Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer.

Unlabelled: Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer.

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative.

Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care.

Transcriptional responses to injury of regenerative lung alveolar epithelium.

The significance of alveolar epithelial type 2 (AT2) cell proliferation for lung alveolar epithelial homeostasis and regeneration after injury has been widely accepted. However, the heterogeneity of AT2 cell population for cell proliferation capacity remains disputed. By single-cell RNA sequencing and genetic lineage labeling using the Ki67 knock-in mouse model, we map all proliferative AT2 cells in homeostatic and regenerating murine lungs after injury induced by infection.

Characterization of Reference Materials for TPMT and NUDT15: A GeT-RM Collaborative Project.

Pharmacogenetic testing is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for many of the TPMT and NUDT15 variants included in clinical tests. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Material (GeT-RM) coordination program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 19 DNA samples derived from Coriell cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using a variety of commercially available and laboratory developed tests and/or Sanger sequencing.

Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells.

Aberrant transcription in cancer cells involves the silencing of tumor suppressor genes (TSGs) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA-hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSGs. To discover novel drugs that trigger TSG reactivation in cancer cells, we used a GFP-reporter system whose expression is silenced by promoter DNA hypermethylation and histone deacetylation.

Hypoxia drives hematopoiesis with the enhancement of T lineage through eliciting arterial specification of hematopoietic endothelial progenitors from hESC.

Background: Hematopoietic stem cells are able to self-renew and differentiate into all blood cell lineages. Hematopoietic stem cell transplantation is a mainstay of life-saving therapy for hematopoietic malignancies and hypoproliferative disorders. In vitro hematopoietic differentiation of human pluripotent stem cells (hPSCs) is a promising approach for modeling hematopoietic development and cell replacement therapies.

An induced pluripotent stem cell line (CIMRi001-A) from a Vici syndrome donor with a homozygous recessive c.1007A>G (p.Q336R) mutation in the EPG5 gene.

Vici syndrome is a rare, congenital disorder that affects multiple systems and is caused by mutations in the EPG5 gene that encodes for ectopic P-granules autophagy protein 5 (EPG5). The induced pluripotent stem cell (iPSC) line described here was generated from a dermal fibroblast cell line from an 8-year-old male donor with a homozygous recessive c.1007A>G (p.

Single cell transcriptomic analysis reveals cellular diversity of murine esophageal epithelium.

Although morphologic progression coupled with expression of specific molecular markers has been characterized along the esophageal squamous differentiation gradient, the molecular heterogeneity within cell types along this trajectory has yet to be classified at the single cell level. To address this knowledge gap, we perform single cell RNA-sequencing of 44,679 murine esophageal epithelial, to identify 11 distinct cell populations as well as pathways alterations along the basal-superficial axis and in each individual population. We evaluate the impact of aging upon esophageal epithelial cell populations and demonstrate age-associated mitochondrial dysfunction.

The nuclear lamina binds the EBV genome during latency and regulates viral gene expression.

The Epstein Barr virus (EBV) infects almost 95% of the population worldwide. While typically asymptomatic, EBV latent infection is associated with several malignancies of epithelial and lymphoid origin in immunocompromised individuals. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes in different patterns, referred to as latency types, which coincide with varying stages of infection and various malignancies.

The Two-Hit Hypothesis Meets Epigenetics.

The landmark paper by Kane and colleagues was the first report of DNA methylation in the promoter of the human MLH1 gene in sporadic colon cancers with mismatch repair (MMR) deficiency. In both cell lines and primary tumors, promoter methylation was associated with loss of MLH1 protein expression and with a lack of mutations in the MLH1 coding region. Together with subsequent papers that showed that this methylation was directly responsible for loss of MLH1 expression and MMR deficiency, the observation expanded the two-hit hypothesis of tumor suppressor gene loss in cancer to include both genetic and epigenetic mechanisms of gene inactivation.

A Novel Humanized Anti-Interleukin-6 Antibody HZ0408b With Anti-Rheumatoid Arthritis Therapeutic Potential.

Interleukin-6 (IL-6), a pleiotropic cytokine that regulates immune responses and inflammatory reactions, plays a pivotal role in the development of rheumatoid arthritis (RA). Blockade of IL-6 signaling with the monoclonal antibody (mAb) represents an important advancement in RA treatment. Although two IL-6 receptor antibodies are already available in the clinic, there is no mAb specifically targeting the human IL-6 to block IL-6 signaling for RA treatment.

