Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart.

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors.

Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity.

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown.

A single-cell multi-omic atlas spanning the adult rhesus macaque brain.

Cataloging the diverse cellular architecture of the primate brain is crucial for understanding cognition, behavior, and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas of the rhesus macaque brain. Together, we profiled 2.

Phase 4 Multinational Multicenter Retrospective and Prospective Real-World Study of Nivolumab in Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck.

This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively.

The genetics of autism spectrum disorder in an East African familial cohort.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry.

Correlation between pathologic complete response, event-free survival/disease-free survival and overall survival in neoadjuvant and/or adjuvant HR+/HER2-breast cancer.

Purpose: The study's purpose was to evaluate the correlation between overall survival (OS) and its potential surrogate endpoints: pathologic complete response (pCR) and event-free survival (EFS)/disease-free survival (DFS) in neoadjuvant and/or adjuvant HR+/HER2- breast cancer.

Methods: Systematic search was performed in MEDLINE, EMBASE, Cochrane Library databases and other relevant sources to identify literature that have reported outcomes of interest in the target setting. The strength of correlation of EFS/DFS with OS, pCR with OS, and pCR with EFS/DFS was measured using Pearson's correlation coefficient (r) based on weighted regression analysis.

Neoadjuvant treatment and survival outcomes by pathologic complete response in HER2-negative early breast cancers.

The benefit of pathologic complete response (pCR) in early breast cancer (eBC) is not well described in the real-world setting. This study used the nationwide Flatiron Health electronic health record-derived deidentified database to describe treatment patterns and survival outcomes by pCR status after neoadjuvant therapy (NAT) in women with triple-negative or HR/HER2 eBC. Observational cohort study analyzing women with eBC who started NAT between 2011 and 2018.

Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment.

Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer's disease.

Cost-Effectiveness of Pharmacologic Treatment Options for Women With Endocrine-Refractory or Triple-Negative Metastatic Breast Cancer.

Purpose: Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making.

Absorption, Distribution, Metabolism, and Excretion of US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.

Absorption, distribution, metabolism, and excretion (ADME) are the key biologic processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy and adverse drug reactions (ADRs). The chemical structures, dosage forms, and sites and routes of administration are the principal determinants of ADME profiles and consequent impacts on their efficacy and ADRs. Newly developed large molecule biologic antisense oligonucleotide (ASO) drugs have completely unique ADME that is not fully defined.

Projecting the Prevalence and Costs of Metastatic Breast Cancer From 2015 through 2030.

Background: This study projected the number of metastatic breast cancer (mBC) cases and costs (medical and productivity) attributable to mBC through 2030 among 3 age groups: younger (aged 18-44 years), midlife (aged 45-64 years), and older women (aged 65 years and older).

Methods: We developed a stock/flow model in which women enter the mBC population at initial diagnosis (de novo stage IV) or through progression of an earlier-stage cancer. Women exit the mBC population through death.

Treatment patterns and outcomes for patients with newly diagnosed glioblastoma multiforme: a retrospective cohort study.

Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Most patients received 1L radiation with temozolomide.

Medical costs associated with metastatic breast cancer in younger, midlife, and older women.

Purpose: We estimated average medical costs due to metastatic breast cancer (mBC) among younger (aged 18-44), midlife (aged 45-64), and older women (aged 65 and older) by phase of care: initial, continuing, and terminal.

Methods: We used 2003-2014 North Carolina cancer registry data linked with administrative claims from public and private payers. We developed a claims-based algorithm to identify breast cancer patients who progressed to metastatic disease.

Human Trophoblast Differentiation Is Associated With Profound Gene Regulatory and Epigenetic Changes.

Defective placental implantation and vascularization with accompanying hypoxia contribute to preeclampsia (PE), a leading cause of maternal and neonatal morbidity and mortality. Genetic and epigenetic mechanisms underlying differentiation of proliferative cytotrophoblasts (CytTs) to multinucleated syncytiotrophoblast (SynT) are incompletely defined. The SynT performs key functions in nutrient and gas exchange, hormone production, and protection of the fetus from rejection by the maternal immune system.

Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation.

The histone variant H3.3 is enriched at enhancers and active genes, as well as repeat regions such as telomeres and retroelements, in mouse embryonic stem cells (mESCs). Although recent studies demonstrate a role for H3.

An updated systematic review of the cost-effectiveness of therapies for metastatic breast cancer.

Purpose: The goal of this systematic review is to provide an update to the review by Pouwels et al. by conducting a systematic review and an assessment of the reporting quality of the economic analyses conducted since 2014.

Methods: This systematic review identified published articles focused on metastatic breast cancer treatment using the Medline/PubMed and Scopus databases and the following search criteria: (((cost effectiveness[MeSH Terms]) OR (cost effectiveness) OR (cost-effectiveness) OR (cost utility) OR (cost-utility) OR (economic evaluation)) AND (("metastatic breast cancer") OR ("advanced breast cancer"))).

Economic Analysis of Neoadjuvant Chemotherapy Versus Primary Debulking Surgery for Advanced Epithelial Ovarian Cancer Using an Aggressive Surgical Paradigm.

Objectives: Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery.

Transcription pausing regulates mouse embryonic stem cell differentiation.

The pluripotency of embryonic stem cells (ESCs) relies on appropriate responsiveness to developmental cues. Promoter-proximal pausing of RNA polymerase II (Pol II) has been suggested to play a role in keeping genes poised for future activation. To identify the role of Pol II pausing in regulating ESC pluripotency, we have generated mouse ESCs carrying a mutation in the pause-inducing factor SPT5.

Dynamic Change of Transcription Pausing through Modulating NELF Protein Stability Regulates Granulocytic Differentiation.

The NELF complex is a metazoan-specific factor essential for establishing transcription pausing. Although NELF has been implicated in cell fate regulation, the cellular regulation of NELF and its intrinsic role in specific lineage differentiation remains largely unknown. Using mammalian hematopoietic differentiation as a model system, here we identified a dynamic change of NELF-mediated transcription pausing as a novel mechanism regulating hematopoietic differentiation.

Bisexuality, sexual risk taking, and HIV prevalence among men who have sex with men accessing voluntary counseling and testing services in Mumbai, India.

Objectives: To describe sociodemographics, sexual risk behavior, and estimate HIV and sexually transmitted infection (STI) prevalence among men who have sex with men (MSM) in Mumbai, India.

Methods: Eight hundred thirty-one MSM attending voluntary counseling and testing (VCT) services at the Humsafar Trust, answered a behavioral questionnaire and consented for Venereal Disease Research Laboratory and HIV testing from January 2003 through December 2004. Multivariate logistic regression was performed for sociodemographics, sexual risk behavior, and STIs with HIV result as an outcome.

A one year prospective study to compare and evaluate diagnostic accuracy of modified Alvarado score and ultrasonography in acute appendicitis, in adults.

Objectives: To compare and evaluate diagnostic accuracy of modified Alvarado score and ultrasonography in co-relation to histopathology report for diagnosis of acute appendicitis.

Methodology: A prospective study of the patients who underwent appendectomy for suspected acute appendicitis at K.L.