Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma.

Unlabelled: We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact.

VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2.

Local Structure Investigations of Sequential Sorption of U and Fe on Polyacrylamide Hydroxamic Acid Resins.

Uranium- and iron-containing waste simulated effluent has been treated sequentially with a novel resin, viz., polyacrylamide hydroxamic acid (PAAHA). The motivation is to investigate the competitive interactions with transition metals during the removal of radiologically and chemically toxic uranium.

Author Correction: Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

Cas9 is commonly introduced into cell lines to enable CRISPR-Cas9-mediated genome editing. Here, we studied the genetic and transcriptional consequences of Cas9 expression itself. Gene expression profiling of 165 pairs of human cancer cell lines and their Cas9-expressing derivatives revealed upregulation of the p53 pathway upon introduction of Cas9, specifically in wild-type TP53 (TP53-WT) cell lines.

Mechanisms and therapeutic implications of hypermutation in gliomas.

A high tumour mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide.

High-intensity exercise-induced oxidative stress in sedentary pre-pubertal & post-pubertal boys: A comparative study.

Background & Objectives: High-intensity exercise results in oxidative stress in adult population. Impact of pubertal attainment on high-intensity exercise-induced oxidative stress in sedentary paediatric population has not been investigated in detail. The present study was conducted to investigate the extent of high-intensity exercise-induced oxidative stress in sedentary pre- and post-pubertal boys through estimation of serum thiobarbituric acid reactive substances (TBARS), total thiol content and activities of superoxide dismutase (SOD) and catalase (CAT).

Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications.

Acquired chromosomal DNA amplifications are features of many tumors. Although overexpression and stabilization of the histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A generates transient site-specific copy number gains (TSSGs), additional mechanisms directly controlling site-specific DNA copy gains are not well defined. In this study, we uncover a collection of H3K4-modifying chromatin regulators that function with H3K9 and H3K36 regulators to orchestrate TSSGs.

Impaired cohesion and homologous recombination during replicative aging in budding yeast.

The causal relationship between genomic instability and replicative aging is unclear. We reveal here that genomic instability at the budding yeast ribosomal DNA (rDNA) locus increases during aging, potentially due to the reduced cohesion that we uncovered during aging caused by the reduced abundance of multiple cohesin subunits, promoting increased global chromosomal instability. In agreement, cohesion is lost during aging at other chromosomal locations in addition to the rDNA, including centromeres.

Proteomic identification of histone post-translational modifications and proteins enriched at a DNA double-strand break.

Here, we use ChAP-MS (chromatin affinity purification with mass spectrometry), for the affinity purification of a sequence-specific single-copy endogenous chromosomal locus containing a DNA double-strand break (DSB). We found multiple new histone post-translational modifications enriched on chromatin bearing a DSB from budding yeast. One of these, methylation of histone H3 on lysine 125, has not previously been reported.

High-Intensity Exercise Induced Oxidative Stress and Skeletal Muscle Damage in Postpubertal Boys and Girls: A Comparative Study.

Pal, S, Chaki, B, Chattopadhyay, S, and Bandyopadhyay, A. High-intensity exercise induced oxidative stress and skeletal muscle damage in post-pubertal boys and girls: a comparative study. J Strength Cond Res 32(4): 1045-1052, 2018-The purpose of this study was to examine the sex variation in high-intensity exercise induced oxidative stress and muscle damage among 44 sedentary postpubertal boys and girls through estimation of postexercise release pattern of muscle damage markers like creatine kinase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and oxidative stress markers like extent of lipid peroxidation (thiobarbituric acid-reactive substances) and catalase activity.

Delineation of the role of chromatin assembly and the Rtt101Mms1 E3 ubiquitin ligase in DNA damage checkpoint recovery in budding yeast.

The DNA damage checkpoint is activated in response to DNA double-strand breaks (DSBs). We had previously shown that chromatin assembly mediated by the histone chaperone Asf1 triggers inactivation of the DNA damage checkpoint in yeast after DSB repair, also called checkpoint recovery. Here we show that chromatin assembly factor 1 (CAF-1) also contributes to chromatin reassembly after DSB repair, explaining its role in checkpoint recovery.

Epigenetics and aging.

Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence.

The Commercial Antibodies Widely Used to Measure H3 K56 Acetylation Are Non-Specific in Human and Drosophila Cells.

Much of our understanding of the function of histone post-translational modifications in metazoans is inferred from their genomic localization and / or extrapolated from yeast studies. For example, acetylation of histone H3 lysine 56 (H3 K56Ac) is assumed to be important for transcriptional regulation in metazoan cells based on its occurrence at promoters and its function in yeast. Here we directly assess the function of H3 K56Ac during chromatin disassembly from gene regulatory regions during transcriptional induction in human cells by using mutations that either mimic or prevent H3 K56Ac.

Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.

All eukaryotic cells divide a finite number of times, although the mechanistic basis of this replicative aging remains unclear. Replicative aging is accompanied by a reduction in histone protein levels, and this is a cause of aging in budding yeast. Here we show that nucleosome occupancy decreased by 50% across the whole genome during replicative aging using spike-in controlled micrococcal nuclease digestion followed by sequencing.

Modification of Fox protocol for prediction of maximum oxygen uptake in male university students.

Background: Direct estimation of VO₂max involves labourious, exhaustive, hazardous, time consuming and expensive experimental protocols. Hence, application of various indirect protocols for prediction of VO₂max has become popular, subject to proper population-specific standardisation of the indirect protocol.

Objectives: Application of Fox (1973) protocol in male sedentary university students of Kolkata, India led to premature fatigue in their leg muscles that hindered the muscular activity leading to inability in completing the exercise.

Pulmonary Function Studies of Healthy Non-smoking Male University Students of Kolkata, India - Revisited.

Background: Pulmonary function tests (PFTs) need to be revisited in light of rapid economic growth and industrial development. Questions have been raised about the validity of existing population-specific norms for predicting PFTs, and therefore, the present study aimed to determine the applicability of existing norms for PFTs in young healthy non-smoking male university students of Kolkata.

Methods: PFTs were carried out for 87 non-smoking male university students who were randomly sampled from the University of Calcutta, Kolkata, India.

SUMOylation affects the interferon blocking activity of the influenza A nonstructural protein NS1 without affecting its stability or cellular localization.

Our pioneering studies on the interplay between the small ubiquitin-like modifier (SUMO) and influenza A virus identified the nonstructural protein NS1 as the first known SUMO target of influenza virus and one of the most abundantly SUMOylated influenza virus proteins. Here, we further characterize the role of SUMOylation for the A/Puerto Rico/8/1934 (PR8) NS1 protein, demonstrating that NS1 is SUMOylated not only by SUMO1 but also by SUMO2/3 and mapping the main SUMOylation sites in NS1 to residues K219 and K70. Furthermore, by using SUMOylatable and non-SUMOylatable forms of NS1 and an NS1-specific artificial SUMO ligase (ASL) that increases NS1 SUMOylation ~4-fold, we demonstrate that SUMOylation does not affect the stability or cellular localization of PR8 NS1.

Influenza A virus interacts extensively with the cellular SUMOylation system during infection.

SUMOylation, the post-translational conjugation of the Small Ubiquitin-like MOdifier (SUMO) to a target protein, regulates a wide array of cellular processes and plays important roles for numerous viruses during infection. However, the relevance of the cellular SUMOylation system for influenza virus infection remains mostly unexplored. We previously reported that the non-structural protein of influenza A virus NS1 is a bona fide SUMO target.

Identification of the non-structural influenza A viral protein NS1A as a bona fide target of the Small Ubiquitin-like MOdifier by the use of dicistronic expression constructs.

The cellular SUMOylation system affects the function of numerous viral proteins. Hence, the identification of novel viral targets for the Small Ubiquitin-like MOdifier (SUMO) is key to our understanding of virus-host interactions. The data obtained in this study demonstrate that the non-structural influenza A viral protein NS1A is an authentic SUMO target through the use of a dicistronic expression plasmid containing SUMO (the modifier) and Ubc9 (the SUMO-conjugating enzyme) separated by an Internal Ribosomal Entry Site (IRES).

Comparison of the genome of the oral pathogen Treponema denticola with other spirochete genomes.

We present the complete 2,843,201-bp genome sequence of Treponema denticola (ATCC 35405) an oral spirochete associated with periodontal disease. Analysis of the T. denticola genome reveals factors mediating coaggregation, cell signaling, stress protection, and other competitive and cooperative measures, consistent with its pathogenic nature and lifestyle within the mixed-species environment of subgingival dental plaque.

Use of PCR to identify enteroaggregative Escherichia coli as an important cause of acute diarrhoea among children living in Calcutta, India.

The importance of enteroaggregative Escherichia coli (EAggEC) as a possible aetiological agent of acute diarrhoea among children in Calcutta, India, was investigated. Simultaneously the use of a previously described PCR diagnostic system was assessed for its ability to identify EAggEC infection. E.