Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer

Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Understanding and meeting the needs of those using growth hormone injection devices

BACKGROUND: Recombinant human growth hormone (r-hGH) is used to treat: growth hormone deficiency in children and adults; children born small for gestational age; Turner's syndrome; and chronic renal failure. r-hGH is administered by daily subcutaneous injection and may be given using a number of different administration devices. The aim of this survey was, firstly, to identify which attributes of an r-hGH administration device are considered most important to physicians, teenage patients, parents of young children requiring GH and nurses who have experience of r-hGH administration, and, secondly, to determine how they rate existing devices in each of these key attributes. METHODS: The opinions of 67 individuals with experience in r-hGH administration were captured in discussion sessions. Parents, physicians and nurses were asked to rate 19 device attributes by completing a questionnaire, and to rank four different r-hGH administration devices (including a conceptual electronic device) in order of preference. RESULTS: Reliability, ease of use, lack of pain during injection, safety in use, storage, and number of steps in preparation before use, during use and after were considered to be the five most desirable attributes of an r-hGH administration device. An electronic device was preferred to an automatic, multi-dose injection device, a needle-free injection device or a manual, ready-to-use, disposable injection device. CONCLUSION: In the opinion of physicians, nurses and parents using r-hGH injection devices, an ideal device must combine reliability with simplicity, while delivering treatment with minimal pain. An electronic device, which combines many of the most useful features of existing devices with novel functions, was the preferred option for r-hGH administration

‘The longest suicide vote in history’: the Labour Party leadership election of 2015

The Labour leadership contest of 2015 resulted in the election of the veteran Left-wing backbencher, Jeremy Corbyn, who clearly defeated the early favourite, Andy Burnham. Yet Corbyn enjoyed very little support among Labour MPs, and his victory plunged the PLP into turmoil, particularly as he was widely viewed as incapable of leading the Party to victory in the 2020 general election. Given that, much of the established academic literature on Party leadership contests emphasises the ability to foster unity, and thereby render a party electable, as two of the key criteria for electing a new leader, coupled with overall competence, important questions are raised about how and why the Labour Party chose someone to lead them who clearly does not meet these criteria. We will argue that whilst these are the natural priorities of MPs when electing a new leader, in Corbyn’s case, much of the extra-parliamentary Labour Party was more concerned about ideological conviction and purity of principles, regardless of how far these diverged from public opinion. This was especially true of those who signed-up to the Labour Party following the 2015 general election defeat. Indeed, many of these only did so after Corbyn had become a candidate. This clearly suggests a serious tension between maximising intra-party democracy and ensuring the electability of the parliamentary party itself

Treatment adherence with the easypod™ growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents

<p>Abstract</p> <p>Background</p> <p>Accurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypod™, automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device.</p> <p>Methods</p> <p>A multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing ≤2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naïve and treatment-experienced children.</p> <p>Results</p> <p>Of 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment-naïve (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; <it>p </it>= 0.0062]. According to self-reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed ≥1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device.</p> <p>Conclusions</p> <p>easypod™ provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypod™, short-term adherence is good, and significantly higher in treatment-naïve children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey.</p

Analysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer

<p>Abstract</p> <p>Background</p> <p><it>MAP2K4 </it>is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer.</p> <p>Methods</p> <p>We screened for mutations in <it>MAP2K4 </it>using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in <it>MAP2K4 </it>using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing <it>MAP2K4 </it>expression in cell lines.</p> <p>Results</p> <p>In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of <it>MAP2K4 </it>homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of <it>MAP2K4 </it>was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between <it>MAP2K4 </it>expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with <it>MAP2K4 </it>siRNA showed some reduction in proliferation.</p> <p>Conclusions</p> <p><it>MAP2K4 </it>is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.</p

Personalized Pathway Enrichment Map of Putative Cancer Genes from Next Generation Sequencing Data

BACKGROUND: Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data. METHODOLOGY: In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation. PRINCIPAL FINDINGS/CONCLUSIONS: We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems