Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance

YesBackground: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. Methods: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. Results: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. Conclusions: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease.Alexander Boag Sarcoma Fund

Numerical study of radiative Maxwell viscoelastic magnetized flow from a stretching permeable sheet with the Cattaneo–Christov heat flux model

In this article, the Cattaneo-Christov heat flux model is implemented to study non-Fourier heat and mass transfer in the magnetohydrodynamic (MHD) flow of an upper convected Maxwell (UCM) fluid over a permeable stretching sheet under a transverse constant magnetic field. Thermal radiation and chemical reaction effects are also considered. The nonlinear partial differential conservation equations for mass, momentum, energy and species conservation are transformed with appropriate similarity variables into a system of coupled, highly nonlinear ordinary differential equations with appropriate boundary conditions. Numerical solutions have been presented for the influence of elasticity parameter (), magnetic parameter (M2), suction/injection parameter (λ), Prandtl number (Pr), conduction-radiation parameter (Rd), sheet stretching parameter (A), Schmidt number (Sc), chemical reaction parameter (γ_c), modified Deborah number with respect to relaxation time of heat flux (i.e. non-Fourier Deborah number) on velocity components, temperature and concentration profiles using the successive Taylor series linearization method (STSLM) utilizing Chebyshev interpolating polynomials and Gauss-Lobatto collocation. The effects of selected parameters on skin friction coefficient, Nusselt number and Sherwood number are also presented with the help of tables. Verification of the STSLM solutions is achieved with existing published results demonstrating close agreement. Further validation of skin friction coefficient, Nusselt number and Sherwood number values computed with STSLM is included using Mathematica software shooting quadrature

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes

Cholangiocarcinoma in Magnetic Resonance Cholangiopancreatography and Fascioliasis in Endoscopic Ultrasonography

Fascioliasis is a worldwide zoonotic infection with Fasciola hepatica and Fasciola gigantica. The zoonoses are particularly endemic in sheep-raising countries and are also endemic in Iran. Typical symptoms that may be associated with fascioliasis can be divided by phases of the disease, including the acute or liver phase, the chronic or biliary phase, and ectopic or pharyngeal fascioliasis. Cholestatic symptoms may be absent, and in some cases diagnosis and treatment may be preceded by a long period of abdominal pain, eosinophilia and vague gastrointestinal symptoms. We report a case with epigastric and upper quadrant abdominal pain for the last 4 years, with imaging suggesting cholangiocarcinoma. Considering a new concept of endoscopic ultrasonography, at last F. hepatica was extracted with endoscopic retrograde cholangiography

Parasite-insecticide interactions: a case study of Nosema ceranae and fipronil synergy on honeybee

In ecosystems, a variety of biological, chemical and physical stressors may act in combination to induce illness in populations of living organisms. While recent surveys reported that parasite-insecticide interactions can synergistically and negatively affect honeybee survival, the importance of sequence in exposure to stressors has hardly received any attention. In this work, Western honeybees (Apis mellifera) were sequentially or simultaneously infected by the microsporidian parasite Nosema ceranae and chronically exposed to a sublethal dose of the insecticide fipronil, respectively chosen as biological and chemical stressors. Interestingly, every combination tested led to a synergistic effect on honeybee survival, with the most significant impacts when stressors were applied at the emergence of honeybees. Our study presents significant outcomes on beekeeping management but also points out the potential risks incurred by any living organism frequently exposed to both pathogens and insecticides in their habitat

Comparative Analysis of Viral Gene Expression Programs during Poxvirus Infection: A Transcriptional Map of the Vaccinia and Monkeypox Genomes

Poxviruses engage in a complex and intricate dialogue with host cells as part of their strategy for replication. However, relatively little molecular detail is available with which to understand the mechanisms behind this dialogue.We designed a specialized microarray that contains probes specific to all predicted ORFs in the Monkeypox Zaire (MPXV) and Vaccinia Western Reserve (VACV) genomes, as well as >18,000 human genes, and used this tool to characterize MPXV and VACV gene expression responses in vitro during the course of primary infection of human monocytes, primary human fibroblasts and HeLa cells. The two viral transcriptomes show distinct features of temporal regulation and species-specific gene expression, and provide an early foundation for understanding global gene expression responses during poxvirus infection.The results provide a temporal map of the transcriptome of each virus during infection, enabling us to compare viral gene expression across species, and classify expression patterns of previously uncharacterized ORFs

The clinical overlap between functional dyspepsia and irritable bowel syndrome based on Rome III criteria

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies suggest considerable overlap between functional dyspepsia (FD) and irritable bowel syndrome (IBS). To date, no surveys have been performed to investigate the clinical overlap between these two disorders using Rome III criteria. Our aim was to investigate the prevalence and risk factors for the overlap of FD and IBS based on Rome III criteria in a large clinical sample.</p> <p>Methods</p> <p>Consecutive patients at the general gastroenterology outpatient clinic were requested to complete a self-report questionnaire. FD and IBS were defined by Rome III criteria.</p> <p>Results</p> <p>Questionnaires were returned by 3014 patients (52.8% female, 89% response rate). FD-IBS overlap was observed in 5.0% of the patients, while 15.2% and 10.9% of the patients were classified as FD alone and IBS alone, respectively. Compared with non-IBS patients, the odds ratio of having FD among IBS patients was 2.09 (95% CI: 1.68–2.59). Patients with FD-IBS overlap had higher severity scores for the postprandial fullness symptom (2.35 ± 1.49 vs. 1.72 ± 1.59, P < 0.001) and overall FD symptom (6.65 ± 2.88 vs. 5.82 ± 2.76, P = 0.002) than those with FD alone. The only independent risk factor for FD-IBS overlap vs. FD alone was the presence of postprandial fullness symptom (OR 2.67, 95% CI: 1.34–5.31).</p> <p>Conclusion</p> <p>Clinical overlap of FD and IBS according to Rome III criteria is very common. One risk factor for FD-IBS overlap is the presence of postprandial fullness symptom. This study provides clues for future pathophysiological studies of FD and IBS.</p

Reprogrammed Transcriptome in Rhesus-Bovine Interspecies Somatic Cell Nuclear Transfer Embryos

Global activation of the embryonic genome (EGA), one of the most critical steps in early mammalian embryo development, is recognized as the time when interspecies somatic cell nuclear transfer (iSCNT) embryos fail to thrive.In this study, we analyzed the EGA-related transcriptome of rhesus-bovine iSCNT 8- to 16-cell embryos and dissected the reprogramming process in terms of embryonic gene activation, somatic gene silencing, and maternal RNA degradation. Compared with fibroblast donor cells, two thousand and seven genes were activated in iSCNT embryos, one quarter of them reaching expression levels comparable to those found in in vitro fertilized (IVF) rhesus embryos. This suggested that EGA in iSCNT embryos had partially recapitulated rhesus embryonic development. Eight hundred and sixty somatic genes were not silenced properly and continued to be expressed in iSCNT embryos, which indicated incomplete nuclear reprogramming. We compared maternal RNA degradation in bovine oocytes between bovine-bovine SCNT and iSCNT embryos. While maternal RNA degradation occurred in both SCNT and iSCNT embryos, we saw more limited overall degradation of maternal RNA in iSCNT embryos than in SCNT embryos. Several important maternal RNAs, like GPF9, were not properly processed in SCNT embryos.Our data suggested that iSCNT embryos are capable of triggering EGA, while a portion of somatic cell-associated genes maintain their expression. Maternal RNA degradation seems to be impaired in iSCNT embryos. Further understanding of the biological roles of these genes, networks, and pathways revealed by iSCNT may expand our knowledge about cell reprogramming, pluripotency, and differentiation