A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2.

BACKGROUND: Variation in an individual\u27s genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons. RESULTS: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p \u3c 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p \u3c 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC. CONCLUSIONS: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies

Automated quantification of mitral valve geometry on multi-slice computed tomography in patients with dilated cardiomyopathy: Implications for transcatheter mitral valve replacement

Objectives The primary aim of this study was to quantify the dimensions and geometry of the mitral valve complex in patients with dilated cardiomyopathy and significant mitral regurgitation. The secondary aim was to evaluate the validity of an automated segmentation algorithm for assessment of the mitral valve compared to manual assessment on computed tomography. Background Transcatheter mitral valve replacement (TMVR) is an evolving technique which relies heavily on the lengthy evaluation of cardiac computed tomography (CT) datasets. Limited data is available on the dimensions and geometry of the mitral valve in pathological states throughout the cardiac cycle, which may have implications for TMVR device design, screening of suitable candidates and annular sizing prior to TMVR. Methods A retrospective study of 15 of patients with dilated cardiomyopathy who had undergone full multiphase ECG gated cardiac CT. A comprehensive evaluation of mitral valve geometry was performed at 10 phases of the cardiac cycle using the recommended D-shaped mitral valve annulus (MA) segmentation model using manual and automated CT interpretation platforms. Mitral annular dimensions and geometries were compared between manual and automated methods. Results Mitral valve dimensions in patients with dilated cardiomyopathy were similar to previously reported values (MAarea Diastole: 12.22 ± 1.90 cm2), with dynamic changes in size and geometry between systole and diastole of up to 5%. The distance from the centre of the MA to the left ventricular apex demonstrated moderate agreement between automated and manual methods (ρc = 0.90) with other measurements demonstrating poor agreement between the two methods (ρc = 0.75–0.86). Conclusions Variability of mitral valve annulus measurements are small during the cardiac cycle. Novel automated algorithms to determine cardiac cycle variations in mitral valve geometry may offer improved segmentation accuracy as well as improved CT interpretation times

Structure of magnetic fields in intracluster cavities

Observations of clusters of galaxies show ubiquitous presence of X-ray cavities, presumably blown by the AGN jets. We consider magnetic field structures of these cavities. Stability requires that they contain both toroidal and poloidal magnetic fields, while realistic configurations should have vanishing magnetic field on the boundary. For axisymmetric configurations embedded in unmagnetized plasma, the continuity of poloidal and toroidal magnetic field components on the surface of the bubble then requires solving the elliptical Grad-Shafranov equation with both Dirichlet and Neumann boundary conditions. This leads to a double eigenvalue problem, relating the pressure gradients and the toroidal magnetic field to the radius of the bubble. We have found fully analytical stable solutions. This result is confirmed by numerical simulation. We present synthetic X-ray images and synchrotron emission profiles and evaluate the rotation measure for radiation traversing the bubble.Comment: 10 pages, 13 figures, accepted by MNRA

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes

Arginine to glutamine variant in olfactomedin-like 3 (OLFML3) is a candidate for severe goniodysgenesis and glaucoma in the Border Collie dog breed

Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and have subsequently been found in this breed in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine single nucleotide variant genotyping chip was used to identify a candidate genetic region. There was a highly significant peak of association over chromosome 17, with a -value of 2 × 10 Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Whole genome sequences of three dogs with glaucoma, three severely affected by goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin like 3 () gene in all six affected animals. This was homozygous for the risk allele in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one was homozygous for this variant (offspring of parents both with goniodysgenesis who were also homozygous for the variant). Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. The identification of a candidate genetic region and putative causative variant will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population

Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature

Defects in cerebrospinal fluid (CSF) flow may contribute to idiopathic scoliosis. However, the mechanisms underlying detection of CSF flow in the central canal of the spinal cord are unknown. Here we demonstrate that CSF flows bidirectionally along the antero-posterior axis in the central canal of zebrafish embryos. In the cfap298tm304 mutant, reduction of cilia motility slows transport posteriorly down the central canal and abolishes spontaneous activity of CSF-contacting neurons (CSF-cNs). Loss of the sensory Pkd2l1 channel nearly abolishes CSF-cN calcium activity and single channel opening. Recording from isolated CSFcNs in vitro, we show that CSF-cNs are mechanosensory and require Pkd2l1 to respond to pressure. Additionally, adult pkd2l1 mutant zebrafish develop an exaggerated spine curvature, reminiscent of kyphosis in humans. These results indicate that CSF-cNs are mechanosensory cells whose Pkd2l1-driven spontaneous activity reflects CSF flow in vivo. Furthermore, Pkd2l1 in CSF-cNs contributes to maintenance of natural curvature of the spine

Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation

Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where combinations of modifications specify unique downstream functions, is widely accepted and can be demonstrated in vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognize trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me2/3 during mitosis. We find that H3T3ph anti-correlates with adjacent H3K4me2/3 in cells, and that the PHD domain of TAF3 can bind H3K4me2/3 in isolated mitotic chromatin despite the presence of H3T3ph. Unlike in vitro, H3K4 readers are still displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.This study was funded by a Wellcome Trust Investigator Award (106951/Z/15/Z) and a Royal Society Wolfson Research Merit Award (WM130089) to J.M.G.H., an EPSRC DTP (Biological Informatics) PhD Studentship to M.H., a Barbour Foundation PhD Studentship to J.L.M., and by a J.G.W. Patterson Foundation grant to L.G.Peer reviewe

Transcatheter Mitral Valve Replacement: Current Evidence and Concepts

Over the past decade, several transcatheter devices have been developed to address the treatment of severe mitral regurgitation (MR) in patients at high surgical risk, mainly aimed at repairing the native mitral valve (MV). MV repair devices have recently been shown to have high efficacy and safety. However, to replicate promising trial results, specific anatomical and pathophysiological criteria have to be met and operators need a high level of experience. As yet, the longer-term durability of transcatheter MV repair remains unknown. Transcatheter MV replacement (TMVR) might be a treatment option able to target various anatomies, reliably abolish MR, and foster ease of use with a standardised implantation protocol. This review presents upcoming TMVR devices and available data and discusses how TMVR might further advance the field of transcatheter treatment of MR

Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral Hhmorrhage

Objective: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. Methods: We performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). Conclusions: We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up

Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers