrations of select phthalate compounds were associated with higher VAT levels over time in postmenopausal women. Efforts to replicate these findings are needed.

RevDate: 2023-01-27

Hsieh E, Janssens DH, Paddison PJ, et al (2023)

A modular CRISPR screen identifies individual and combination pathways contributing to HIV-1 latency.

PLoS pathogens, 19(1):e1011101 pii:PPATHOGENS-D-22-01869 [Epub ahead of print].

Transcriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms that pose a major barrier to in vivo elimination of HIV-1. We developed a new latency CRISPR screening strategy, called Latency HIV-CRISPR which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as a direct readout of factors involved in the maintenance of HIV-1 latency. We developed a custom guideRNA library targeting epigenetic regulatory genes and paired the screen with and without a latency reversal agent-AZD5582, an activator of the non-canonical NFκB pathway-to examine a combination of mechanisms controlling HIV-1 latency. A component of the Nucleosome Acetyltransferase of H4 histone acetylation (NuA4 HAT) complex, ING3, acts in concert with AZD5582 to activate proviruses in J-Lat cell lines and in a primary CD4+ T cell model of HIV-1 latency. We found that the knockout of ING3 reduces acetylation of the H4 histone tail and BRD4 occupancy on the HIV-1 LTR. However, the combination of ING3 knockout accompanied with the activation of the non-canonical NFκB pathway via AZD5582 resulted in a dramatic increase in initiation and elongation of RNA Polymerase II on the HIV-1 provirus in a manner that is nearly unique among all cellular promoters.

RevDate: 2023-01-27

Aslam S, Li E, Bell E, et al (2023)

Risk of chemotherapy-induced febrile neutropenia in intermediate-risk regimens: Clinical and economic outcomes of granulocyte colony-stimulating factor prophylaxis.

Journal of managed care & specialty pharmacy, 29(2):128-138.

BACKGROUND: Chemotherapy-induced neutropenia increases the risk of febrile neutropenia (FN) and infection with resultant hospitalizations, with substantial health care resource utilization (HCRU) and costs. Granulocyte-colony stimulating factor (GCSF) is recommended as primary prophylaxis for chemotherapy regimens having more than a 20% risk of FN. Yet, for intermediate-risk (10%-20%) regimens, it should be considered only for patients with 1 or more clinical risk factors (RFs) for FN. It is unclear whether FN prophylaxis for intermediate-risk patients is being optimally implemented. OBJECTIVE: To examine RFs, prophylaxis use, HCRU, and costs associated with incident FN during chemotherapy. METHODS: This retrospective study used administrative claims data for commercial and Medicare Advantage enrollees with nonmyeloid cancer treated with intermediate-risk chemotherapy regimens during January 1, 2009, to March 31, 2020. Clinical RFs, GCSF prophylaxis, incident FN, HCRU, and costs were analyzed descriptively by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis. Multivariable Cox regression analysis was used to examine the association between number of RFs and cumulative FN risk. RESULTS: The sample comprised 13,937 patients (mean age 67 years, 55% female). Patients had a mean of 2.3 RFs, the most common being recent surgery, were aged 65 years or greater, and had baseline liver or renal dysfunction; 98% had 1 or more RFs. However, only 35% of patients received primary prophylaxis; 12% received secondary prophylaxis. The hazard ratio of incident FN was higher with increasing number of RFs during the first line of therapy, yet more than 54% of patients received no prophylaxis, regardless of RFs. Use of GCSF prophylaxis varied more by chemotherapeutic regimen than by number of RFs. Among patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits-adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively. CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes. DISCLOSURES: This work was funded by Sandoz Inc., which participated in the design of the study, interpretation of the data, writing and revision of the manuscript, and the decision to submit the manuscript for publication. The study was performed by Optum under contract with Sandoz Inc. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Dr Li is an employee of Sandoz Inc. Drs Bell and Lal and Mr Peterson-Brandt were employees of Optum at the time of the study. Ms Anderson and Dr Aslam are employees of Optum. Dr Lyman has been primary investigator on a research grant from Amgen to their institution and has consulted for Sandoz, G1 Therapeutics, Partners Healthcare, BeyondSpring, ER Squibb, Merck, Jazz Pharm, Kallyope, Teva; Fresenius Kabi, Seattle Genetics, and Samsung.

RevDate: 2023-01-27

Schiffer JT (2023)

The continuing puzzle of defining duration of SARS-CoV-2 infectivity.

The Journal of infectious diseases pii:7006898 [Epub ahead of print].

RevDate: 2023-01-26

Chen F, Wang X, Jang SK, et al (2023)

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Nature genetics [Epub ahead of print].

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

RevDate: 2023-01-26

Cheng E, Shi Q, Shields AF, et al (2023)

Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer.

JAMA oncology pii:2800946 [Epub ahead of print].

IMPORTANCE: The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.

OBJECTIVE: To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.

This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022.

EXPOSURES: Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization.

MAIN OUTCOMES AND MEASURES: The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression.

RESULTS: Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.

CONCLUSIONS AND RELEVANCE: This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.

RevDate: 2023-01-27
CmpDate: 2023-01-20

Kumar SK, Callander NS, Adekola K, et al (2023)

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 21(1):67-81.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

RevDate: 2023-01-27

Ling W, Qi Y, Hua X, et al (2021)

Deep ensemble learning over the microbial phylogenetic tree (DeepEn-Phy).

Proceedings. IEEE International Conference on Bioinformatics and Biomedicine, 2021:470-477.

Successful prediction of clinical outcomes facilitates tailored diagnosis and treatment. The microbiome has been shown to be an important biomarker to predict host clinical outcomes. Further, the incorporation of microbial phylogeny, the evolutionary relationship among microbes, has been demonstrated to improve prediction accuracy. We propose a phylogeny-driven deep neural network (PhyNN) and develop an ensemble method, DeepEn-Phy, for host clinical outcome prediction. The method is designed to optimally extract features from phylogeny, thereby take full advantage of the information in phylogeny while harnessing the core principles of phylogeny (in contrast to taxonomy). We apply DeepEn-Phy to a real large microbiome data set to predict both categorical and continuous clinical outcomes. DeepEn-Phy demonstrates superior prediction performance to existing machine learning and deep learning approaches. Overall, DeepEn-Phy provides a new strategy for designing deep neural network architectures within the context of phylogeny-constrained microbiome data.

RevDate: 2023-01-26

Goodrum F, Lowen A, Lakdawala S, et al (2023)

Virology under the Microscope-a Call for Rational Discourse.

mSphere [Epub ahead of print].

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

RevDate: 2023-01-26

Goodrum F, Lowen A, Lakdawala S, et al (2023)

Virology under the Microscope-a Call for Rational Discourse.

mBio [Epub ahead of print].

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

RevDate: 2023-01-26

Goodrum F, Lowen A, Lakdawala S, et al (2023)

Virology under the Microscope-a Call for Rational Discourse.

Journal of virology [Epub ahead of print].

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

RevDate: 2023-01-25

Doebley AL, Ko M, Liao H, et al (2023)

Author Correction: A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA.

Nature communications, 14(1):403 pii:10.1038/s41467-023-36187-8.

RevDate: 2023-01-25

Sheikh MT, Chen MH, Gelfond JA, et al (2023)

New C-indices for assessing importance of longitudinal biomarkers in fitting competing risks survival data in the presence of partially masked causes.

Statistics in medicine [Epub ahead of print].

Competing risks survival data in the presence of partially masked causes are frequently encountered in medical research or clinical trials. When longitudinal biomarkers are also available, it is of great clinical importance to examine associations between the longitudinal biomarkers and the cause-specific survival outcomes. In this article, we propose a cause-specific C-index for joint models of longitudinal and competing risks survival data accounting for masked causes. We also develop a posterior predictive algorithm for computing the out-of-sample cause-specific C-index using Markov chain Monte Carlo samples from the joint posterior of the in-sample longitudinal and competing risks survival data. We further construct the Δ $$ \Delta $$ C-index to quantify the strength of association between the longitudinal and cause-specific survival data, or between the out-of-sample longitudinal and survival data. Empirical performance of the proposed assessment criteria is examined through an extensive simulation study. An in-depth analysis of the real data from large cancer prevention trials is carried out to demonstrate the usefulness of the proposed methodology.

RevDate: 2023-01-25

Nguyen S, LaCroix AZ, Hayden KM, et al (2023)

Accelerometer-measured physical activity and sitting with incident mild cognitive impairment or probable dementia among older women.

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

INTRODUCTION: Physical activity (PA) is prospectively inversely associated with dementia risk, but few studies examined accelerometer measures of PA and sitting with rigorously-adjudicated mild cognitive impairment (MCI) and dementia risk.

METHODS: We examined the associations of accelerometer measures (PA and sitting) with incident MCI/probable dementia in the Women's Health Initiative (n = 1277; mean age = 82 ± 6 years) RESULTS: Over a median follow-up of 4.2 years, 267 MCI/probable dementia cases were identified. Adjusted Cox regression HRs (95% CI) across moderate-to-vigorous PA (MVPA) min/d quartiles were 1.00 (reference), 1.28 (0.90 to 1.81), 0.79 (0.53 to 1.17), and 0.69 (0.45 to 1.06); P-trend = 0.01. Adjusted HRs (95% CI) across steps/d quartiles were 1.00 (reference), 0.73 (0.51 to 1.03), 0.64 (0.43 to 0.94), and 0.38 (0.23 to 0.61); P-trend < 0.001. The HR (95% CI) for each 1-SD increment in MVPA (31 min/d) and steps/d (1865) were 0.79 (0.67 to 0.94) and 0.67 (0.54 to 0.82), respectively. Sitting was not associated with MCI/probable dementia.

DISCUSSION: Findings suggest ≥ moderate intensity PA, particularly stepping, associates with lower MCI and dementia risk.

HIGHLIGHTS: Few studies have examined accelerometer-measured physical activity, including steps, and sitting with incident ADRD. Moderate-to-vigorous physical activity and steps, but not light physical activity or sitting, were inversely associated with lower ADRD risk. Among older women, at least moderate intensity physical activity may be needed to reduce ADRD risk.

RevDate: 2023-01-25

Siegel DA, Thanh C, Wan E, et al (2023)

Host variation in type I interferon signaling genes (MX1), C-C chemokine receptor type 5 gene, and major histocompatibility complex class I alleles in treated HIV+ noncontrollers predict viral reservoir size.

AIDS (London, England), 37(3):477-488.

OBJECTIVE: Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy.

DESIGN: Cross-sectional genomewide association study.

METHODS: We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression.

RESULTS: Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression.

CONCLUSIONS: We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

RevDate: 2023-01-24

Perchetti GA, Biernacki MA, Xie H, et al (2023)

Cytomegalovirus breakthrough and resistance during letermovir prophylaxis.

Bone marrow transplantation [Epub ahead of print].

Letermovir is a relatively new antiviral for prophylaxis against cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT). CMV-seropositive HCT recipients who received letermovir prophylaxis from 2018 to 2020 at our center were evaluated for letermovir resistance and breakthrough CMV reactivation. Two-hundred twenty-six letermovir recipients were identified and 7/15 (47%) with CMV DNAemia ≥200 IU/mL were successfully genotyped for UL56 resistance. A single C325Y resistance mutation was identified in an umbilical cord blood recipient. Ninety-five (42%), 43 (19%), and 15 (7%) patients had breakthrough CMV at any level, ≥150 IU/mL, and ≥500 IU/mL, respectively. Risk factors for breakthrough CMV reactivation at each viral threshold were examined. Cumulative steroid exposure was the strongest risk factor for CMV at all evaluated viral thresholds. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide (aHR 2.34, 95% CI 1.28-4.28, p = 0.001) or calcineurin inhibitors plus mycophenolate (aHR 2.24, 95% CI 1.30-3.86, p = 0.004) were also associated with an increased risk of CMV reactivation at any level. De novo letermovir resistance is rare and can be successfully treated using other antivirals. Letermovir effectively prevents clinically significant CMV, however, subclinical CMV reactivation occurs frequently at our center.

RevDate: 2023-01-24

Weil BR, Murphy AJ, Liu Q, et al (2023)

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

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

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.

METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents.

RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.

CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

RevDate: 2023-01-24

Yokoo T, Masaki N, Parikh ND, et al (2023)

Multicenter Validation of Abbreviated MRI for Detecting Early-Stage Hepatocellular Carcinoma.

Radiology [Epub ahead of print].

Background Abbreviated MRI is a proposed paradigm shift for hepatocellular carcinoma (HCC) surveillance, but data on its performance are lacking for histopathologically confirmed early-stage HCC. Purpose To evaluate the sensitivity and specificity of dynamic contrast-enhanced abbreviated MRI for early-stage HCC detection, using surgical pathologic findings as the reference standard. Materials and Methods This retrospective study was conducted at three U.S. liver transplant centers in patients with cirrhosis who underwent liver resection or transplant between January 2009 and December 2019 and standard "full" liver MRI with and without contrast enhancement within 3 months before surgery. Patients who had HCC-directed treatment before surgery were excluded. Dynamic abbreviated MRI examinations were simulated from the presurgical full MRI by selecting the coronal T2-weighted and axial three-dimensional fat-suppressed T1-weighted dynamic contrast-enhanced sequences at precontrast, late arterial, portal venous, and delayed phases. Two abdominal radiologists at each center independently interpreted the simulated abbreviated examinations with use of the Liver Imaging Reporting and Data System version 2018. Patients with any high-risk liver observations (>LR-3) were classified as positive; otherwise, they were classified as negative. With liver pathologic findings as the reference standard for the presence versus absence of early-stage HCC, the sensitivity, specificity, and their 95% CIs were calculated. Logistic regression was used to identify factors associated with correct classification. Results A total of 161 patients with early-stage HCC (median age, 62 years [IQR, 58-67 years]; 123 men) and 138 patients without HCC (median age, 55 years [IQR, 47-63 years]; 85 men) were confirmed with surgical pathologic findings. The sensitivity and specificity of abbreviated MRI were 88.2% (142 of 161 patients) (95% CI: 83.5, 92.5) and 89.1% (123 of 138 patients) (95% CI: 84.4, 93.8), respectively. Sensitivity was lower for Child-Pugh class B or C versus Child-Pugh class A cirrhosis (64.1% vs 94.2%; P < .001). Conclusion With surgical pathologic findings as the reference standard, dynamic abbreviated MRI had high sensitivity and specificity for early-stage hepatocellular carcinoma detection in patients with compensated cirrhosis but lower sensitivity in those with decompensated cirrhosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kim in this issue.

RevDate: 2023-01-24

Hu C, Bugbee T, Palinski R, et al (2023)

Beta human papillomavirus 8E6 promotes alternative end-joining.

eLife, 12: pii:81923 [Epub ahead of print].

Double strand breaks (DSBs) are one of the most lethal DNA lesions in cells. The E6 protein of beta-human papillomavirus (HPV8 E6) impairs two critical DSB repair pathways; homologous recombination (HR) and non-homologous end-joining (NHEJ). However, HPV8 E6 only delays DSB repair. How DSBs are repaired in cells with HPV8 E6 remains to be studied. We hypothesize that HPV8 E6 promotes a less commonly used DSB repair pathway, alternative end-joining (Alt-EJ). Using CAS9 based Alt-EJ reporters, we show that HPV8 E6 promotes Alt-EJ. Further, using small molecule inhibitors, CRISPR/CAS9 gene knockout, and HPV8 E6 mutant, we find that HPV8 E6 promotes Alt-EJ by binding p300, an acetyltransferase that facilitates DSB repair by HR and NHEJ. At least some of this repair occurs through a subset of Alt-EJ known as polymerase theta dependent end joining. Finally, whole genome sequencing analysis showed HPV8 E6 caused an increased frequency of deletions bearing the microhomology signatures of Alt-EJ. This study fills the knowledge gap of how DSB is repaired in cells with HPV8 E6 and the mutagenic consequences of HPV8 E6 mediated p300 destabilization. Broadly, this study supports the hypothesis that beta-HPV promotes cancer formation by increasing genomic instability.

RevDate: 2023-01-24

Guest DD, Cox T, Voss AC, et al (2023)

Assessing Impact of Nutrition Care by Registered Dietitian Nutritionists on Patient Medical and Treatment Outcomes in Outpatient Cancer Clinics: A Cohort Feasibility Study.

Nutrition and cancer [Epub ahead of print].

More information is needed about the impact of outpatient nutrition care from a registered dietitian nutritionist (RDN) on patient outcomes. This study aimed to assess the feasibility of a cohort study design to evaluate impact of RDN nutrition care on patient outcomes, describe clinic malnutrition screening practices, and estimate statistical parameters for a larger study. Seventy-seven patients with lung, esophageal, colon, rectal, or pancreatic cancer from six facilities were included (41 received RDN care and 36 did not). RDN nutrition care was prospectively documented for six months and documented emergency room visits, unplanned hospitalizations and treatment changes were retrospectively abstracted from medical records. Most facilities used the Malnutrition Screening Tool (MST) to determine malnutrition risk. Patients receiving RDN care had, on average, five, half hour visits and had more severe disease and higher initial malnutrition risk, although this varied across sites. Documented medical and treatment outcomes were relatively rare and similar between groups. Estimated sample size requirements varied from 113 to 5856, depending on tumor type and outcome, and intracluster correlation coefficients (ICCs) ranged from 0 to 0.47. Overall, the methods used in this study are feasible but an interventional or implementation design might be advantageous for a larger study.

RevDate: 2023-01-23

Marrero RJ, Cao X, Wu H, et al (2023)

SAMHD1 Single Nucleotide Polymorphisms Impact Outcome in Children with Newly Diagnosed Acute Myeloid Leukemia.

Blood advances pii:494211 [Epub ahead of print].

Cytarabine arabinoside (Ara-C) has been the cornerstone of AML chemotherapy for decades. Following cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway have been shown to impact intracellular abundance of Ara-CTP and thus its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance and consequently, clinical response in AML. Despite this the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within SAMHD1 gene for association with clinical outcome in 400 newly diagnosed pediatric AML patients from two clinical trials- AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least one clinical outcome endpoint: minimal residual disease (MRD) after induction I, event free survival (EFS), or overall survival (OS) in the two cohorts. In an independent cohort of patients from COG-AAML1031 trial (n=854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, adjusting for other prognostic factors such as race, age, risk group, and white blood cell count, all the SNPs remained independent predictors of clinical outcome endpoints. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

RevDate: 2023-01-24

Mena Lora AJ, Long JE, Huang Y, et al (2023)

Rapid Development of an Integrated Network Infrastructure to Conduct Phase 3 COVID-19 Vaccine Trials.

JAMA network open, 6(1):e2251974 pii:2800703.

IMPORTANCE: The COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts.

OBSERVATIONS: To support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing clinical and laboratory infrastructure, community partnerships, and research expertise to quickly pivot clinical trial sites to conduct COVID-19 vaccine trials as soon as the investigational products were ready for phase 3 testing. The mission of CoVPN was to operationalize phase 3 vaccine trials using harmonized protocols, laboratory assays, and a single data and safety monitoring board to oversee the various studies. These trials, while staggered in time of initiation, overlapped in time and course of conduct and ultimately led to the successful completion of multiple studies and US Food and Drug Administration-licensed or -authorized vaccines, the first of which was available to the public less than 1 year from the discovery of the virus.

CONCLUSIONS AND RELEVANCE: This Special Communication describes the design, geographic distribution, and underlying principles of conduct of these efficacy trials and summarizes data from 136 382 prospectively followed-up participants, including more than 2500 with documented COVID-19. These successful efforts can be replicated for other important research initiatives and point to the importance of investments in clinical trial infrastructure integral to pandemic preparedness.

RevDate: 2023-01-23

Shi J, Kraft P, Rosner B, et al (2023)

Risk prediction models for endometrial cancer: development and validation in an international consortium.

Journal of the National Cancer Institute pii:6998216 [Epub ahead of print].

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors.

METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal white women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium. Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in three cohorts: Nurses' Health Study (NHS), Nurses' Health Study II (NHS II) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% CI: 0.62, 0.67) to 0.69 (95% CI: 0.66, 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in AUC in NHS,; PLCO: 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall E/O = 1.09; 95% CI: 0.98, 1.22) and PLCO (overall E/O = 1.04; 95% CI: 0.95, 1.13) but poorly calibrated in NHS (overall E/O = 0.55; 95% CI: 0.51, 0.59).

CONCLUSION: Using data from the largest, most heterogeneous study population to date, prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

RevDate: 2023-01-23

Fu Z, Brooks MM, Irvin S, et al (2023)

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

Journal of the National Cancer Institute pii:6998214 [Epub ahead of print].

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive (OC) use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26,204 controls and 21,267 cases from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models to expected estimates assuming one year of ovulation suppression has the same effect regardless of source.

RESULTS: LOY was associated with increased EOC risk (ORs per year increase: 1.014 (95%CI 1.009-1.020) to 1.044 (95%CI 1.041-1.048)). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for OC use and pregnancies were 4.45 times and 12-15 fold greater than expected, respectively. LOY was associated with high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid, and clear cell histotypes (ORs per year increase: 1.054, 1.040, 1.065, and 1.098, respectively), but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for HGSOC but larger than expected for LGSOC, endometrioid, and clear cell histotypes.

CONCLUSIONS: LOY is positively associated with non-mucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

RevDate: 2023-01-23

Zheng J, Zheng Y, L Hsu (2022)

Risk Projection for Time-to-event Outcome Leveraging Summary Statistics With Source Individual-level Data.

Journal of the American Statistical Association, 117(540):2043-2055.

Predicting risks of chronic diseases has become increasingly important in clinical practice. When a prediction model is developed in a cohort, there is a great interest to apply the model to other cohorts. Due to potential discrepancy in baseline disease incidences between different cohorts and shifts in patient composition, the risk predicted by the model built in the source cohort often under- or over-estimates the risk in a new cohort. In this article, we assume the relative risks of predictors are the same between the two cohorts, and propose a novel weighted estimating equation approach to re-calibrating the projected risk for the targeted population through updating the baseline risk. The recalibration leverages the knowledge about survival probabilities for the disease of interest and competing events, and summary information of risk factors from the target population. We establish the consistency and asymptotic normality of the proposed estimators. Extensive simulation demonstrate that the proposed estimators are robust, even if the risk factor distributions differ between the source and target populations, and gain efficiency if they are the same, as long as the information from the target is precise. The method is illustrated with a recalibration of colorectal cancer prediction model.

RevDate: 2023-01-23

Zhang L, Gilbert PB, Capparelli E, et al (2022)

Simulation-Based Pharmacokinetics Sampling Design for Evaluating Correlates of Prevention Efficacy of Passive HIV Monoclonal Antibody Prophylaxis.

Statistics in biopharmaceutical research, 14(4):611-625.

We address sampling design of population pharmacokinetics (popPK) experiments in the context of two ongoing phase 2b efficacy trials that evaluate the efficacy of VRC01 (vs. placebo) in reducing the rate of HIV infection among 4625 participants. Blood samples are collected at up to 22 study visits from all participants for immediate HIV diagnosis as the primary trial outcome, and stored for future outcome-dependent marker measurements. A key secondary objective of the trials is to evaluate correlates of prevention efficacy among a sub-cohort of VRC01 recipients in terms of whether the current value of VRC01 serum concentration is associated with the instantaneous rate of HIV infection. To accomplish this, concentrations on a daily grid are estimated via non-linear mixed effects popPK modeling of observed 4-weekly concentrations. Given the impracticality of measuring concentrations in all stored blood samples, we devised a simulation-based sampling design framework to evaluate the impact of sub-cohort sample sizes (m) and sampling schemes of time-points on the accuracy and precision of the popPK model parameters. We accounted for specific study schedules and heterogeneity in participants' characteristics and study adherence patterns. We found that with m = 120, reasonably unbiased and consistent estimates of most fixed and random effect terms could be obtained without complete sampling of all 22 time-points, even under low study adherence (about half of the 4-weekly visits missing per participant). The described simulation framework is not only novel in its application to popPK sampling design for studying correlates of prevention efficacy in a subcohort of the parent trial, but also flexible in accommodating real-life study setup options, and can be generalized to other single- or multiple-dose PK sampling design settings.

RevDate: 2023-01-23

Santiago-Torres M, Mull KE, Sullivan BM, et al (2023)

Acceptance and Commitment Therapy-Based Smartphone Applications for Cessation of Tobacco Use among Adults with High Nicotine Dependence: Results from the iCanQuit Randomized Trial.

Substance use & misuse [Epub ahead of print].

Background: With 1 in 2 adult tobacco users being highly dependent on nicotine, population-based interventions specifically designed for this group are urgently needed. This study used data from a randomized trial to evaluate whether (1) Acceptance and Commitment Therapy (ACT) delivered via a smartphone application (iCanQuit) would be more efficacious for cessation of nicotine-containing tobacco products than the US Clinical Practice Guidelines (USCPG)-based application (QuitGuide) among highly nicotine-dependent adults, (2) the effect of treatment on cessation was mediated by increases in acceptance of cravings to smoke, and (3) treatment utilization and satisfaction differed by arm. Methods: A total of 1452 highly nicotine-dependent adults received the iCanQuit or QuitGuide application for 12-months. Cessation outcomes were self-reported complete-case 30-day abstinence of nicotine-containing tobacco products (e.g., combustible cigarettes, e-cigarettes, chewing tobacco, snus, hookahs, cigars, cigarillos, tobacco pipes, and kreteks) at 3, 6, and 12-month post-randomization timepoints, missing-as-smoking, and multiple imputation analyses. Acceptance of cues to smoke and satisfaction with the applications was also reported. Results: Participants who received iCanQuit were significantly more likely to report 30-day abstinence of nicotine-containing tobacco products than those who received QuitGuide at 12-months (24% vs. 17%; OR = 1.47 95% CI: 1.11, 1.95). iCanQuit participants utilized their application more frequently and reported greater satisfaction than those who received QuitGuide. Increases in participants' acceptance of cues to smoke mediated the intervention effect on cessation of nicotine-containing tobacco products. Conclusions: Among nicotine-dependent adults, an application-delivered ACT-based intervention was more engaging and efficacious than a USCPG-based intervention for cessation of nicotine-containing tobacco products.

RevDate: 2023-01-22

Bricker JB, Mull KE, Sullivan BM, et al (2023)

Telehealth acceptance and commitment therapy for weight loss: Protocol of the WeLNES full scale randomized controlled trial.

Contemporary clinical trials pii:S1551-7144(23)00014-9 [Epub ahead of print].

Behavioral interventions delivered via one-on-one telephone coaching (hereafter referred to as telehealth) for weight loss have had great population-level reach but to date limited efficacy. Acceptance and Commitment Therapy (ACT) has promise to improve behavioral weight loss treatment efficacy by addressing the fundamental challenges of weight loss and maintenance: overeating in response to internal (stress) and external (high calorie foods) cues. Here we describe the Weight Loss, Nutrition, and Exercise Study (WeLNES) randomized controlled trial that is testing the efficacy of an ACT-based telehealth coaching intervention for weight loss in comparison to a Standard Behavioral Therapy (SBT)-based telehealth coaching intervention. A total of 398 adults with overweight or obesity are being recruited and randomized to either ACT or SBT telehealth coaching. Participants in both arms are offered twenty-five telehealth coaching sessions in year one and nine booster sessions in year two. All participants receive a Bluetooth-enabled scale to self-monitor weight and a Fitbit Inspire + Fitbit app for tracking diet and physical activity. The primary aim is to determine whether a greater proportion of ACT participants will achieve a clinically significant weight loss of ≥10% compared with SBT participants at 12-months. Secondary outcomes include change in weight from baseline to 6, 12, and 24-months. Whether the effect of ACT on weight loss is mediated by ACT processes and is moderated by baseline factors will also be examined. If ACT proves efficacious, ACT telehealth coaching will offer an effective, broadly scalable weight loss treatment-thereby making a high public health impact.

RevDate: 2023-01-23

Morgan C, Nayak A, Hosoya N, et al (2023)

Meiotic chromosome organization and its role in recombination and cancer.

Current topics in developmental biology, 151:91-126.

Chromosomes adopt specific conformations to regulate various cellular processes. A well-documented chromosome configuration is the highly compacted chromosome structure during metaphase. More regional chromatin conformations have also been reported, including topologically associated domains encompassing mega-bases of DNA and local chromatin loops formed by kilo-bases of DNA. In this review, we discuss the changes in chromatin conformation taking place between somatic and meiotic cells, with a special focus on the establishment of a proteinaceous structure, called the chromosome axis, at the beginning of meiosis. The chromosome axis is essential to support key meiotic processes such as chromosome pairing, homologous recombination, and balanced chromosome segregation to transition from a diploid to a haploid stage. We review the role of the chromosome axis in meiotic chromatin organization and provide a detailed description of its protein composition. We also review the conserved and distinct roles between species of axis proteins in meiotic recombination, which is a major factor contributing to the creation of genetic diversity and genome evolution. Finally, we discuss situations where the chromosome axis is deregulated and evaluate the effects on genome integrity and the consequences from protein deregulation in meiocytes exposed to heat stress, and aberrant expression of genes encoding axis proteins in mammalian somatic cells associated with certain types of cancers.

RevDate: 2023-01-21

Chuang YC, GR Smith (2023)

Meiotic crossover interference: Methods of analysis and mechanisms of action.

Current topics in developmental biology, 151:217-244.

Segregation of chromosomes during meiosis, to form haploid gametes from diploid precursor cells, requires in most species formation of crossovers physically connecting homologous chromosomes. Along with sister chromatid cohesion, crossovers allow tension to be generated when chromosomes begin to segregate; tension signals that chromosome movement is proceeding properly. But crossovers too close to each other might result in less sister chromatid cohesion and tension and thus failed meiosis. Interference describes the non-random distribution of crossovers, which occur farther apart than expected from independence. We discuss both genetic and cytological methods of assaying crossover interference and models for interference, whose molecular mechanism remains to be elucidated. We note marked differences among species.

RevDate: 2023-01-21

Kourelis T, Bansal R, Berdeja J, et al (2023)

Ethical challenges with multiple myeloma BCMA CAR-T slot allocation: a multi-institution experience.

Transplantation and cellular therapy pii:S2666-6367(23)00036-2 [Epub ahead of print].

CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CART manufacturing slot allocation. MM CAR T physician leaders at each CART treatment center across the US were surveyed. We received response from 17/20 centers. A median of one slot is allocated per month per center and the median number of patients per center on the waitlist since ide-cel approval was 20 (range 5-100). As a result, patients remained on the waitlist for a median of 6 months prior to leukapheresis (range 2-8). For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timeline and priority score readily available for CAR-T providers. Centers also reported using ethical values for selection: a) equal treatment: time spent on waiting list (n=12); b) priority to the worst-off: limited therapeutic options (n=14), MM burden (n=11), high comorbidity index (n=5); c) maximize benefit: most likely to complete apheresis (n=13) or infusion (n=13) or achieve response (n=8) and d) social value: younger pts (n=3). Maximizing benefit was considered the most important criterion by 10 centers. Our study is the first attempt to evaluate existing issues with MM CAR T access and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to the ones described here, into formal institutional policies would help streamline CAR-T access and protect the needs of both current and future patients and physicians.

RevDate: 2023-01-21

Johnson AM, Teoh D, Jewett P, et al (2023)

Genetic variants associated with post-traumatic stress symptoms in patients with gynecologic cancer.

Gynecologic oncology, 170:102-107 pii:S0090-8258(23)00006-9 [Epub ahead of print].

OBJECTIVE: Patients with cancer experience symptoms of post-traumatic stress disorder (PTSD) more commonly than the general population. The objective of this study was to identify single nucleotide polymorphisms (SNPs) associated with increased risk of post-traumatic stress disorder (PTSD) in patients with gynecologic cancer.

METHODS: A prospective cohort study recruited 181 gynecologic cancer survivors receiving care at the University of Minnesota between 2017 and 2020 who completed PTSD DSM-V surveys to self-report their symptoms of PTSD and provided saliva samples. DNA samples were genotyped for 11 SNPs in 9 genes involved in dopaminergic, serotonergic, and opioidergic systems previously associated with risk of PTSD in populations without cancer.

RESULTS: Most participants had either ovarian (42.5%) or endometrial (46.4%) cancer; fewer had cervical (7.7%) or vaginal/vulvar (3.3%) cancer. Two SNPS were identified as statistically significantly associated with higher PTSD scores: rs622337 in HTR2A and rs510769 in OPRM1.

CONCLUSIONS: Genetic variation likely plays a role in development of PTSD. HTR2A is involved in the serotonin pathway, and OPRM1 is involved in the opioid receptor pathway. This information can be used by oncologic providers to identify patients at greater risk of developing PTSD and may facilitate referral to appropriate consultants and resources early in their treatment.

RevDate: 2023-01-21

Abraham A, Barcenas CH, Bleicher RJ, et al (2023)

Clinicopathologic and sociodemographic factors associated with late relapse triple negative breast cancer in a multivariable logistic model: A multi-institution cohort study.

Breast (Edinburgh, Scotland), 67:89-93 pii:S0960-9776(23)00004-8 [Epub ahead of print].

BACKGROUND: Most metastatic recurrences of triple negative breast cancer (TNBC) occur within five years of diagnosis, yet late relapses of TNBC (lrTNBC) do occur. Our objective was to develop a risk prediction model of lrTNBC using readily available clinicopathologic and sociodemographic features.

METHODS: We included patients diagnosed with stage I-III TNBC between 1998 and 2012 at ten academic cancer centers. lrTNBC was defined as relapse or mortality greater than 5 years from diagnosis. Features associated with lrTNBC were included in a multivariable logistic model using backward elimination with a p < 0.10 criterion, with a final multivariable model applied to training (70%) and independent validation (30%) cohorts.

RESULTS: A total 2210 TNBC patients with at least five years follow-up and no relapse before 5 years were included. In final multivariable model, lrTNBC was significantly associated with higher stage at diagnosis (adjusted Odds Ratio [aOR] for stage III vs I, 10.9; 95% Confidence Interval [CI], 7.5-15.9; p < 0.0001) and BMI (aOR for obese vs normal weight, 1.4; 95% CI, 1.0-1.8; p = 0.03). Final model performance was consistent between training (70%) and validation (30%) cohorts.

CONCLUSIONS: A risk prediction model incorporating stage, BMI, and age at diagnosis offers potential utility for identification of patients at risk of development of lrTNBC and warrants further investigation.

RevDate: 2023-01-21

Goldman JD, Wang K, Röltgen K, et al (2022)

Reinfection with SARS-CoV-2 and Waning Humoral Immunity: A Case Report.

Vaccines, 11(1): pii:vaccines11010005.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a different strain harboring the spike variant D614G. This case of reinfection was one of the first cases of reinfection reported in 2020. With antibody, B cell and T cell analytics, we show correlates of adaptive immunity at reinfection, including a differential response in neutralizing antibodies to a D614G pseudovirus. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

RevDate: 2023-01-21

Xu H, Nguyen K, Gaynor BJ, et al (2022)

Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.

Genes, 14(1): pii:genes14010061.

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10[-7]), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

RevDate: 2023-01-21

Orvain C, Rodríguez-Arbolí E, Othus M, et al (2023)

Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia.

Cancers, 15(2): pii:cancers15020352.

(1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary AML is now considered a diagnostic qualifier rather than a separate disease entity. (2) Methods: To assess the association between clinical history and AML outcomes in the context of allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 759 patients with de novo AML, 115 with AHD AML, and 105 with therapy-related AML who received first allografts while in first or second remission. (3) Results: At the time of HCT, these three cohorts differed significantly regarding many patient and disease-specific characteristics, including age (p < 0.001), gender (p < 0.001), disease risk (p = 0.005), HCT-CI score (p < 0.001), blood count recovery (p = 0.003), first vs. second remission (p < 0.001), remission duration (p < 0.001), measurable residual disease (MRD; p < 0.001), and conditioning intensity (p < 0.001). Relative to patients with de novo AML, relapse rates were similar for patients with AHD (hazard ratio [HR] = 1.07, p = 0.7) and therapy-related AML (HR = 0.86, p = 0.4) after multivariable adjustment, as were relapse-free survival (HR = 1.20, p = 0.2, and HR = 0.89, p = 0.5) and overall survival (HR = 1.19, p = 0.2, and HR = 0.93, p = 0.6). Non-relapse mortality was higher for AHD AML (HR = 1.59, p = 0.047). (4) Conclusions: These data suggest that the clinical history by itself contains limited prognostic value for adults with AML undergoing allografting, supporting the most recent approach to use this information as a diagnostic qualifier rather than a disease entity.

RevDate: 2023-01-20

Chow EJ, Aggarwal S, Doody DR, et al (2023)

Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.

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

PURPOSE: For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.

METHODS: Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m[2] across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m[2] ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.

RESULTS: From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m[2]). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m[2].

CONCLUSION: Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

RevDate: 2023-01-20

Crivello P, Arrieta-Bolaños E, He M, et al (2023)

Impact of the HLA Immunopeptidome on Survival of Leukemia Patients After Unrelated Donor Transplantation.

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

PURPOSE: Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we tested this concept in HLA-A, -B, and -C disparities after single class I HLA-mismatched UD-HCT.

PATIENTS AND METHODS: We studied 2,391 single class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 for acute leukemia or myelodysplastic syndromes. Hierarchical clustering of experimentally determined peptide-binding motifs (PBM) was used as a proxy for immunopeptidome divergence of HLA-A, -B, or -C disparities, allowing us to classify 1,629/2,391 (68.1%) of the HLA-mismatched UD-HCT as PBM-matched or PBM-mismatched. Risks associated with PBM-matching status were assessed by Cox proportional hazards models, with overall survival (OS) as the primary end point.

RESULTS: Relative to full matches, bidirectional or unidirectional PBM mismatches in graft-versus-host (GVH) direction (PBM-GVH mismatches, 60.7%) were associated with significantly lower OS (hazard ratio [HR], 1.48; P < .0001), while unidirectional PBM mismatches in host-versus-graft direction or PBM matches (PBM-GVH matches, 39.3%) were not (HR, 1.13; P = .1017). PBM-GVH mismatches also had significantly lower OS than PBM-GVH matches in direct comparison (HR, 1.32; P = .0036). The hazards for transplant-related mortality and acute and chronic graft-versus-host disease but not relapse increased stepwise from full HLA matches to single PBM-GVH matches, and single PBM-GVH mismatches. A webtool for PBM-matching of single class I HLA-mismatched donor-recipient pairs was developed.

CONCLUSION: PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome. These findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.

RevDate: 2023-01-21

Mehta R, Ray RM, Tussing-Humphreys LM, et al (2022)

Effect of Low-Fat Dietary Modification on Incident Open-Angle Glaucoma.

Ophthalmology pii:S0161-6420(22)00915-0 [Epub ahead of print].

PURPOSE: We tested whether dietary modification (DM) altered the risk for incident primary open-angle glaucoma (POAG).

DESIGN: Secondary analysis of a randomized intervention trial.

PARTICIPANTS: We linked Medicare claims data to 45 203 women in the Women's Health Initiative Dietary Modification Trial, of which 23 776 participants were enrolled in fee-for-service Medicare Part B and had physician claims.

METHODS: Women were randomized to follow either DM (a low-fat diet, with increased vegetable, fruit, and grain intake) or their usual diet without modification. Nine thousand three hundred forty women were randomized to the DM intervention, whereas 13 877 women were randomized to the control group. Our analyses were based on an intention-to-treat design, with a follow-up to the end of continuous Medicare coverage, death, or the last clams date (12/31/2018), whichever occurred first. Primary open-angle glaucoma was defined as the first claim with the International Classification of Diseases, Ninth or Tenth Revision, codes. Dietary data were assessed using a food frequency questionnaire.

MAIN OUTCOME MEASURES: We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of POAG. Subgroup analyses were performed with P values for interaction.

RESULTS: After exclusion of women with Medicare-derived glaucoma before randomization, the final analysis included 23 217 women (mean age, 64.4 ± 5.8 years). Baseline characteristics were balanced between the intervention and control groups. Primary open-angle glaucoma incidence was 11.1 per 1000 woman-years (mean follow-up, 11.6 ± 7.4 years; mean DM duration, 5.2 ± 3.2 years). We found no overall benefit of DM in reducing incident POAG (HR, 1.04; 95% CI, 0.96-1.12). Race and participant age did not modify this relation (P = 0.08 and P = 0.24 for interaction, respectively). In further analysis of baseline nutrient and food intake stratified by quartile groups, risk of open-angle glaucoma (OAG) in DM participants in the lowest quartile group for percentage calories (kilocalories) from total fat (33.8 or lower) was increased (HR, 1.22; 95% CI, 1.05-1.41; P = 0.007 for interaction).

CONCLUSIONS: Analysis suggests that DM in participants in the lowest quartile group for percentage calories from total fat at baseline increased the risk of incident OAG among women regardless of age or race.

FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

RevDate: 2023-01-20

Meric-Bernstam F, Ford JM, O'Dwyer PJ, et al (2023)

National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH).

Clinical cancer research : an official journal of the American Association for Cancer Research pii:716092 [Epub ahead of print].

Over the past decade, multiple trials, including the precision medicine trial NCI-MATCH (National Cancer Institute-Molecular Analysis for Therapy Choice, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the National Cancer Institute (NCI) and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. While NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. While NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. While NCI-MATCH consisted of single arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design and logistics supporting the ComboMATCH study.

RevDate: 2023-01-20

Bricker J, Miao Z, Mull K, et al (2023)

Can a Single Variable Predict Early Dropout From Digital Health Interventions? Comparison of Predictive Models From Two Large Randomized Trials.

Journal of medical Internet research, 25:e43629 pii:v25i1e43629.

BACKGROUND: A single generalizable metric that accurately predicts early dropout from digital health interventions has the potential to readily inform intervention targets and treatment augmentations that could boost retention and intervention outcomes. We recently identified a type of early dropout from digital health interventions for smoking cessation, specifically, users who logged in during the first week of the intervention and had little to no activity thereafter. These users also had a substantially lower smoking cessation rate with our iCanQuit smoking cessation app compared with users who used the app for longer periods.

OBJECTIVE: This study aimed to explore whether log-in count data, using standard statistical methods, can precisely predict whether an individual will become an iCanQuit early dropout while validating the approach using other statistical methods and randomized trial data from 3 other digital interventions for smoking cessation (combined randomized N=4529).

METHODS: Standard logistic regression models were used to predict early dropouts for individuals receiving the iCanQuit smoking cessation intervention app, the National Cancer Institute QuitGuide smoking cessation intervention app, the WebQuit.org smoking cessation intervention website, and the Smokefree.gov smoking cessation intervention website. The main predictors were the number of times a participant logged in per day during the first 7 days following randomization. The area under the curve (AUC) assessed the performance of the logistic regression models, which were compared with decision trees, support vector machine, and neural network models. We also examined whether 13 baseline variables that included a variety of demographics (eg, race and ethnicity, gender, and age) and smoking characteristics (eg, use of e-cigarettes and confidence in being smoke free) might improve this prediction.

RESULTS: The AUC for each logistic regression model using only the first 7 days of log-in count variables was 0.94 (95% CI 0.90-0.97) for iCanQuit, 0.88 (95% CI 0.83-0.93) for QuitGuide, 0.85 (95% CI 0.80-0.88) for WebQuit.org, and 0.60 (95% CI 0.54-0.66) for Smokefree.gov. Replacing logistic regression models with more complex decision trees, support vector machines, or neural network models did not significantly increase the AUC, nor did including additional baseline variables as predictors. The sensitivity and specificity were generally good, and they were excellent for iCanQuit (ie, 0.91 and 0.85, respectively, at the 0.5 classification threshold).

CONCLUSIONS: Logistic regression models using only the first 7 days of log-in count data were generally good at predicting early dropouts. These models performed well when using simple, automated, and readily available log-in count data, whereas including self-reported baseline variables did not improve the prediction. The results will inform the early identification of people at risk of early dropout from digital health interventions with the goal of intervening further by providing them with augmented treatments to increase their retention and, ultimately, their intervention outcomes.

RevDate: 2023-01-20

Bradley P (2023)

Structure-based prediction of T cell receptor:peptide-MHC interactions.

eLife, 12: pii:82813.

The regulatory and effector functions of T cells are initiated by the binding of their cell-surface T cell receptor (TCR) to peptides presented by major histocompatibility complex (MHC) proteins on other cells. The specificity of TCR:peptide-MHC interactions, thus, underlies nearly all adaptive immune responses. Despite intense interest, generalizable predictive models of TCR:peptide-MHC specificity remain out of reach; two key barriers are the diversity of TCR recognition modes and the paucity of training data. Inspired by recent breakthroughs in protein structure prediction achieved by deep neural networks, we evaluated structural modeling as a potential avenue for prediction of TCR epitope specificity. We show that a specialized version of the neural network predictor AlphaFold can generate models of TCR:peptide-MHC interactions that can be used to discriminate correct from incorrect peptide epitopes with substantial accuracy. Although much work remains to be done for these predictions to have widespread practical utility, we are optimistic that deep learning-based structural modeling represents a path to generalizable prediction of TCR:peptide-MHC interaction specificity.

RevDate: 2023-01-20

Gornalusse G, Spengler RM, Sandford E, et al (2023)

Men who inject opioids exhibit altered tRNA-Gly-GCC isoforms in semen.

Molecular human reproduction pii:6994192 [Epub ahead of print].

In addition to their role in protein translation, tRNAs can be cleaved into shorter, biologically active fragments called tRFs. Specific tRFs from spermatocytes can propagate metabolic disorders in second generations of mice. Thus, tRFs in germline cells are a mechanism of epigenetic inheritance. It has also been shown that stress and toxins can cause alterations in tRF patterns. We were therefore interested in whether injecting illicit drugs, a major stressor, impacts tRFs in germline cells. We sequenced RNA from spermatocytes and from semen-derived exosomes from people who inject illicit drugs (PWID) and from non-drug using controls, both groups of unknown fertility status. All PWID injected opioids daily, but most also used other illicit drugs. The tRF cleavage products from Gly-GCC tRNA were markedly different between spermatocytes from PWID compared to controls. Over 90% of reads in controls mapped to shorter Gly-GCC tRFs, while in PWID only 45% did. In contrast, only 4.1% of reads in controls mapped to a longer tRFs versus 45.6% in PWID. The long/short tRF ratio was significantly higher in PWID than controls (0.23 versus 0.16, p = 0.0128). We also report differential expression of a group of small nucleolar RNAs in semen-derived exosomes, including, among others, ACA14a, U19 and U3-3. Thus, PWID exhibited an altered cleavage pattern of tRNA-Gly-GCC in spermatocytes and an altered cargo of snoRNAs in semen-derived exosomes. Participants were not exclusively using opioids and were not matched with controls in terms of diet, chronic disease, or other stressors, so our finding are not conclusively linked to opioid use. However, all individuals in the PWID group did inject heroin daily. Our study indicates a potential for opioid injection and/or its associated multi-drug use habits and lifestyle changes to influence epigenetic inheritance.

RevDate: 2023-01-19

Song H, Ling W, Zhao N, et al (2023)

Accommodating multiple potential normalizations in microbiome associations studies.

BMC bioinformatics, 24(1):22.

Microbial communities are known to be closely related to many diseases, such as obesity and HIV, and it is of interest to identify differentially abundant microbial species between two or more environments. Since the abundances or counts of microbial species usually have different scales and suffer from zero-inflation or over-dispersion, normalization is a critical step before conducting differential abundance analysis. Several normalization approaches have been proposed, but it is difficult to optimize the characterization of the true relationship between taxa and interesting outcomes. RESULTS: To avoid the challenge of picking an optimal normalization and accommodate the advantages of several normalization strategies, we propose an omnibus approach. Our approach is based on a Cauchy combination test, which is flexible and powerful by aggregating individual p values. We also consider a truncated test statistic to prevent substantial power loss. We experiment with a basic linear regression model as well as recently proposed powerful association tests for microbiome data and compare the performance of the omnibus approach with individual normalization approaches. Experimental results show that, regardless of simulation settings, the new approach exhibits power that is close to the best normalization strategy, while controling the type I error well. CONCLUSIONS: The proposed omnibus test releases researchers from choosing among various normalization methods and it is an aggregated method that provides the powerful result to the underlying optimal normalization, which requires tedious trial and error. While the power may not exceed the best normalization, it is always much better than using a poor choice of normalization.

RevDate: 2023-01-19

Fong Y, Huang Y, Benkeser D, et al (2023)

Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial.

Nature communications, 14(1):331.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

RevDate: 2023-01-19

Wang M, Tapia K, Oluoch LM, et al (2023)

Adolescent Girls and Young Women in Kenya Demonstrate Rapid STI Incidence Following First Sex: Data From a Longitudinal Cohort.

The Journal of adolescent health : official publication of the Society for Adolescent Medicine pii:S1054-139X(22)00730-3 [Epub ahead of print].

PURPOSE: Adolescent girls and young women (AGYW) are disproportionately affected by STIs. Observation of life course events can describe behavioral and biological factors associated with STI risk.

METHODS: Sexually inexperienced AGYW aged 16-20 years in Kenya were followed for five years. Quarterly visits assessed for C. trachomatis (CT), N. gonorrhea (GC), and T. vaginalis (TV), bacterial vaginosis (BV), HSV-2, and HIV. Sexual activity was self-reported but amended if incongruent with results from STI, pregnancy, or any other testing. Cox regression and Generalized Estimating Equation models were used to determine hazard ratios (HRs) and relative risks (RRs) of STI.

RESULTS: During follow-up, 293 of 400 participants reported sex, 163 AGYW experienced an STI, and 72 participants had multiple STIs. Among 163 participants that experienced an STI, there were a total of 259 visits where STIs were detected, 78% (n = 201) of which included CT. Cox regression found participants with BV had over two-fold higher risk of first STI acquisition (adjusted hazard ratio (aHR): 2.35; 95% confidence interval (CI) 1.43-3.88; p = .001). Increased risk for first STI episode was associated with a new partner (aHR: 3.16; 95% CI 1.59-6.28; p = .001). AGYW who did not disclose sexual activity had the highest risk (aHR: 3.60; 95% CI 1.93-6.70; p < .001). Condom use was low, with 21% reporting condom use with sex. GEE analysis of all STIs including incident, prevalent, and recurrent, confirmed these risk factors.

DISCUSSION: During the critical years after first sex, AGYW with BV, new sexual partners, and those who did not disclose sexual activity were at highest risk for STI events, especially CT.

RevDate: 2023-01-19

Cespedes Feliciano EM, Vasan S, Luo J, et al (2023)

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

JAMA oncology pii:2800753 [Epub ahead of print].

IMPORTANCE: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls.

OBJECTIVE: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls.

This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women's Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm.

EXPOSURES: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records.

MAIN OUTCOMES AND MEASURES: Trajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis.

RESULTS: This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 [95% CI, -6.4 to -4.3] points per year in regional vs -2.8 [95% CI, -3.4 to -2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 [95% CI, -12.2 to -3.6] points per year with any chemotherapy; -3.1 [95% CI, -6.0 to -0.3] with radiation therapy alone; and -2.6 [95% CI, -4.2 to -1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 [95% CI, -5.9 to -2.6] points per year in the year following diagnosis vs -1.4 [95% CI, -1.7 to -1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis.

CONCLUSIONS AND RELEVANCE: In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

RevDate: 2023-01-19

Fong Y, Huang Y, Borate B, et al (2023)

Antibody Correlates of Protection From Severe Respiratory Syncytial Virus Disease in a Vaccine Efficacy Trial.

Open forum infectious diseases, 10(1):ofac693.

