The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 ...genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Four biomass wastes (rice husk, coffee husk, coarse wool, and landfill wood) were added with biochar and polypropylene (PP) to manufacture biocomposites. Individual biomasses were tested for their ...combustion behavior using cone calorimeter. Biocomposites were analyzed for their fire/thermal, mechanical, and morphological properties. Wood had the most desirable comprehensive effect on both the mechanical and fire properties of composites. In particular, wood and biochar composite exhibited the highest values of tensile/flexural properties with a relatively low peak heat release rate. In general, application of waste derived biochar and biomasses drastically reduced the susceptibility of neat PP towards fire.
Introduction
Whereas the interpersonal theory of suicide entails the assumption that thwarted belongingness and perceived burdensomeness are equally important, mutually moderating, proximal causes of ...active ideation, evidence suggests these may not be co‐moderating processes. We tested an alternative perspective, hypothesizing that burden mediates the longitudinal relationship of thwarted belonging with active ideation.
Methods
A 6‐week, four‐wave prospective online survey was completed by 298 undergraduates. We tested cross‐sectional and cross‐lagged panel models (CLPM, with and without random effects) with belonging, burden, and ideation at 2‐week lags, and post hoc models with burden as a concurrent mediator of ideation.
Results
Approximately 28% of undergraduates reported active ideation at baseline. Cross‐sectionally, thwarted belonging had no direct influence on ideation but indirectly affected ideation via burden. This result was not confirmed in the 2‐week CLPM analyses. In post hoc analyses, we found belonging operated indirectly via later burden to influence contemporaneous ideation.
Conclusions
Findings suggest thwarted belonging influences active ideation indirectly via perceived burden. The effect of burden as a mediator appears to depend on its temporal proximity to ideation. Future research should delimit the period during which perceived burden is an active mediator, accommodate dual‐process approaches, and explore other mediation alternatives to co‐moderation.
Allelic exchange is an efficient method of bacterial genome engineering. This protocol describes the use of this technique to make gene knockouts and knock-ins, as well as single-nucleotide ...insertions, deletions and substitutions, in Pseudomonas aeruginosa. Unlike other approaches to allelic exchange, this protocol does not require heterologous recombinases to insert or excise selective markers from the target chromosome. Rather, positive and negative selections are enabled solely by suicide vector-encoded functions and host cell proteins. Here, mutant alleles, which are flanked by regions of homology to the recipient chromosome, are synthesized in vitro and then cloned into allelic exchange vectors using standard procedures. These suicide vectors are then introduced into recipient cells by conjugation. Homologous recombination then results in antibiotic-resistant single-crossover mutants in which the plasmid has integrated site-specifically into the chromosome. Subsequently, unmarked double-crossover mutants are isolated directly using sucrose-mediated counter-selection. This two-step process yields seamless mutations that are precise to a single base pair of DNA. The entire procedure requires ∼2 weeks.
Summary Background Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed ...approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.
Background The number of oral anticancer medications has increased over the past few decades, opening new possibilities in cancer care and improving convenience for patients and caregivers. However, ...adherence levels continue to be suboptimal, potentially jeopardizing therapeutic benefits. Poor adherence levels may indicate gaps in current strategies and interventions aimed at enhancing medication adherence and the extent to which they address the complex and multi-faceted medication management needs of patients and their caregivers. Beyond commonly understood barriers (e.g., forgetting to take medications), adherence interventions must address systemic barriers that may not be fully appreciated by members of the healthcare system. This scoping review aims to apply a systems framework (human factors engineering framework) to examine system elements targeted by adherence enhancing interventions. Methods Studies published in English, reporting adherence interventions for oral anticancer medications with adherence and/or persistence as primary outcome measures will be included in this review. We will search the following electronic databases with no limits on dates: Ovid MEDLINE, Cochrane Library, Web of Science Core Collection, Embase, CINAHL Complete, PsycInfo, and Scopus. Two reviewers will independently screen study titles and abstracts for inclusion with a third reviewer adjudicating conflicts. Full text of included articles will be used to extract information on systemic barriers targeted by adherence interventions as well as information about intervention type, outcomes, and study characteristics. Extracted information will be synthesized to generate a summary of work system factors targeted by adherence interventions. Discussion Through application of a systems-based approach, this scoping review is expected to shed light on the complex and multifaceted nature of factors influencing adherence to oral anticancer agents. The review may also identify areas that are ripe for further research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate ...tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138(+) multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138(neg) B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138(+) multiple myeloma plasma cells but had little effect on CD138(neg) precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138(neg) cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury.
Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk irrespective of conventional risk factors. The role of gut-liver interaction is implicated in its ...development. We investigated the effects of VSL#3
probiotic supplementation on biomarkers of cardiovascular risk and liver injury in patients with NAFLD.
A randomised, double-blinded, placebo-controlled, proof-of-concept study was undertaken. Patients with NAFLD were randomly allocated to take 2 sachets VSL#3
probiotic or placebo twice daily for 10 weeks. Measurements of endothelial function (digital photoplethysmography, sVCAM-1 and cGMP), oxidative stress (glutathione ratio and LHP), inflammation (hsCRP), insulin resistance (HOMA-IR) and liver injury transaminases, fibrosis risk score and acoustic structure quantification (ASQ) were undertaken before and after intervention. Difference in baseline characteristics between the treatment groups was analysed using independent t-test or Mann Whitney U test for non-parametric data. Independent t-test was used to compare the outcomes at the end of the study between the two treatment groups. Wilcoxon Signed Rank test was used to determine the difference in fibrosis risk scores before and after treatment. Spearman's correlation was used to determine any association between cardiovascular and hepatic markers at baseline.
Thirty-five patients completed the study (28 males and 7 females) with a mean age of 57 ± 8 years, body mass index of 32.6 ± 5.0 kg/m
and a relatively short duration of NAFLD (median duration 0.3 IQR 2.0 years). No significant difference was observed in biomarkers of cardiovascular risk and liver injury following VSL#3
supplementation. Significant correlations were noted between sVCAM-1 and hsCRP (rho = 0.392, p = 0.01), and HOMA-IR and AST (rho = 0.489, p < 0.01) at baseline.
This is the first study to evaluate the effect of VSL#3
on ASQ in patients with NAFLD. VSL#3
did not significantly improve markers of cardiovascular risk and liver injury in patients with NAFLD. However, the study supports an association between endothelial dysfunction and inflammation in patients with NAFLD and suggests that NAFLD is linked with insulin resistance.
ISRCTN05474560 ( https://doi.org/10.1186/ISRCTN05474560 ) Registered 9 August 2012 (retrospectively registered).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Survival outcome for elderly patients with newly diagnosed diffuse large B-cell lymphoma remains suboptimal in the rituximab era. In this systematic review, we summarize available evidence relevant ...to the inclusion of anthracycline in upfront chemoimmunotherapy for these elderly patients and highlight the need of prospective clinical trials. With limited prospective data, we find that pretreatment comprehensive geriatric assessment accurately predicts survival and treatment-related toxicities, suggesting its potential role in guiding overall treatment decision-making.
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