Use of DNA–Damaging Agents and RNA Pooling to Assess Expression Profiles Associated with BRCA1 and BRCA2 Mutation Status in Familial Breast Cancer Patients

A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA–damaging agents (irradiation and mitomycin C) on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA–pooling strategy, we found that treating LCLs with 1.2 µM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2, and BRCAX mutation status. A classifier was built using the expression profile of nine QRT–PCR validated genes that were associated with BRCA1, BRCA2, and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2, and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2, and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis

A blind ATCA HI survey of the Fornax galaxy cluster:Properties of the HI detections

We present the first interferometric blind HI survey of the Fornax galaxy cluster, which covers an area of 15 deg2 out to the cluster virial radius. The survey has a spatial and velocity resolution of 67″ × 95″(∼6 × 9 kpc at the Fornax cluster distance of 20 Mpc) and 6.6 km s−1 and a 3σ sensitivity of NHI ∼ 2 × 1019 cm−2 and MHI ∼ 2 × 107 M⊙, respectively. We detect 16 galaxies out of roughly 200 spectroscopically confirmed Fornax cluster members. The detections cover about three orders of magnitude in HI mass, from 8 × 106 to 1.5 × 1010 M⊙. They avoid the central, virialised region of the cluster both on the sky and in projected phase-space, showing that they are recent arrivals and that, in Fornax, HI is lost within a crossing time, ∼2 Gyr. Half of these galaxies exhibit a disturbed HI morphology, including several cases of asymmetries, tails, offsets between HI and optical centres, and a case of a truncated HI disc. This suggests that these recent arrivals have been interacting with other galaxies, the large-scale potential or the intergalactic medium, within or on their way to Fornax. As a whole, our Fornax HI detections are HI-poorer and form stars at a lower rate than non-cluster galaxies in the same M⋆ range. This is particularly evident at M⋆  ≲  109 M⊙, indicating that low mass galaxies are more strongly affected throughout their infall towards the cluster. The MHI/M⋆ ratio of Fornax galaxies is comparable to that in the Virgo cluster. At fixed M⋆, our HI detections follow the non-cluster relation between MHI and the star formation rate, and we argue that this implies that thus far they have lost their HI on a timescale ≳1−2 Gyr. Deeper inside the cluster HI removal is likely to proceed faster, as confirmed by a population of HI-undetected but H2-detected star-forming galaxies. Overall, based on ALMA data, we find a large scatter in H2-to-HI mass ratio, with several galaxies showing an unusually high ratio that is probably caused by faster HI removal. Finally, we identify an HI-rich subgroup of possible interacting galaxies dominated by NGC 1365, where pre-processing is likely to have taken place

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

WALLABY – an SKA Pathfinder H i survey

The Widefield ASKAP L-band Legacy All-sky Blind surveY (wallaby) is a next-generation survey of neutral hydrogen (H i) in the Local Universe. It uses the widefield, high-resolution capability of the Australian Square Kilometer Array Pathfinder (ASKAP), a radio interferometer consisting of 36 × 12 -m dishes equipped with Phased-Array Feeds (PAFs), located in an extremely radio-quiet zone in Western Australia. wallaby aims to survey three-quarters of the sky (− 90 ∘\u3c δ\u3c + 30 ∘) to a redshift of z≲ 0.26 , and generate spectral line image cubes at ∼30 arcsec resolution and ∼1.6 mJy beam−1 per 4 km s−1 channel sensitivity. ASKAP’s instantaneous field of view at 1.4 GHz, delivered by the PAF’s 36 beams, is about 30 sq deg. At an integrated signal-to-noise ratio of five, wallaby is expected to detect around half a million galaxies with a mean redshift of z∼ 0.05 (∼200 Mpc). The scientific goals of wallaby include: (a) a census of gas-rich galaxies in the vicinity of the Local Group; (b) a study of the H i properties of galaxies, groups and clusters, in particular the influence of the environment on galaxy evolution; and (c) the refinement of cosmological parameters using the spatial and redshift distribution of low-bias gas-rich galaxies. For context we provide an overview of recent and planned large-scale H i surveys. Combined with existing and new multi-wavelength sky surveys, wallaby will enable an exciting new generation of panchromatic studies of the Local Universe. — First results from the wallaby pilot survey are revealed, with initial data products publicly available in the CSIRO ASKAP Science Data Archive (CASDA)

Regional differences in lumbar spinal posture and the influence of low back pain

<p>Abstract</p> <p>Background</p> <p>Spinal posture is commonly a focus in the assessment and clinical management of low back pain (LBP) patients. However, the link between spinal posture and LBP is not fully understood. Recent evidence suggests that considering regional, rather than total lumbar spine posture is important. The purpose of this study was to determine; if there are regional differences in habitual lumbar spine posture and movement, and if these findings are influenced by LBP.</p> <p>Methods</p> <p>One hundred and seventy female undergraduate nursing students, with and without LBP, participated in this cross-sectional study. Lower lumbar (LLx), Upper lumbar (ULx) and total lumbar (TLx) spine angles were measured using an electromagnetic tracking system in static postures and across a range of functional tasks.</p> <p>Results</p> <p>Regional differences in lumbar posture and movement were found. Mean LLx posture did not correlate with ULx posture in sitting (r = 0.036, p = 0.638), but showed a moderate inverse correlation with ULx posture in usual standing (r = -0.505, p < 0.001). Regional differences in range of motion from reference postures in sitting and standing were evident. BMI accounted for regional differences found in all sitting and some standing measures. LBP was not associated with differences in regional lumbar spine angles or range of motion, with the exception of maximal backward bending range of motion (F = 5.18, p = 0.007).</p> <p>Conclusion</p> <p>This study supports the concept of regional differences within the lumbar spine during common postures and movements. Global lumbar spine kinematics do not reflect regional lumbar spine kinematics, which has implications for interpretation of measures of spinal posture, motion and loading. BMI influenced regional lumbar posture and movement, possibly representing adaptation due to load.</p