Breast cancer in young women: prevalence of LOH at p53, BRCA1 and BRCA2

Breast cancer in young women: prevalance of LOH at p53, BRCA1 and BRCA

Functional analysis of altered Tenascin isoform expression in breast cancer

Background: Cellular interactions with the extracellular matrix (ECM) control many aspects of cell function. The complex ECM protein Tenascin-C (TN), which exists as multiple isoforms, is upregulated in breast cancer. We previously have identified a change in the TN isoform profile in breast cancer, with detection of two additional isoforms — TN16 and TN14/16 — not seen in normal breast [1]. The purpose of this study was to investigate directly the effects of these tumour-associated TNC isoforms on breast cancer cell behaviour

Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud \ud Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud \ud Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud \ud Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising

Discordant bioinformatic predictions of antimicrobial resistance from whole-genome sequencing data of bacterial isolates: an inter-laboratory study.

Antimicrobial resistance (AMR) poses a threat to public health. Clinical microbiology laboratories typically rely on culturing bacteria for antimicrobial-susceptibility testing (AST). As the implementation costs and technical barriers fall, whole-genome sequencing (WGS) has emerged as a 'one-stop' test for epidemiological and predictive AST results. Few published comparisons exist for the myriad analytical pipelines used for predicting AMR. To address this, we performed an inter-laboratory study providing sets of participating researchers with identical short-read WGS data from clinical isolates, allowing us to assess the reproducibility of the bioinformatic prediction of AMR between participants, and identify problem cases and factors that lead to discordant results. We produced ten WGS datasets of varying quality from cultured carbapenem-resistant organisms obtained from clinical samples sequenced on either an Illumina NextSeq or HiSeq instrument. Nine participating teams ('participants') were provided these sequence data without any other contextual information. Each participant used their choice of pipeline to determine the species, the presence of resistance-associated genes, and to predict susceptibility or resistance to amikacin, gentamicin, ciprofloxacin and cefotaxime. We found participants predicted different numbers of AMR-associated genes and different gene variants from the same clinical samples. The quality of the sequence data, choice of bioinformatic pipeline and interpretation of the results all contributed to discordance between participants. Although much of the inaccurate gene variant annotation did not affect genotypic resistance predictions, we observed low specificity when compared to phenotypic AST results, but this improved in samples with higher read depths. Had the results been used to predict AST and guide treatment, a different antibiotic would have been recommended for each isolate by at least one participant. These challenges, at the final analytical stage of using WGS to predict AMR, suggest the need for refinements when using this technology in clinical settings. Comprehensive public resistance sequence databases, full recommendations on sequence data quality and standardization in the comparisons between genotype and resistance phenotypes will all play a fundamental role in the successful implementation of AST prediction using WGS in clinical microbiology laboratories

Defining critical factors in multi-country studies of assisted reproductive technologies (ART): data from the US and UK health systems

As the worldwide use of assisted reproductive technologies (ART) continues to grow, there is a critical need to assess the safety of these treatment parameters and the potential adverse health effects of their use in adults and their offspring. While key elements remain similar across nations, geographic variations both in treatments and populations make generalizability challenging. We describe and compare the demographic factors between the USA and the UK related to ART use and discuss implications for research. The USA and the UK share some common elements of ART practice and in how data are collected regarding long-term outcomes. However, the monitoring of ART in these two countries each brings strengths that complement each other’s limitations

Detection of HER2 amplification in circulating free DNA in patients with breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in 20-25% of breast cancers. This study investigated circulating free DNA (cfDNA) for detection of HER2 gene amplification in patients with breast cancer. METHODS: Circulating free DNA was extracted from plasma of unselected patients with primary breast cancer (22 before surgery and 68 following treatment), 30 metastatic patients and 98 female controls using the QIAamp Blood DNA Mini Kit (Qiagen). The ratio of HER2 to an unamplified reference gene (contactin-associated protein 1 (CNTNAP1)) was measured in cfDNA samples by quantitative PCR (qPCR) using SK-BR-3 cell line DNA as a positive control. RESULTS: We validated the qPCR assay with DNA extracted from 23 HER2 3+ and 40 HER2-negative tumour tissue samples; the results agreed for 60 of 63 (95.2%) tumours. Amplification was detected in cfDNA for 8 of 68 patients following primary breast cancer treatment and 5 of 30 metastatic patients, but was undetected in 22 patients with primary breast cancer and 98 healthy female controls. Of the patients with amplification in cfDNA, 10 had HER2 3+ tumour status by immunohistochemistry. CONCLUSIONS: The results demonstrate for the first time the existence of amplified HER2 in cfDNA in the follow-up of breast cancer patients who are otherwise disease free. This approach could potentially provide a marker in patients with HER2-positive breast cancer

Towards Subject and Diagnostic Identifiability in the Alzheimer’s Disease Spectrum Based on Functional Connectomes

Alzheimer’s disease (AD) is the only major cause of mortality in the world without an effective disease modifying treatment. Evidence supporting the so called “disconnection hypothesis” suggests that functional connectivity biomarkers may have clinical potential for early detection of AD. However, known issues with low test-retest reliability and signal to noise in functional connectivity may prevent accuracy and subsequent predictive capacity. We validate the utility of a novel principal component based diagnostic identifiability framework to increase separation in functional connectivity across the Alzheimer’s spectrum by identifying and reconstructing FC using only AD sensitive components or connectivity modes. We show that this framework (1) increases test-retest correspondence and (2) allows for better separation, in functional connectivity, of diagnostic groups both at the whole brain and individual resting state network level. Finally, we evaluate a posteriori the association between connectivity mode weights with longitudinal neurocognitive outcomes

Mathematizing Darwin

Ernst Mayr called the first part of the evolutionary synthesis the ‘Fisherian synthesis’ on account of the dominant role played by R.A. Fisher in forging a mathematical theory of natural selection together with J.B.S. Haldane and Sewall Wright in the decade 1922–1932. It is here argued that Fisher’s contribution relied on a close reading of Darwin’s work to a much greater extent than did the contributions of Haldane and Wright, that it was synthetic in contrast to their analytic approach and that it was greatly influenced by his friendship with the Darwin family, particularly with Charles’s son Leonard