The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity.

Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1's role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome.

Genome-wide DNA methylation profile in feline haematological tumours: A preliminary study.

Although DNA methylation has been analysed in few studies for a limited number of loci in cats with diseases, genome-wide profile of DNA methylation has never been addressed. The hypothesis for this study is that next-generation sequencing with sequential digestion of genomic DNA with SmaI and XmaI enzymes could provide highly quantitative information on methylation levels in cats. Using blood from four healthy control cats and two disease cats as well as three feline lymphoma/leukemia cell lines, approximately 74-94 thousand CpG sites across the cat genome could be analysed.

Microsatellite Markers in Biobanking: A New Multiplexed Assay.

Microsatellites, or MSATs, offer a fast and cost-effective way for biobanks to establish a biospecimen genetic profile. Importantly, this genetic profile can be used to authenticate multiple submissions derived from the same individual as well as biospecimens derived from the same original sample submission over time. While the Certificate of Confidentiality provided by the National Institutes of Health offers some meaningful protection to prevent the disclosure of potentially identifiable information to entities within the United States, we consider, in this study, the potential to offer additional protection to participants who choose to donate to biobanks by minimizing the use of forensic Combined DNA Index System (CODIS) MSAT markers in biobanking.

Pharmacogenomics: From Basic Research to Clinical Implementation.

The established contribution of genetic variation to drug response has the potential to improve drug efficacy and reduce drug toxicity [...

Obese status is associated with accelerated DNA methylation change in peripheral blood of senior dogs.

Obesity and its associated comorbidities constitute a major and growing health problem worldwide not only involved with people but also dogs and cats. Although few genetic mutations have been associated with obesity in dogs, molecular mechanism remains to be clearly understood. Given the fact that DNA methylation leads to gene expression variability and has plasticity affected by metabolic phenotypes such as obesity in human, the objective of this study is to identify obesity-associated differentially methylated cytosine-phosphate-guanine (CpG) dinucleotide sites in dogs.

The Roles of DNA Demethylases in Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as the absence of overexpression and/or amplification of HER2. DNA methylation plays an important role in breast cancer carcinogenesis and TNBCs have a distinct DNA methylation profile characterized by marked hypomethylation and lower gains of methylations compared to all other subtypes.

Accelerated aging in normal breast tissue of women with breast cancer.

Background: DNA methylation alterations have similar patterns in normal aging tissue and in cancer. In this study, we investigated breast tissue-specific age-related DNA methylation alterations and used those methylation sites to identify individuals with outlier phenotypes. Outlier phenotype is identified by unsupervised anomaly detection algorithms and is defined by individuals who have normal tissue age-dependent DNA methylation levels that vary dramatically from the population mean.

Characterization of Reference Materials with an Association for Molecular Pathology Pharmacogenetics Working Group Tier 2 Status: CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, and GGCX: A GeT-RM Collaborative Project.

Pharmacogenetic testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials are currently available for many of the variants that are tested. The Association for Molecular Pathology Pharmacogenetic Work Group has published a series of papers recommending alleles for inclusion in clinical testing.

DNA methylation landscape of 16 canine somatic tissues by methylation-sensitive restriction enzyme-based next generation sequencing.

DNA methylation plays important functions in gene expression regulation that is involved in individual development and various diseases. DNA methylation has been well studied in human and model organisms, but only limited data exist in companion animals like dog. Using methylation-sensitive restriction enzyme-based next generation sequencing (Canine DREAM), we obtained canine DNA methylation maps of 16 somatic tissues from two dogs.

Genome-wide DNA methylation analysis of dogs with high lead exposure living near a lead mining area in Kabwe, Zambia.

Lead (Pb) is a heavy metal that has been proven to be toxic to both animals and humans. Genom-wide DNA methylation in domestic dogs exposed to high levels of Pb in Kabwe, Zambia was analyzed in this study. Using next-generation sequencing on samples from 20 domestic dogs (mean blood Pb concentration: 43.

Astrocytes in cocaine addiction and beyond.

Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been increasingly recognized as an "accomplice." According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination.

Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants.

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX.