Seasonal variation of heavy metals in water and Cyprinus carpio L. from Umiam Lake reservoir of Meghalaya, India: Potential health risk assessment for human consumption.

The purpose of this study is to assess the seasonal variation of heavy metal concentration in water and fish tissues of common carp (Cyprinus carpio L.) from the Umiam Lake reservoir located in the Ri bhoi district of Meghalaya, India, and to elucidate the possible human health risk of ingesting fish captured from the contaminated lake. Results show significant (p < 0.

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non-small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial.

Background: Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284).

Materials And Methods: Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years.

Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models.

Inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscape for patients with cancer. Clinical activity of anti-PD-(L)1 antibodies has resulted in increased median overall survival and durable responses in patients across selected tumor types. To date, 6 PD-1 and PD-L1, here collectively referred to as PD-(L)1, pathway inhibitors are approved by the US Food and Drug Administration for clinical use.

Promoter-associated DNA methylation & expression profiling of genes ( & ) in patients with oral squamous cell carcinoma in the & population of Meghalaya, India.

Background & Objectives: Oral squamous cell carcinoma is one of the most lethal forms of cancer, and its aetiology has been attributed to both genetic and epigenetic factors working in liaison to contribute to the disease. Epigenetic changes especially DNA methylation is involved in the activation or repression of gene functions. The aim of this study was to investigate the DNA methylation pattern and expression profiling of the promoter regions of FMS-related tyrosine kinase 3 (FLT3), erythrocyte membrane protein band 4.

Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor.

The transcription factor nuclear factor of activated T cells (NFAT) has a key role in both T cell activation and tolerance and has emerged as an important target of immune modulation. NFAT directs the effector arm of the immune response in the presence of activator protein-1 (AP-1), and T cell anergy/exhaustion in the absence of AP-1. Envisioning a strategy for selective modulation of the immune response, we designed a FRET-based high-throughput screen to identify compounds that disrupt the NFAT:AP-1:DNA complex.

TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade and .

Progressive upregulation of checkpoints on tumor-infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a coinhibitory receptor associated with impaired T-cell function and is frequently coexpressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone.

Non-neuronal cell outgrowth in .

Cell outgrowth is a hallmark of some non-migratory developing cells during morphogenesis. Understanding the mechanisms that control cell outgrowth not only increases our knowledge of tissue and organ development, but can also shed light on disease pathologies that exhibit outgrowth-like behavior. is a highly useful model for the analysis of genes and the function of their respective proteins.

Suppression of T17-mediated pathology through BET bromodomain inhibition.

Epigenetic control of gene expression is enforced in part through histone modifications. Bromodomain and extra terminal domain (BET) proteins function as crucial chromatin readers, responsible for interpretation of the chromatin code in diverse cellular contexts, ultimately impacting gene transcription. BET proteins can play a major role in inflammation by profoundly affecting the biology of the T 17 (T17) lineage.

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.

Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors.

Spatial and molecular cues for cell outgrowth during C. elegans uterine development.

The Caenorhabditis elegans uterine seam cell (utse) is an H-shaped syncytium that connects the uterus to the body wall. Comprising nine nuclei that move outward in a bidirectional manner, this synctium undergoes remarkable shape change during development. Using cell ablation experiments, we show that three surrounding cell types affect utse development: the uterine toroids, the anchor cell and the sex myoblasts.

Identification of frequent differentially methylated region in sporadic bladder cancers.

Introduction: Aberrant methylation levels in the cytosine-phosphate-guanine island (CpGi) region from exon 1 to intron 1 of the zygote arrest 1 (ZAR1) gene have been reported in several types of human cancers, including melanoma, brain tumor, and hepatocellular carcinoma. In the present study, methylation levels at the CpGi of ZAR1 exon 1/intron 1 in bladder cancer specimens were analyzed using mass spectrometry.

Materials And Methods: Genomic DNA was extracted from 20 sporadic bladder cancers, and the methylation levels at ZAR1 CpGi were quantitatively examined by the MassARRAY EpiTYPER method.

Nr4a3, a possibile oncogenic factor for neuroblastoma associated with CpGi methylation within the third exon.

Aberrant methylation of Nr4a3 exon 3 CpG island (CpGi) was initially identified during multistep mouse skin carcinogenesis. Nr4a3 is also known as a critical gene for neuronal development. Thus, we examined the Nr4a3 exon 3 CpGi methylation in mouse brain tissues from 15-day embryos, newborns and 12-week-old adults and found significant increase of its methylation and Nr4a3 expression during mouse brain development after birth.

Genome-wide screening of aberrant DNA methylation which associated with gene expression in mouse skin cancers.

Epigenetic alteration of genomic DNA is a common and key process in carcinogenesis. There is considerable evidence indicating that some of the somatic alterations occurring during carcinogenesis in humans also involve the same processes as those observed in mice. Therefore, we analyzed mouse skin cancer tissues induced by the 2-stage carcinogenesis model to identify skin tumor-specific differentially methylated regions (ST-DMRs) during the multistep carcinogenesis process.

BET bromodomain inhibition suppresses TH17-mediated pathology.

Interleukin (IL) 17-producing T helper (T(H)17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine T(H)17 differentiation from naive CD4(+) T cells, as well as in the activation of previously differentiated T(H)17 cells.

Identification of aberrant methylation regions in neuroblastoma by screening of tissue-specific differentially methylated regions.

Background: The identification of tissue-specific differentially methylated regions (tDMRs) is key to our understanding of mammalian development. Research has indicated that tDMRs are aberrantly methylated in cancer and may affect the oncogenic process.

Procedure: We used the MassARRAY EpiTYPER system to determine the quantitative methylation levels of seven neuroblastomas (NBs) and two control adrenal medullas at 12 conserved tDMRs.

Synchronous and symmetric migration of Drosophila caudal visceral mesoderm cells requires dual input by two FGF ligands.

Caudal visceral mesoderm (CVM) cells migrate synchronously towards the anterior of the Drosophila embryo as two distinct groups located on each side of the body, in order to specify longitudinal muscles that ensheath the gut. Little is known about the molecular cues that guide cells along this path, the longest migration of embryogenesis, except that they closely associate with trunk visceral mesoderm (TVM). The expression of the fibroblast growth factor receptor (FGFR) heartless and its ligands, pyramus (pyr) and thisbe (ths), within CVM and TVM cells, respectively, suggested FGF signaling may influence CVM cell guidance.

Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development.

Background: Changes in DNA methylation in the mammalian genome during development are frequent events and play major roles regulating gene expression and other developmental processes. It is necessary to identify these events so that we may understand how these changes affect normal development and how aberrant changes may impact disease.

Results: In this study Methylated DNA ImmunoPrecipitation (MeDIP) was used in conjunction with a NimbleGen promoter plus CpG island (CpGi) array to identify Tissue and Developmental Stage specific Differentially Methylated DNA Regions (T-DMRs and DS-DMRs) on a genome-wide basis.

Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.

The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA.

Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis.

Nuclear factor of activated T cells (NFAT) proteins are a group of Ca(2+)-regulated transcription factors residing in the cytoplasm of resting cells. Dephosphorylation by calcineurin results in nuclear translocation of NFAT and subsequent expression of target genes; rephosphorylation by kinases, including casein kinase 1 (CK1), restores NFAT to its latent state in the cytoplasm. We engineered a hyperactivable version of NFAT1 with increased affinity for calcineurin and decreased affinity for casein kinase 1.

Planar cell polarity acts through septins to control collective cell movement and ciliogenesis.

The planar cell polarity (PCP) signaling pathway governs collective cell movements during vertebrate embryogenesis, and certain PCP proteins are also implicated in the assembly of cilia. The septins are cytoskeletal proteins controlling behaviors such as cell division and migration. Here, we identified control of septin localization by the PCP protein Fritz as a crucial control point for both collective cell movement and ciliogenesis in Xenopus embryos.

Identification and analysis of an early diagnostic marker for malignant melanoma: ZAR1 intra-genic differential methylation.

Background: Epigenetic changes such as aberrant DNA methylation and histone modification have been shown to play an important role in the tumorigenesis of malignant melanoma.

Objective: To identify novel tumor-specific differentially methylated regions (DMRs) in human malignant melanoma.

Methods: The aberrant methylation at 14 candidate human genomic regions identified through a mouse model study with quantitative DNA methylation analysis using the Sequenom MassARRAY system was performed.