Pritha Bhattacharjee

Abstract: Arsenic in drinking water may cause major deleterious health impacts including death. Although arsenic in rice has recently been demonstrated to be a potential exposure route for humans, there has been to date no direct evidence for the impact of such exposure on human health. Here we show for the first time, through a cohort study in West Bengal, India, involving over 400 human subjects not otherwise significantly exposed to arsenic through drinking water, elevated genotoxic effects, as measured by micronuclei (MN) in urothelial cells, associated with the staple consumption of cooked rice with >200 μg/kg arsenic. Further work is required to determine the applicability to populations with different dietary and genetic characteristics, but with over 3 billion people in the world consuming rice as a staple food and several percent of this rice containing such elevated arsenic concentrations, this study raises considerable concerns over the threat to human health.

Abstract: Exposure to chronic arsenic toxicity is associated with cancer. Although unstable genome is a characteristic feature of cancer cells, the mechanisms leading to genomic instability in arsenic-induced carcinogenesis are poorly understood. While there are excellent reviews relating to genomic instability in general, there is no comprehensive review presenting the mechanisms involved in arsenic-induced genomic instability. This review was undertaken to present the current state of research in this area and to highlight the major mechanisms that may involved in arsenic-induced genomic instability leading to cancer. Genomic instability is broadly classified into chromosomal instability (CIN), primarily associated with mitotic errors; and microsatellite instability (MIN), associated with DNA level instability. Arsenic-induced genomic instability is essentially multi-factorial in nature and involves molecular cross-talk across several cellular pathways, and is modulated by a number of endogenous and exogenous factors. Arsenic and its metabolites generate oxidative stress, which in turn induces genomic instability through DNA damage, irreversible DNA repair, telomere dysfunction, mitotic arrest and apoptosis. In addition to genetic alteration; epigenetic regulation through promoter methylation and miRNA expression alters gene expression profiling leading to genome more vulnerable and unstable towards cancer risk. Moreover, mutations or silencing of pro-apoptotic genes can lead to genomic instability by allowing survival of damaged cells that would otherwise die. Although a large body of information is now generated regarding arsenic-induced carcinogenesis; further studies exploring genome-wide association, role of environment and diet are needed for a better understanding of the arsenic-induced genomic instability.

Abstract: The gene for glutathione-S-transferase (GST) M1 (GSTM1), a member of the GST-superfamily, is widely studied in cancer risk with regard to the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity. Many of these studies have reported inconsistent findings regarding its association with cancer risk. Therefore, we employed in silico, in vitro, and in vivo approaches to investigate whether the absence of a functional GSTM1 enzyme in a null variant can be compensated for by other family members. Through the in silico approach, we identified maximum structural homology between GSTM1 and GSTM2. Total plasma GST enzymatic activity was similar in recruited individuals, irrespective of their GSTM1 genotype (positive/null). Furthermore, expression profiling using real-time PCR, western blotting, and GSTM2 overexpression following transient knockdown of GSTM1 in HeLa cells confirmed that the absence of GSTM1 activity can be compensated for by the overexpression of GSTM2.

Abstract: Long term exposure to arsenic, either through groundwater, food stuff or occupational sources, results in a plethora of dermatological and non-dermatological health effects including multi-organ cancer and early mortality Several epidemiological studies, across the globe have reported arsenic-induced health effects and cancerous outcomes; but the prevalence of such diseases varies depending on environmental factors (geographical location, exposure level), and genetic makeup (and variants thereof); which is further modulated by several other factors like ethnicity, age-sex, smoking status, diet, etc It is also interesting to note that, chronic arsenic exposure to a similar extent, even among the same family members, result in wide inter-individual variations To understand the adverse effect of this toxic metabolite on biological system (cellular targets), and to unravel the underlying molecular basis (at the level of transcript, proteome, or metabolite), a holistic, systems biology approach was taken Due to the paradoxical nature and unavailability of any suitable animal model system; the literature review is primarily based on cell line and population based studies Thus, here we present a comprehensive review on the systems biology approaches to explore the underlying mechanism of arsenic-induced carcinogenicity, along with our own observations and an overview of mitigation strategies and their effectiveness till date

Abstract: In the state of West Bengal in India, over 26 million individuals are exposed to arsenic via drinking water. Dermatological, non-dermatological disorders and cancers are associated with arsenic toxicity. Of late, there has been a decrease in the arsenic concentration in drinking water owing to governmental efforts, raising the possibility of remediation. A cross-sectional study was conducted, where 189 arsenicosis and 171 unexposed individuals were recruited at two time points, (2005–06 and 2010–11) with concomitant decrease in the level of arsenic exposure via drinking water in the arsenicosis group in 2010–11. Parameters studied included dermatological, non-dermatological health status and cytogenetic damage. Decrease of arsenic exposure (190.1 μg/l to 37.94 μg/l) resulted in significant decline in the number of individuals having dermatological disorders (P<0.01) and in the severity of each dermatological outcome (P<0.0001). Micronucleus formation in urothelial cells and lymphocytes decreased significantly (P<0.001). However, there was a significant (P<0.001) rise in the incidence of each of the non-dermatological diseases, that is, peripheral neuropathy, conjunctivitis and respiratory distress over the period. Thirteen (6.87%) of the initially recruited arsenicosis individuals died of cancer, in this period. Remediation by arsenic-safe drinking water can reduce dermatological manifestations and cytogenetic insult; but is unable to counter the non-dermatological symptoms.

Abstract: Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Abstract: PLoS BIOLOGY Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor Jean-Philippe Coppe 1 , Christopher K. Patil 1[ , Francis Rodier 1,2[ , Yu Sun 3 , Denise P. Mun oz 1,2 , Joshua Goldstein 1¤ , Peter S. Nelson 3 , Pierre-Yves Desprez 1,4 , Judith Campisi 1,2* 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 2 Buck Institute for Age Research, Novato, California, United States of America, 3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 4 California Pacific Medical Center Research Institute, San Francisco, California, United States of America Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA- damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. Citation: Coppe JP, Patil CK, Rodier F, Sun Y, Mun oz DP, et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12): e301. doi:10.1371/journal.pbio.0060301 Introduction Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes. These phenotypes are acquired in part by somatic mutations, which derange normal controls over cell proliferation (growth), survival, invasion, and other processes important for malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue microenvironment is an important determinant of whether and how malignancies develop [2,3]. Normal tissue environ- ments tend to suppress malignant phenotypes, whereas abnormal tissue environments such at those caused by inflammation can promote cancer progression. Cancer development is restrained by a variety of tumor suppressor genes. Some of these genes permanently arrest the growth of cells at risk for neoplastic transformation, a process termed cellular senescence [4–6]. Two tumor suppressor pathways, controlled by the p53 and p16INK4a/pRB proteins, regulate senescence responses. Both pathways integrate multiple aspects of cellular physiology and direct cell fate towards survival, death, proliferation, or growth arrest, depending on the context [7,8]. Several lines of evidence indicate that cellular senescence is a potent tumor-suppressive mechanism [4,9,10]. Many poten- tially oncogenic stimuli (e.g., dysfunctional telomeres, DNA PLoS Biology | www.plosbiology.org damage, and certain oncogenes) induce senescence [6,11]. Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [12,13]. Most cancers harbor mutations in one or both of these pathways [14,15]. Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [16–19]. Academic Editor: Julian Downward, Cancer Research UK, United Kingdom Received June 27, 2008; Accepted October 22, 2008; Published December 2, 2008 Copyright: O 2008 Coppe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: CM, conditioned medium; DDR, DNA damage response; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; GSE, genetic suppressor element; IL, interleukin; MIT, mitoxantrone; PRE, presenescent; PrEC, normal human prostate epithelial cell; REP, replicative exhaustion; SASP, senescence-associated secretory phenotype; SEN, senescent; shRNA, short hairpin RNA; XRA, X-irradiation * To whom correspondence should be addressed. E-mail: jcampisi@lbl.gov [ These authors contributed equally to this work. ¤ Current address: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America December 2008 | Volume 6 | Issue 12 | e301

Abstract: 长期以来,对于肿瘤的发病机制,就存在两种意见,一种意见认为,肿瘤的发生是由于基因突变导致的遗传特性改变引起的,另一种意见认为,肿瘤的发生是由于基因表达的失调,即通过表遗传学机制引起的.只是近几十年来,由于癌基因与抑癌基因的发现及对之研究的巨大进步,使得肿瘤表遗传学的研究一直处于遗传学研究的阴影之下而已[1]。

Abstract: Abstract The EMBL-EBI search and sequence analysis tools frameworks provide integrated access to EMBL-EBI’s data resources and core bioinformatics analytical tools. EBI Search (https://www.ebi.ac.uk/ebisearch) provides a full-text search engine across nearly 5 billion entries, while the Job Dispatcher tools framework (https://www.ebi.ac.uk/services) enables the scientific community to perform a diverse range of sequence analysis using popular bioinformatics applications. Both allow users to interact through user-friendly web applications, as well as via RESTful and SOAP-based APIs. Here, we describe recent improvements to these services and updates made to accommodate the increasing data requirements during the COVID-19 pandemic.