SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair

The research leading to these results is supported by Cancer Research UK (XYG, RAB, EG, PM, PE, SG, C Santos, AJR, NM, PAB, AS and C Swanton), Breast Cancer Research Foundation (C Swanton and NK), Medical Research Council (ID: G0902275 to MG and C Santos; ID: G0701935/2 to AJR and C Swanton), the Danish Cancer Society (AMM, J Bartkova and J Bartek), the Lundbeck Foundation (R93-A8990 to J Bartek), the Ministry of the interior of the Czech Republic (grant VG20102014001 to MM and J Bartek), the National Program of Sustainability (grant LO1304 to MM and J Bartek), the Danish Council for Independent Research (grant DFF-1331-00262 to J Bartek), NIHR RMH/ICR Biomedical Research Centre for Cancer (JL), the EC Framework 7 (PREDICT 259303 to XYG, EG, PM, MG, TJ and C Swanton; DDResponse 259892 to J Bartek and J Bartkova and RESPONSIFY ID:259303 to C Swanton), UCL Overseas Research Scholarship (SG). C Swanton is also supported by the European Research Council, Rosetrees Trust and The Prostate Cancer Foundation. This research is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Identification of Novel Human Damage Response Proteins Targeted through Yeast Orthology

Studies in Saccharomyces cerevisiae show that many proteins influence cellular survival upon exposure to DNA damaging agents. We hypothesized that human orthologs of these S. cerevisiae proteins would also be required for cellular survival after treatment with DNA damaging agents. For this purpose, human homologs of S. cerevisiae proteins were identified and mapped onto the human protein-protein interaction network. The resulting human network was highly modular and a series of selection rules were implemented to identify 45 candidates for human toxicity-modulating proteins. The corresponding transcripts were targeted by RNA interference in human cells. The cell lines with depleted target expression were challenged with three DNA damaging agents: the alkylating agents MMS and 4-NQO, and the oxidizing agent t-BuOOH. A comparison of the survival revealed that the majority (74%) of proteins conferred either sensitivity or resistance. The identified human toxicity-modulating proteins represent a variety of biological functions: autophagy, chromatin modifications, RNA and protein metabolism, and telomere maintenance. Further studies revealed that MMS-induced autophagy increase the survival of cells treated with DNA damaging agents. In summary, we show that damage recovery proteins in humans can be identified through homology to S. cerevisiae and that many of the same pathways are represented among the toxicity modulators

An evaluation of DNA damage in human lymphocytes and sperm exposed to methyl methanesulfonate involving the regulation pathways associated with apoptosis

YesExposure to DNA-damaging agents produces a range of stress-related responses. These change the expression of genes leading to mutations that cause cell cycle arrest, induction of apoptosis and cancer. We have examined the contribution of haploid and diploid DNA damage and genes involved in the regulation of the apoptotic process associated with exposure, The Comet assay was used to detect DNA damage and quantitative RT-PCR analysis (qPCR) to detect gene expression changes in lymphocytes and sperm in response to methyl methanesulfonate. In the Comet assay, cells were administered 0–1.2 mM of MMS at 37 °C for 30 min for lymphocytes and 32 °C for 60 min for sperm to obtain optimal survival for both cell types. In the Comet assay a significant increase in Olive tail moment (OTM) and % tail DNA indicated DNA damage at increasing concentrations compared to the control group. In the qPCR study, cells were treated for 4 h, and RNA was isolated at the end of the treatment. qPCR analysis of genes associated with DNA stress responses showed that TP53 and CDKN1A are upregulated, while BCL2 is downregulated compared with the control. Thus, MMS caused DNA damage in lymphocytes at increasing concentrations, but appeared not to have the same effect in sperm at the low concentrations. These results indicate that exposure to MMS increased DNA damage and triggered the apoptotic response by activating TP53, CDKN1A and BCL2. These findings of the processing of DNA damage in human lymphocytes and sperm should be taken into account when genotoxic alterations in both cell types are produced when monitoring human exposure.Libyan Governmen

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

A survey of Danshukai members in Okayama Prefecture

A survey of Danshukai (Alcohol Abstinence Society) members was conducted in Okayama Prefecture, November, 1978. It was based on selfcompletion quetionaircs given to members attending the meetings of Okayama and Tsuyama Danshukai. Out of 290 resistered members, 202 attendants gave answers to the quetionaires (response rate: 69.7%). All of the respondents were male alcoholics. Among them, 80.6% were married, 81.2% had jobs, and 82.7% were accompanied by their wives or other family members in the meetings. This favorable family situation was in sharp contrast to that of long-term inpatient alcoholics. Admission to the Department of Psychiatry had been experienced by 63.9% of attendants and 17.3% to the Department of Internal Medicine. Many of the patients had been introduced to Danshukai by hospital staff and the activities of Danshukai were largely supported by psychiatric hospitals. In future, however, Danshukai must be more independent, establishing good relationships with community health centers or other local agencies. This means the development from a hospital-based Danshukai to a community-based one. This survey also suggested that intervention at an early stage of alcoholism is needed when alcohol-related impairment is limited to occasional violence at home. At this satage, spouses and Danshukai members might have important therapeutic roles. Regular attendance at Danshukai meetings at least once a week or twice a month seemed indispensable for continued abstinence

Impacts of Microplastics on the Swimming Behavior of the Copepod Temora turbinata (Dana, 1849)

Zooplankton are prone to the ingestion of microplastics by mistaking them for prey. However, there is a lack of knowledge about the impacts of microplastic availability on zooplankton behavior. In this study, we investigated the effects of polystyrene microbeads on swimming patterns of the calanoid copepod Temora turbinata under laboratory conditions. We acquired high-resolution video sequences using an optical system containing a telecentric lens and a digital camera with an acquisition rate of 20 frames per second. We estimated the mean speed, NGDR (Net-to-Gross Displacement Ratio, a dimensionless single-valued measure of straightness) and turning angle to describe the swimming behavior in three different treatments (control, low and high concentration of microplastics). Our results revealed that swimming speeds decreased up to 40% (instantaneous speed) compared to controls. The NGDR and turning angle distribution of the organisms also changed in the presence of polystyrene microbeads, both at low (100 beads mL−1) and high microplastic concentration (1000 beads mL−1). These results suggest that the swimming behavior of Temora turbinata is affected by microbeads

A survey of inpatient alcoholics in Okayama Prefecture

A survey of inpatient alcoholics in Okayama Prefecture was carried out on September 1, 1977. Questionnaires for each alcoholic were sent to the psychiatrists of 23 psychiatric hospitals and wards (the total number of psychiatric beds was 4591). Psychiatrists from 21 hospitals (93.9% of the total beds) supplied data. There were 4198 psychiatric inpatients, of whom 230 (5.5%) were alcoholics. Of these alcoholics, 14 were women (6.1% of all alcoholics). Marked differences were found among the hospitals concerning the number of inpatient alcoholics. The number of senile alcoholics over 60 was high (49 persons, 21.4%) and many inpatient alcoholics (102 persons, 44.3%) continued admission for more than one year. The hospital bills of 110 alcoholics (47.8%) were paid by Seikatsuhogo (financial support by the Welfare Office) and obligatory admissions were only 3 (1.3%) of the total alcoholics. 83 of the guardians (36.1%) were spouses and 20 (8.7%) were mayors or village heads. 30.4% of them remained divorced. Thus, inpatient alcoholics had handicaps in family and economical backgrounds, and it is necessary to carry on treatment sufficiently supported by social work