Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection

Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25−/− or Usp25C178S cells, activating Srebp2, with increased cholesterol flux and attenuated TLR3-dependent responses. Our study therefore defines the function of a deubiquitylase that serves to restrict a range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses

The evolution of intracranial aneurysm treatment techniques and future directions.

Treatment techniques and management guidelines for intracranial aneurysms (IAs) have been continually developing and this rapid development has altered treatment decision-making for clinicians. IAs are treated in one of two ways: surgical treatments such as microsurgical clipping with or without bypass techniques, and endovascular methods such as coiling, balloon- or stent-assisted coiling, or intravascular flow diversion and intrasaccular flow disruption. In certain cases, a single approach may be inadequate in completely resolving the IA and successful treatment requires a combination of microsurgical and endovascular techniques, such as in complex aneurysms. The treatment option should be considered based on factors such as age; past medical history; comorbidities; patient preference; aneurysm characteristics such as location, morphology, and size; and finally the operator's experience. The purpose of this review is to provide practicing neurosurgeons with a summary of the techniques available, and to aid decision-making by highlighting ideal or less ideal cases for a given technique. Next, we illustrate the evolution of techniques to overcome the shortfalls of preceding techniques. At the outset, we emphasize that this decision-making process is dynamic and will be directed by current best scientific evidence, and future technological advances

FUNCIONALIDADE DE MEMBROS SUPERIORES E QUALIDADE DE VIDA EM MASTECTOMIAS TARDIAS

O câncer de mama é a neoplasia que mais acomete as mulheres e seu tratamento pode desencadear alterações físicas, emocionais, sociais e psicológicas. Com este estudo, objetivou-se avaliar a capacidade funcional e a qualidade de vida (QV) de mulheres submetidas à mastectomia no pós-operatório tardio. Para isso, a avaliação constituiu-se da mensuração da amplitude de movimento (ADM) em flexão e abdução de ombro, aplicação da escala de Karnofsky e do questionário de Qualidade de Vida FACT – B + 4 (Functional Assessment of Cancer Therapy – Breast plus Arm Morbidity). Foram avaliadas 99 mulheres mastectomizadas, com idade média de 52 anos (± 11,01), por um período de 20 meses. Observou-se redução de ADM nos movimentos de flexão e abdução de ombro no membro homolateral à cirurgia, sendo considerada estatisticamente significativa. Na escala de Karnofsky, nenhuma das participantes apresentou índice menor que 50, e a maioria se classificou com o índice de 90. Na QV, os domínios físico e emocional apresentaram-se mais comprometidos. Evidenciou-se que as mulheres submetidas ao tratamento cirúrgico do câncer de mama demonstraram comprometimentos na capacidade funcional, entretanto, não tiveram piora extrema na QV no pós-operatório tardio. As disfunções relacionadas à patologia e aos procedimentos terapêuticos são consideradas pertinentes para a indicação de tratamento multidisciplinar, o que pode interferir positivamente nesses casos específicos.Palavras-chave: Neoplasias da mama. Mastectomia. Qualidade de vida. Fisioterapia.

Targeting CDK 9 for treatment of colorectal cancer

Colorectal cancer (CRC) remains one of the most lethal human malignancies and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumor efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9 targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 downregulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumor efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumors. CDKI‐73 significantly inhibited tumor growth (***p < 0.001) without overt toxicity. Analysis of the tumor tissues collected from the xenografted animals confirmed that the in vivo anti‐tumor efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against &gt;100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Genetic determinants of HSP70 gene expression following heat shock

The regulation of heat shock protein expression is of significant physiological and pathophysiological significance. Here we show that genetic diversity is an important determinant of heat shock protein 70 expression involving local, likely cis-acting, polymorphisms. We define DNA sequence variation for the highly homologous HSPA1A and HSPA1B genes in the major histocompatibility complex on chromosome 6p21 and establish quantitative and specific assays for determining transcript abundance. We show for lymphoblastoid cell lines established from individuals of African ancestry that following heat shock, expression of HSPA1B is associated with rs400547 (P 3.88 × 10−8) and linked single nucleotide polymorphisms (SNPs) located 62–93 kb telomeric to HSPA1B. This association was found to explain 31 and 29% of the variance in HSPA1B expression following heat shock or in resting cells, respectively. The associated SNPs show marked variation in minor allele frequency among populations, being more common in individuals of African ancestry, and are located in a region showing population-specific haplotypic block structure. The work illustrates how analysis of a heritable induced expression phenotype can be highly informative in defining functionally important genetic variation

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

(Not) being at home: Hsu Ming Teo's Behind the Moon (2005) and Michelle de Kretser's Questions of Travel (2012)

This article examines some interventions of Asian Australian writing into the debate over multiculturalism, and the shift from negative stereotyping of Asian migrants, to reification of racial divisions and propagation of a masked racism, to the creation of new alignments and the revival of pre-existing affiliations by migrant and second generation subjects. It compares the practices of not-at-homeness by Asian migrants and their descendants and white Australians in Hsu Ming Teo’s Behind the Moon with those of a Sri Lankan refugee and a white Australian traveller in Michelle de Kretser’s Questions of Travel. The changing concepts of belonging in the novels show a realignment of core and periphery relations within the nation state under the pressures of multiculturalism and globalization: where home is and how it is configured are questions as important for white Australians whose sense of territory is challenged as they are for Asian migrants who seek to establish a new belonging

Leucocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases.

OBJECTIVES: Type 1 interferons (IFN-1) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-1 on mixed cell populations. We aimed to define modules of IFN-1-associated genes in purified leucocyte populations and use these as a basis for a detailed comparative analysis. METHODS: CD4+ and CD8+ T cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers and gene expression then determined by microarray. Modules of IFN-1-associated genes were defined using weighted gene coexpression network analysis. The composition and expression of these modules was analysed. RESULTS: 1150 of 1288 IFN-1-associated genes were specific to myeloid subsets, compared with 11 genes unique to T cells. IFN-1 genes were more highly expressed in myeloid subsets compared with T cells. A subset of neutrophil samples from healthy volunteers (HV) and conditions not classically associated with IFN-1 signatures displayed increased IFN-1 gene expression, whereas upregulation of IFN-1-associated genes in T cells was restricted to SLE. CONCLUSIONS: Given the broad upregulation of IFN-1 genes in neutrophils including in some HV, investigators reporting IFN-1 signatures on the basis of whole blood samples should be cautious about interpreting this as evidence of bona fide IFN-1-mediated pathology. Instead, specific upregulation of IFN-1-associated genes in T cells may be a useful biomarker and a further mechanism by which elevated IFN-1 contributes to autoimmunity in SLE.SMF holds a Translational Medicine and Therapeutics PhD studentship from the Wellcome Trust and GlaxoSmithKline and has also received funding for this work from the Addenbrooke’s Charitable Trust. KGCS is the Khoo Oon Teik Professor of Nephrology, National University of Singapore. Singapore recruitment was supported by the Khoo Investigator Grant from the Duke-NUS Graduate Medical School, Singapore, and by National Medical Research Council of Singapore grants (NMRC/1164/2008 and IRG07nov089). This work was also supported by UK National Institute of Health Research Cambridge Biomedical Research Centre, the Lupus Research Institute (Distinguished Innovator Award, KGCS), the Medical Research Council UK (programme grant MR/L019027/1) and the Wellcome Trust (programme grant 083650/Z/07/Z and project grant 094227/Z/10/Z). The Cambridge Institute for Medical Research is in receipt of Wellcome Trust Strategic Award 079895.This is the final version of the article. It first appeared from BMJ Group via https://doi.org/10.1136/rmdopen-2015-00018