Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

<p>Abstract</p> <p>Background</p> <p>The gene <it>CHEK2 </it>encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though <it>CHEK2 </it>has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether <it>CHEK2 </it>was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in <it>BRCA1</it> or <it>BRCA2</it> had been identified.</p> <p>Methods</p> <p>We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment.</p> <p>Results</p> <p>We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of <it>CHEK2 </it>that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs.</p> <p>Conclusions</p> <p>Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.</p

Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal AnalySiS Consortium

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas (TCGA) and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal AnalySiS Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient population in need

Denial of long-term issues with agriculture on tropical peatlands will have devastating consequences

Non peer reviewe

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

):e2511409 c Communicable Diseases Branch

Abstract Creutzfeldt-Jakob disease (CJD) is a fatal disease caused by the accumulation of abnormal prion proteins in neurological tissues. Routine notification data reveal that NSW has similar rates of CJD to other states and territories in Australia; however, it is likely that there is significant underascertainment of cases. It is important that clinicians and public health staff remain vigilant for the clinical signs of CJD and understand the limitations of the different diagnostic tests available. This paper provides a brief overview of the epidemiology of CJD in NSW, as well as current issues in the diagnosis and public health investigation of CJD

An update on the epidemiology and key issues associated with the diagnosis and management of Creutzfeldt-Jakob disease cases in NSW

Creutzfeldt-Jakob disease (CJD) is a fatal disease caused by the accumulation of abnormal prion proteins in neurological tissues. Routine notification data reveal that NSW has similar rates of CJD to other states and territories in Australia; however, it is likely that there is significant under-ascertainment of cases. It is important that clinicians and public health staff remain vigilant for the clinical signs of CJD and understand the limitations of the different diagnostic tests available. This paper provides a brief overview of the epidemiology of CJD in NSW, as well as current issues in the diagnosis and public health investigation of CJD

Laparoscopic Versus Open Pyeloplasty for Pelvicoureteric Junction Obstruction: A Systematic Review and Meta-Analysis

ObjectivesTo compare outcomes of laparoscopic versus open pyeloplasty for the management of pelvicoureteric junction obstruction (PUJO) using a systematic review and meta-analysis.In September 2022, electronic database searches were conducted using the Cochrane Library, the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, clinical trial registries, and relevant conferences to identify relevant abstracts and presentations. MethodsProspective randomized controlled trials comparing laparoscopic to open pyeloplasty for PUJO were included in the review. There were no restrictions on date or language. All populations were included. The authors performed data extraction and risk of bias assessment using the risk of bias tool. Meta-analysis was performed using RevMan software. ResultsSix prospective randomized controlled trials involving 335 participants were included in the analysis. Six studies included data on the failure rate, with a slight favouring of open pyeloplasty compared to laparoscopic pyeloplasty, although this was not statistically significant (odds ratio [OR], 1.39; 95% confidence interval [CI] 0.50 to 3.83).Five studies compared operative time, with open pyeloplasty found to have shorter times across all studies (mean difference [MD], 54.97 minutes; 95% CI 47.08 to 62.85).Based on 5 studies, laparoscopic pyeloplasty has a shorter hospital stay (MD, 4.12 days; 95% CI 3.64 to 4.59).Two studies compared postoperative analgesia requirements, showing a lower diclofenac requirement in the laparoscopic group (MD, 330.08 mg; 95% CI 298.05 to 362.11 mg).One study compared blood loss intraoperatively and found no significant difference between the groups (MD, 8.52 mL; 95% CI -2.49 to 19.53).Based on 4 studies, laparoscopic pyeloplasty may result in slightly higher complication rates postoperatively (OR, 1.49; 95% CI 0.53 to 4.18); however, there was no statistically significant difference.No subgroup analyses were conducted. ConclusionsLimited, low-quality evidence from small-scale trials suggests that laparoscopic pyeloplasty has improved outcomes in terms of shorter hospital stays and reduced postoperative pain compared to open pyeloplasty. Open pyeloplasty, on the other hand, had a shorter operative time. Failure rate, complication rate, and blood loss were comparable between the 2 approaches