Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that ...genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as
, and
are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.
Intimate partner violence is a significant public health problem in our society, affecting women disproportionately. Intimate partner violence takes many forms, including physical violence, sexual ...violence, stalking, and psychological aggression. While the scope of intimate partner violence is not fully documented, nearly 40% of women in the United States are victims of sexual violence in their lifetimes and 20% are victims of physical intimate partner violence. Other forms of intimate partner violence are likely particularly underreported. Intimate partner violence has a substantial impact on a woman’s physical and mental health. Physical disorders include the direct consequences of injuries sustained after physical violence, such as fractures, lacerations and head trauma, sexually transmitted infections and unintended pregnancies as a consequence of sexual violence, and various pain disorders. Mental health impacts include an increased risk of depression, anxiety, posttraumatic stress disorder, and suicide. These adverse health effects are amplified in pregnancy, with an increased risk of pregnancy outcomes such as preterm birth, low birthweight, and small for gestational age. In many US localities, suicide and homicide are leading causes of pregnancy-associated mortality. We herein review the issues noted previously in greater depth and introduce the basic principles of intimate partner violence prevention. We separately address current recommendations for intimate partner violence screening and the evidence surrounding effectiveness of intimate partner violence interventions.
High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly diverse sequences such as ...antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells sampled from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.
Summary
The skull bones must grow in a coordinated, three‐dimensional manner to coalesce and form the head and face. Mammalian skull bones have a dual embryonic origin from cranial neural crest cells ...(CNCC) and paraxial mesoderm (PM) and ossify through intramembranous ossification. The calvarial bones, the bones of the cranium which cover the brain, are derived from the supraorbital arch (SOA) region mesenchyme. The SOA is the site of frontal and parietal bone morphogenesis and primary center of ossification. The objective of this review is to frame our current in vivo understanding of the morphogenesis of the calvarial bones and the gene networks regulating calvarial bone initiation in the SOA mesenchyme.
In the first part of this review, we provided currently accepted definitions of categories and subcategories of intimate partner violence and discussed the prevalence and health impacts of intimate ...partner violence in nonpregnant and pregnant women. Herein we review current recommendations for intimate partner violence screening and the evidence surrounding the effectiveness of intimate partner violence interventions. Screening for intimate partner violence may include exclusively identification of victims of intimate partner violence or both the identification of and intervention for victims. Until recently, many professional organizations did not recommend universal screening for intimate partner violence because of a lack of evidence of effectiveness of screening, lack of evidence demonstrating that screening is not harmful, and/or a lack of consensus regarding the most effective screening tool. The lack of evidence supporting an intervention posed an additional barrier to screening. The American College of Obstetricians and Gynecologists has been a staunch advocate for universal intimate partner violence screening, even when other groups either did not endorse screening or recommended it only for high-risk women. Recent published data confirm that screening is more reliable than usual care in identifying victims of intimate partner violence, both during pregnancy and in nonpregnant women. Likewise, recent published data show that there are no apparent harms of screening for intimate partner violence and that the act of screening may have an empowering effect on women and improve their relationship with and trust in their health care providers. Despite these findings, the implementation rate of intimate partner violence screening remains low. Most encouraging are the recent data showing that interventions performed after screening for intimate partner violence are effective in reducing depression symptoms and episodes of violence as well as improving some outcomes of pregnancy. Although there remains a lack of consensus regarding which screening tool may be the most effective, we exhort all obstetrician-gynecologists to screen all women for intimate partner violence at regular intervals and to familiarize themselves with available community resources to assist those women who have been identified as experiencing intimate partner violence through screening.
Background
Long noncoding RNAs (lncRNAs) are RNA molecules with over 200 nucleotides that do not code for proteins, but are known to be widely expressed and have key roles in gene regulation and ...cellular functions. They are also found to be involved in the onset and development of various cancers, including prostate cancer (PCa). Since PCa are commonly driven by androgen regulated signaling, mainly stimulated pathways, identification and determining the influence of lncRNAs in androgen response is useful and necessary. LncRNAs regulated by the androgen receptor (AR) can serve as potential biomarkers for PCa. In the present study, gene expression data analysis were performed to distinguish lncRNAs related to the androgen response pathway.
Methods and Results
We used publicly available RNA‐sequencing and ChIP‐seq data to identify lncRNAs that are associated with the androgen response pathway. Using Universal Correlation Coefficient (UCC) and Pearson Correlation Coefficient (PCC) analyses, we found 15 lncRNAs that have (a) highly correlated expression with androgen response genes in PCa and are (b) differentially expressed in the setting of treatment with an androgen agonist as well as antagonist compared to controls. Using publicly available ChIP‐seq data, we investigated the role of androgen/AR axis in regulating expression of these lncRNAs. We observed AR binding in the promoter regions of 5 lncRNAs (MIR99AHG, DUBR, DRAIC, PVT1, and COLCA1), showing the direct influence of AR on their expression and highlighting their association with the androgen response pathway.
Conclusion
By utilizing publicly available multiomics data and by employing in silico methods, we identified five candidate lncRNAs that are involved in the androgen response pathway. These lncRNAs should be investigated as potential biomarkers for PCa.
Development of the skull bones requires the coordination of two stem progenitor populations, the cranial neural crest cells (CNCC) and head paraxial mesoderm (PM), to ensure cell fate selection and ...morphogenesis. The epigenetic methyltransferase, Ezh2, plays a role in skull bone formation, but the spatiotemporal function of Ezh2 between the CNCC- and PM-derived bone formation in vivo remains undefined. Here, using a temporally-inducible conditional deletion of Ezh2 in both the CNCC- and PM- derived cranial mesenchyme between E8.5 and E9.5, we find a reduction of the CNCC-derived calvarial bones and a near complete loss of the PM-derived calvarial bones due to an arrest in calvarial bone fate commitment. In contrast, deletion of Ezh2 after E9.5 permits PM-derived skull bone development, suggesting that Ezh2 is required early to guide calvarial bone progenitor commitment. Furthermore, exposure to all-trans Retinoic acid at E10.0 can mimic the Ezh2 mutant calvarial phenotype, and administration of the pan retinoic acid receptor (RAR) antagonist, BMS-453, to Ezh2 mutants partially restores the commitment to the calvarial bone lineage and PM-derived bone development in vivo. Exogenous RA signaling activation in the Ezh2 mutants leads to synergistic activation of the anti-osteogenic factors in the cranial mesenchyme in vivo. Thus, RA signaling and EZH2 can function in parallel to guide calvarial bone progenitor commitment by balancing the suppression of anti-osteogenic factors.
•Development stage-specific requirement of Ezh2 for calvarial bone lineage fate.•RA signaling inhibitors partially rescue the calvarial bone loss in Ezh2 mutants.•Suppression of anti-osteogenic factors occurs via an incoherent type-1 feedforward loop.
Abstract
Motivation
Nanopore sequencing is emerging as a key pillar in the genomic technology landscape but computational constraints limiting its scalability remain to be overcome. The translation ...of raw current signal data into DNA or RNA sequence reads, known as ‘basecalling’, is a major friction in any nanopore sequencing workflow. Here, we exploit the advantages of the recently developed signal data format ‘SLOW5’ to streamline and accelerate nanopore basecalling on high-performance computing (HPC) and cloud environments.
Results
SLOW5 permits highly efficient sequential data access, eliminating a potential analysis bottleneck. To take advantage of this, we introduce Buttery-eel, an open-source wrapper for Oxford Nanopore’s Guppy basecaller that enables SLOW5 data access, resulting in performance improvements that are essential for scalable, affordable basecalling.
Availability and implementation
Buttery-eel is available at https://github.com/Psy-Fer/buttery-eel.
Viral whole-genome sequencing (WGS) provides critical insight into the transmission and evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Long-read sequencing devices from ...Oxford Nanopore Technologies (ONT) promise significant improvements in turnaround time, portability and cost, compared to established short-read sequencing platforms for viral WGS (e.g., Illumina). However, adoption of ONT sequencing for SARS-CoV-2 surveillance has been limited due to common concerns around sequencing accuracy. To address this, here we perform viral WGS with ONT and Illumina platforms on 157 matched SARS-CoV-2-positive patient specimens and synthetic RNA controls, enabling rigorous evaluation of analytical performance. We report that, despite the elevated error rates observed in ONT sequencing reads, highly accurate consensus-level sequence determination was achieved, with single nucleotide variants (SNVs) detected at >99% sensitivity and >99% precision above a minimum ~60-fold coverage depth, thereby ensuring suitability for SARS-CoV-2 genome analysis. ONT sequencing also identified a surprising diversity of structural variation within SARS-CoV-2 specimens that were supported by evidence from short-read sequencing on matched samples. However, ONT sequencing failed to accurately detect short indels and variants at low read-count frequencies. This systematic evaluation of analytical performance for SARS-CoV-2 WGS will facilitate widespread adoption of ONT sequencing within local, national and international COVID-19 public health initiatives.
Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart ...disease, and many cancers. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost five-times.
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