Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Study protocol for a hybrid type 1 effectiveness-implementation trial testing virtual tobacco treatment in oncology practices [Smokefree Support Study 2.0]

Abstract Background Persistent smoking among patients diagnosed with cancer is associated with adverse clinical outcomes, yet an evidence-based tobacco use intervention has not been well-integrated into cancer care in community oncology settings. This paper describes the protocol of a nation-wide clinical trial conducted by the ECOG-ACRIN National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base to assess the effectiveness of a virtual tobacco treatment intervention and the process of implementing tobacco treatment in NCORP community oncology settings. Methods/design This two-arm, multisite (n: 49 NCORP sites) hybrid type 1 effectiveness-implementation randomized controlled trial compares the effectiveness of a Virtual Intervention Treatment (VIT) versus an Enhanced Usual Control (EUC) among English and Spanish speaking patients recently diagnosed with cancer, reporting current smoking and receiving care at a participating NCORP Community or Minority/Underserved Site. The VIT includes up to 11 virtual counseling sessions with a tobacco treatment specialist and up to 12 weeks of nicotine replacement therapy (NRT). The EUC arm receives a referral to the NCI Quitline. The primary study outcome is biochemically confirmed 7-day point prevalence smoking abstinence. Moderators of treatment effect will be assessed. The study evaluates implementation processes from participating NCORP site staff via survey, administrative, and focus group data, including reach, acceptability, appropriateness, fidelity, feasibility, adoption, cost and sustainability outcomes. Discussion This trial will generate findings about the effectiveness of an evidence-based virtual tobacco treatment intervention targeting patients diagnosed with cancer and illuminate barriers and facilitators that influence implementing tobacco treatment into community oncology settings nationally. In the era of COVID-19, virtual care solutions are vital for maximizing access and utilization of tobacco treatment delivery. Trial registration ClinicalTrials.gov (NCT03808818) on January 18th, 2019; Last update posted: May 21st, 2020.http://deepblue.lib.umich.edu/bitstream/2027.42/173518/1/12889_2022_Article_13631.pd