BACKGROUND: Respiratory syncytial virus (RSV) can cause serious lung infections in young children and there is currently no available vaccine.

METHODS: We used complementary statistical frameworks to analyze 4 RSV serology measurements in mothers and their infants in South Africa who participated in a phase 3 maternal immunization trial of an RSV F protein nanoparticle vaccine as correlates of risk and of protection against different RSV disease endpoints.

RESULTS: We found evidence to support each antibody measurement-encompassing RSV-neutralizing antibodies and F surface glycoprotein-binding antibodies-as an inverse correlate of risk of RSV-associated acute lower respiratory tract infection with severe hypoxia in at least 1 framework, with vaccine-induced fold-rise from the maternal enrollment to day 14 samples of anti-F immunoglobulin G (IgG) binding antibodies having the most consistent evidence. This evidence includes a significant association of fold-rise anti-F IgG with vaccine efficacy (VE); achieving a baseline covariate-adjusted VE of 75% requires a vaccine-induced maternal anti-F IgG fold-rise of around 16. Neither multivariable logistic regression nor superlearning analyses showed benefit to including multiple time points or assays in the same model, suggesting a parsimonious correlate. Post hoc exploratory analyses supported adherence of vaccine-induced maternal anti-F IgG fold-rise to the Prentice criteria for a valid surrogate endpoint.

CONCLUSIONS: Our results suggest that the vaccine induced protective anti-F antibody responses. If this finding is confirmed, VE could potentially be augmented by increasing these responses.

RevDate: 2023-01-18

Midttun Ø, Ulvik A, Meyer K, et al (2023)

A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium.

Scientific reports, 13(1):1011.

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

RevDate: 2023-01-18

Pintye J, Odoyo J, Nyerere B, et al (2023)

Nurse-facilitated PrEP delivery for adolescent girls and young women seeking contraception at retail pharmacies in Kisumu, Kenya.

AIDS (London, England) pii:00002030-990000000-00160 [Epub ahead of print].

OBJECTIVE: We evaluated PrEP uptake, initiation, and continuation within a nurse-facilitated pharmacy-based delivery model for Kenyan adolescent girls and young women (AGYW) seeking contraception at retail pharmacies.

METHODS: From October 2020 to March 2021, PrEP-trained nurses were stationed at three retail pharmacies in Kisumu, Kenya. AGYW (aged 15-24 years) purchasing contraception (emergency contraception [EC], oral contraceptive pills, injectables, implants, condoms) were counseled on PrEP, completed HIV testing, and offered a free one-month supply of PrEP pills per national guidelines by nurses under supervision of a remote physician. We evaluated uptake among all AGYW offered PrEP. At 30 days after uptake, we evaluated PrEP use initiation and plans for continuation.

RESULTS: We enrolled 235 AGYW clients who were HIV-negative and purchasing contraception at pharmacies. EC was the most frequently purchased contraceptive (35%). Median age was 22 years (IQR 19-23), 44% were currently in school, and 33% currently had multiple sexual partners. One-fourth (24%) exchanged sex for money or favors and 14% had sex while intoxicated in the prior 6 months. Overall, PrEP uptake was 85%; at one month, 82% had initiated PrEP use and 68% planned to continue use. Among those initiating PrEP, 69% were willing to pay for PrEP at retail pharmacies (median KES 150, IQR 100-200) even if available for free at public sector facilities.

CONCLUSIONS: In this evaluation of nurse-facilitated PrEP delivery at pharmacies in Kenya, a substantial proportion of AGYW who purchased contraception subsequently initiated PrEP, planned to continue use, and were willing to pay for PrEP.

RevDate: 2023-01-18

Davis K, Mitchell C, Weissenfels O, et al (2023)

G protein-coupled receptor kinase-2 (GRK-2) controls exploration through neuropeptide signaling in Caenorhabditis elegans.

PLoS genetics, 19(1):e1010613 pii:PGENETICS-D-22-00899 [Epub ahead of print].

Animals alter their behavior in manners that depend on environmental conditions as well as their developmental and metabolic states. For example, C. elegans is quiescent during larval molts or during conditions of satiety. By contrast, worms enter an exploration state when removed from food. Sensory perception influences movement quiescence (defined as a lack of body movement), as well as the expression of additional locomotor states in C. elegans that are associated with increased or reduced locomotion activity, such as roaming (exploration behavior) and dwelling (local search). Here we find that movement quiescence is enhanced, and exploration behavior is reduced in G protein-coupled receptor kinase grk-2 mutant animals. grk-2 was previously shown to act in chemosensation, locomotion, and egg-laying behaviors. Using neuron-specific rescuing experiments, we show that GRK-2 acts in multiple ciliated chemosensory neurons to control exploration behavior. grk-2 acts in opposite ways from the cGMP-dependent protein kinase gene egl-4 to control movement quiescence and exploration behavior. Analysis of mutants with defects in ciliated sensory neurons indicates that grk-2 and the cilium-structure mutants act in the same pathway to control exploration behavior. We find that GRK-2 controls exploration behavior in an opposite manner from the neuropeptide receptor NPR-1 and the neuropeptides FLP-1 and FLP-18. Finally, we show that secretion of the FLP-1 neuropeptide is negatively regulated by GRK-2 and that overexpression of FLP-1 reduces exploration behavior. These results define neurons and molecular pathways that modulate movement quiescence and exploration behavior.

RevDate: 2023-01-18

Kessler RC, Bauer MS, Bishop TM, et al (2023)

Evaluation of a Model to Target High-risk Psychiatric Inpatients for an Intensive Postdischarge Suicide Prevention Intervention.

JAMA psychiatry pii:2800171 [Epub ahead of print].

IMPORTANCE: The months after psychiatric hospital discharge are a time of high risk for suicide. Intensive postdischarge case management, although potentially effective in suicide prevention, is likely to be cost-effective only if targeted at high-risk patients. A previously developed machine learning (ML) model showed that postdischarge suicides can be predicted from electronic health records and geospatial data, but it is unknown if prediction could be improved by adding additional information.

OBJECTIVE: To determine whether model prediction could be improved by adding information extracted from clinical notes and public records.

Models were trained to predict suicides in the 12 months after Veterans Health Administration (VHA) short-term (less than 365 days) psychiatric hospitalizations between the beginning of 2010 and September 1, 2012 (299 050 hospitalizations, with 916 hospitalizations followed within 12 months by suicides) and tested in the hospitalizations from September 2, 2012, to December 31, 2013 (149 738 hospitalizations, with 393 hospitalizations followed within 12 months by suicides). Validation focused on net benefit across a range of plausible decision thresholds. Predictor importance was assessed with Shapley additive explanations (SHAP) values. Data were analyzed from January to August 2022.

MAIN OUTCOMES AND MEASURES: Suicides were defined by the National Death Index. Base model predictors included VHA electronic health records and patient residential data. The expanded predictors came from natural language processing (NLP) of clinical notes and a social determinants of health (SDOH) public records database.

RESULTS: The model included 448 788 unique hospitalizations. Net benefit over risk horizons between 3 and 12 months was generally highest for the model that included both NLP and SDOH predictors (area under the receiver operating characteristic curve range, 0.747-0.780; area under the precision recall curve relative to the suicide rate range, 3.87-5.75). NLP and SDOH predictors also had the highest predictor class-level SHAP values (proportional SHAP = 64.0% and 49.3%, respectively), although the single highest positive variable-level SHAP value was for a count of medications classified by the US Food and Drug Administration as increasing suicide risk prescribed the year before hospitalization (proportional SHAP = 15.0%).

CONCLUSIONS AND RELEVANCE: In this study, clinical notes and public records were found to improve ML model prediction of suicide after psychiatric hospitalization. The model had positive net benefit over 3-month to 12-month risk horizons for plausible decision thresholds. Although caution is needed in inferring causality based on predictor importance, several key predictors have potential intervention implications that should be investigated in future studies.

RevDate: 2023-01-19

Armistead B, Jiang Y, Carlson M, et al (2022)

Spike-specific T cells are enriched in breastmilk following SARS-CoV-2 mRNA vaccination.

medRxiv : the preprint server for health sciences.

UNLABELLED: Human breastmilk is rich in T cells; however, their specificity and function are largely unknown. We compared the phenotype, diversity, and antigen specificity of T cells in the breastmilk and peripheral blood of lactating individuals who received SARS-CoV-2 mRNA vaccination. Relative to blood, breastmilk contained higher frequencies of T effector and central memory populations that expressed mucosal-homing markers. T cell receptor (TCR) sequence overlap was limited between blood and breastmilk. Overabundan t breastmilk clones were observed in all individuals, were diverse, and contained CDR3 sequences with known epitope specificity including to SARS-CoV-2 Spike. Spike-specific TCRs were more frequent in breastmilk compared to blood and expanded in breastmilk following a third mRNA vaccine dose. Our observations indicate that the lactating breast contains a distinct T cell population that can be modulated by maternal vaccination with potential implications for infant passive protection.

ONE-SENTENCE SUMMARY: The breastmilk T cell repertoire is distinct and enriched for SARS-CoV-2 Spike-specificity after maternal mRNA vaccination.

RevDate: 2023-01-18

Klebanoff MA, Schuit E, Lamont RF, et al (2023)

Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis.

Paediatric and perinatal epidemiology [Epub ahead of print].

BACKGROUND: Bacterial vaginosis (BV) increases preterm delivery (PTD) risk, but treatment trials showed mixed results in preventing PTD.

OBJECTIVES: Determine, using individual participant data (IPD), whether BV treatment during pregnancy reduced PTD or prolonged time-to-delivery.

DATA SOURCES: Cochrane Systematic Review (2013), MEDLINE, EMBASE, journal searches, and searches (January 2013-September 2022) ("bacterial vaginosis AND pregnancy") of (i) clinicaltrials.gov; (ii) Cochrane Central Register of Controlled Trials; (iii) World Health Organization International Clinical Trials Registry Platform Portal; and (iv) Web of Science ("bacterial vaginosis").

Studies randomising asymptomatic pregnant individuals with BV to antibiotics or control, measuring delivery gestation. Extraction was from original data files. Bias risk was assessed using the Cochrane tool. Analysis used "one-step" logistic and Cox random effect models, adjusting gestation at randomisation and PTD history; heterogeneity by I[2] . Subgroup analysis tested interactions with treatment. In sensitivity analyses, studies not providing IPD were incorporated by "multiple random-donor hot-deck" imputation, using IPD studies as donors.

RESULTS: There were 121 references (96 studies) with 23 eligible trials (11,979 participants); 13 studies (6915 participants) provided IPD; 12 (6115) were incorporated. Results from 9 (4887 participants) not providing IPD were imputed. Odds ratios for PTD for metronidazole and clindamycin versus placebo were 1.00 (95% CI 0.84, 1.17), I[2]  = 62%, and 0.59 (95% CI 0.42, 0.82), I[2]  = 0 before; and 0.95 (95% CI 0.81, 1.11), I[2]  = 59%, and 0.90 (95% CI: 0.72, 1.12), I[2]  = 0, after imputation. Time-to-delivery did not differ from null with either treatment. Including imputed IPD, there was no evidence that either drug was more effective when administered earlier, or among those with a PTD history.

CONCLUSIONS: Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation.

RevDate: 2023-01-18

Kato I, Sun J, Hastert TA, et al (2023)

Association of calcium and vitamin D supplementation with cancer incidence and cause-specific mortality in Black women: extended follow-up of the Women's Health Initiative calcium-vitamin D trial.

International journal of cancer [Epub ahead of print].

Low circulating vitamin D levels are more prevalent in Black than White individuals. We analyzed the Women's Health Initiative (WHI) calcium plus vitamin D (CaD) randomized clinical trial extended follow-up data to evaluate associations between calcium plus vitamin D supplementation and incident cancer, cardiovascular disease (CVD), and cause-specific mortality endpoints among Black women. Intent-to-treat analysis was performed. Among 3325 Black women in the CaD trial who were randomized into either daily calcium (1000 mg of calcium carbonate) plus vitamin D (400 IU D3) or placebos for an average of 7 years, there were 813 deaths, 588 incident cancers, and 837 CVD events during an average of 15.7 years of follow up (52,230 total person-years). Using Cox's proportional hazards models, we calculated hazard ratios and their confidence intervals for outcomes ascertained during the trial period, post-trial follow-up period and overall periods combined. We found that total mortality, cause-specific mortality, and total cancer incidence were almost identical between CaD and placebo groups. These results suggest that calcium plus vitamin D supplementation does not reduce risks of cancer, CVD, or other major causes of death in Black women overall and, thus, other medical, behavioral or social interventions should be considered to narrow health disparities related to these outcomes. However, other finer endpoints, such as colorectal cancer, warrants further investigation. This article is protected by copyright. All rights reserved.

RevDate: 2023-01-17

Lawrence MG, Taylor RA, Cuffe GB, et al (2023)

The future of patient-derived xenografts in prostate cancer research.

Nature reviews. Urology [Epub ahead of print].

Patient-derived xenografts (PDXs) are generated by engrafting human tumours into mice. Serially transplantable PDXs are used to study tumour biology and test therapeutics, linking the laboratory to the clinic. Although few prostate cancer PDXs are available in large repositories, over 330 prostate cancer PDXs have been established, spanning broad clinical stages, genotypes and phenotypes. Nevertheless, more PDXs are needed to reflect patient diversity, and to study new treatments and emerging mechanisms of resistance. We can maximize the use of PDXs by exchanging models and datasets, and by depositing PDXs into biorepositories, but we must address the impediments to accessing PDXs, such as institutional, ethical and legal agreements. Through collaboration, researchers will gain greater access to PDXs representing diverse features of prostate cancer.

RevDate: 2023-01-17

Islam Z, Saravanan B, Walavalkar K, et al (2023)

Active enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundaries.

Genome research pii:gr.276643.122 [Epub ahead of print].

Vertebrate genomes are partitioned into chromatin domains or topologically associating domains (TADs), which are typically bound by head-to-head pairs of CTCF binding sites. Transcription at domain boundaries correlates with better insulation; however, it is not known whether the boundary transcripts themselves contribute to boundary function. Here we characterize boundary-associated RNAs genome-wide, focusing on the disease-relevant INK4a/ARF and MYC TAD. Using CTCF site deletions and boundary-associated RNA knockdowns, we observe that boundary-associated RNAs facilitate recruitment and clustering of CTCF at TAD borders. The resulting CTCF enrichment enhances TAD insulation, enhancer-promoter interactions, and TAD gene expression. Importantly, knockdown of boundary-associated RNAs results in loss of boundary insulation function. Using enhancer deletions and CRISPRi of promoters, we show that active TAD enhancers, but not promoters, induce boundary-associated RNA transcription, thus defining a novel class of regulatory enhancer RNAs.

RevDate: 2023-01-17

Neofytos D, Steinbach WJ, Hanson K, et al (2023)

American Society for Transplantation and Cellular Therapy Series: #6 - Management of Invasive Candidiasis in Hematopoietic Cell Transplant Recipients.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transplant Infectious Disease Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables and figures.[1] Adult and pediatric infectious disease and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This sixth guideline in the series focuses on invasive candidiasis (IC) with FAQs to address epidemiology, clinical diagnosis, prophylaxis and treatment of IC, plus special considerations for pediatric, cord blood, haploidentical and T-cell depleted HCT recipients, CAR-T cell recipients, as well as future research directions.

RevDate: 2023-01-17

Begnel ER, Chohan BH, Ojee E, et al (2023)

HIV and SARS-CoV-2 infection in postpartum Kenyan women and their infants.

PloS one, 18(1):e0278675 pii:PONE-D-22-00319.

BACKGROUND: HIV may increase SARS-CoV-2 infection risk and COVID-19 severity generally, but data are limited about its impact on postpartum women and their infants. As such, we characterized SARS-CoV-2 infection among mother-infant pairs in Nairobi, Kenya.

METHODS: We conducted a nested study of 62 HIV-uninfected and 64 healthy women living with HIV, as well as their HIV-exposed uninfected (N = 61) and HIV-unexposed (N = 64) infants, participating in a prospective cohort. SARS-CoV-2 serology was performed on plasma collected between May 1, 2020-February 1, 2022 to determine the incidence, risk factors, and symptoms of infection. SARS-CoV-2 RNA PCR and sequencing was also performed on available stool samples from seropositive participants.

RESULTS: SARS-CoV-2 seropositivity was found in 66% of the 126 mothers and in 44% of the 125 infants. There was no significant association between SARS-CoV-2 infection and maternal HIV (Hazard Ratio [HR] = 0.810, 95% CI: 0.517-1.27) or infant HIV exposure (HR = 1.47, 95% CI: 0.859-2.53). Maternal SARS-CoV-2 was associated with a two-fold increased risk of infant infection (HR = 2.31, 95% CI: 1.08-4.94). Few participants (13% mothers, 33% infants) had symptoms; no participant experienced severe COVID-19 or death. Seroreversion occurred in about half of mothers and infants. SARS-CoV-2 sequences obtained from stool were related to contemporaneously circulating variants.

CONCLUSIONS: These data indicate that postpartum Kenyan women and their infants were at high risk for SARS-CoV-2 infection and that antibody responses waned over an average of 8-10 months. However, most cases were asymptomatic and healthy women living with HIV did not have a substantially increased risk of infection or severe COVID-19.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

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

Biographies

Biographical information about many key scientists.

Selected Bibliographies

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

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