BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame.

Integrating deep mutational scanning and low-throughput mutagenesis data to predict the impact of amino acid variants.

Background: Evaluating the impact of amino acid variants has been a critical challenge for studying protein function and interpreting genomic data. High-throughput experimental methods like deep mutational scanning (DMS) can measure the effect of large numbers of variants in a target protein, but because DMS studies have not been performed on all proteins, researchers also model DMS data computationally to estimate variant impacts by predictors.

Results: In this study, we extended a linear regression-based predictor to explore whether incorporating data from alanine scanning (AS), a widely used low-throughput mutagenesis method, would improve prediction results.

A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review.

Background: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a gene fusion in approximately 90% of cases, or a gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia.

Targeting homologous recombination deficiency in uterine leiomyosarcoma.

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.

secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi.

svaRetro and svaNUMT: modular packages for annotating retrotransposed transcripts and nuclear integration of mitochondrial DNA in genome sequencing data.

Nuclear integration of mitochondrial genomes and retrocopied transcript insertion are biologically important but often-overlooked aspects of structural variant (SV) annotation. While tools for their detection exist, these typically rely on reanalysis of primary data using specialised detectors rather than leveraging calls from general purpose structural variant callers. Such reanalysis potentially leads to additional computational expense and does not take advantage of advances in general purpose structural variant calling.

CIS controls the functional polarization of GM-CSF-derived macrophages.

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs.

Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin.

Unlabelled: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal.

From a large-scale genomic analysis of insertion sequences to insights into their regulatory roles in prokaryotes.

Background: Insertion sequences (ISs) are mobile repeat sequences and most of them can copy themselves to new host genome locations, leading to genome plasticity and gene regulation in prokaryotes. In this study, we present functional and evolutionary relationships between IS and neighboring genes in a large-scale comparative genomic analysis.

Results: IS families were located in all prokaryotic phyla, with preferential occurrence of IS3, IS4, IS481, and IS5 families in Alpha-, Beta-, and Gammaproteobacteria, Actinobacteria and Firmicutes as well as in eukaryote host-associated organisms and autotrophic opportunistic pathogens.

Ripening-Induced Changes in the Nutraceutical Compounds of Differently Coloured Pepper ( L.) Breeding Lines.

To date, several research studies addressed the topic of phytochemical analysis of the different coloured pepper berries during ripening, but none discussed it in the case of purple peppers. In this study we examine whether the anthocyanin accumulation of the berries in the early stages of ripening could result in a higher antioxidant capacity due to the elevated amount of polyphenolic compounds. Therefore, enzymatic and non-enzymatic antioxidant capacity was measured in four distinct phenophases of fruit maturity.

Lung Imaging Reveals Stroke-Induced Impairment in Pulmonary Intravascular Neutrophil Function, a Response Exacerbated with Aging.

In stroke patients, infection is a significant contributor to morbidity and mortality. Moreover, older stroke patients show an increased risk of developing stroke-associated infection, although the mechanisms underlying this increased susceptibility to infection are unknown. In this study, using an experimental mouse model of ischemic stroke, we showed that older (12-15 mo of age) mice had elevated lung bacterial infection and inflammatory damage after stroke when compared with young (8-10 wk of age) counterparts, despite undergoing the same degree of brain injury.

Blood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients.

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease.

Collateral Sensitivity to β-Lactam Drugs in Drug-Resistant Tuberculosis Is Driven by the Transcriptional Wiring of BlaI Operon Genes.

The evolution of resistance to one antimicrobial can result in enhanced sensitivity to another, known as "collateral sensitivity." This underexplored phenomenon opens new therapeutic possibilities for patients infected with pathogens unresponsive to classical treatments. Intrinsic resistance to β-lactams in Mycobacterium tuberculosis (the causative agent of tuberculosis) has traditionally curtailed the use of these low-cost and easy-to-administer drugs for tuberculosis treatment.

Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival.

Background: Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival.

Unifying package managers, workflow engines, and containers: Computational reproducibility with BioNix.

Motivation: A challenge for computational biologists is to make our analyses reproducible-i.e. to rerun, combine, and share, with the assurance that equivalent runs will generate identical results.

Improved HLA-based prediction of coeliac disease identifies two novel genetic interactions.

Human Leucocyte Antigen (HLA) testing is useful in the clinical work-up of coeliac disease (CD) with high negative but low positive predictive value. We construct a genomic risk score (GRS) using HLA risk genotypes to improve CD prediction and guide exclusion criteria. Imputed HLA genotypes for five European CD case-control GWAS (n > 15,000) were used to construct and validate an interpretable HLA-based risk model (HDQ), which shows statistically significant improvements in predictive performance upon all previous HLA-based risk models.

MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.

In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost.

BioShake: a Haskell EDSL for bioinformatics workflows.

Typical bioinformatics analyses comprise of long running computational workflows. An important part of reproducible research is the management and execution of these workflows to allow robust execution and to minimise errors. BioShake is an embedded domain specific language in Haskell for specifying and executing computational workflows for bioinformatics that significantly reduces the possibility of errors occurring.

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy.

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function.

RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.

In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process.

Development and validation of a gene expression tumour classifier for cancer of unknown primary.

Accurate identification of the primary tumour in cancer of unknown primary (CUP) is required for effective treatment selection and improved patient outcomes. The aim of this study was to develop and validate a gene expression tumour classifier and integrate it with histopathology to identify the likely site of origin in CUP.RNA was extracted from 450 formalin fixed, paraffin embedded samples of known origin comprising 18 tumour groups.

Stability of bivariate GWAS biomarker detection.

Given the difficulty and effort required to confirm candidate causal SNPs detected in genome-wide association studies (GWAS), there is no practical way to definitively filter false positives. Recent advances in algorithmics and statistics have enabled repeated exhaustive search for bivariate features in a practical amount of time using standard computational resources, allowing us to use cross-validation to evaluate the stability. We performed 10 trials of 2-fold cross-validation of exhaustive bivariate analysis on seven Wellcome-Trust Case-Control Consortium GWAS datasets, comparing the traditional [Formula: see text] test for association, the high-performance GBOOST method and the recently proposed GSS statistic (Available at http://bioinformatics.

Reducing hospital-acquired pressure damage: an NHS acute trust initiative.

During 2009, Maidstone and Tunbridge Wells NHS Trust reviewed its pressure ulcer prevention strategy; this included patient interventions and equipment provision. Standard hospital mattresses were requiring replacement and dynamics were used frequently, while the overall prevalence of pressure damage remained high. Replacing the standard foam mattress with a non-powered pressure-redistributing system (AtmosAir) was proposed.

A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification.