On discontinuous Galerkin and discrete ordinates approximations for neutron transport equation and the critical eigenvalue

The objective of this paper is to give a mathematical framework for a fully discrete numerical approach for the study of the neutron transport equation in a cylindrical domain (container model). More specifically, we consider the discontinuous Galerkin (DG) finite element method for spatial approximation of the mono-energetic, critical neutron transport equation in an infinite cylindrical domain e Ω in R3 with a polygonal convex cross-section Ω. The velocity discretization relies on a special quadrature rule developed to give optimal estimates in discrete ordinate parameters compatible with the quasi-uniform spatial mesh. We use interpolation spaces and derive optimal error estimates, up to maximal available regularity, for the fully discrete scalar flux. Finally we employ a duality argument and prove superconvergence estimates for the critical eigenvalue

A systematic review and meta-analysis of outcomes after elective surgery for ulcerative colitis.

AIM: Approximately 20%-30% of patients with ulcerative colitis (UC) will undergo surgery during their disease course, the vast majority being elective due to chronic refractory disease. The risks of elective surgery are reported variably. The aim of this systematic review and meta-analysis is to summarize the outcomes after elective surgery for UC. METHODS: A systematic review was conducted that analysed studies reporting outcomes for elective surgery in the modern era (>2002). It was prospectively registered on the PROSPERO database (ref: CRD42018115513). Searches were performed of Embase and MEDLINE on 15 January 2019. Outcomes were split by operation performed. Primary outcome was quality of life; secondary outcomes were early, late and functional outcomes after surgery. Outcomes reported in five or more studies underwent a meta-analysis of incidence using random effects. Heterogeneity is reported with I2 , and publication bias was assessed using Doi plots and the Luis Furuya-Kanamori index. RESULTS: A total of 34 studies were included (11 774 patients). Quality of life was reported in 12 studies, with variable and contrasting results. Thirteen outcomes (eight early surgical complications, five functional outcomes) were included in the formal meta-analysis, all of which were outcomes for ileal pouch-anal anastomosis (IPAA). A further 71 outcomes were reported (50 IPAA, 21 end ileostomy). Only 14 of 84 outcomes received formal definitions, with high inter-study variation of definitions. CONCLUSION: Outcomes after elective surgery for UC are variably defined. This systematic review and meta-analysis highlights the range of reported incidences and provides practical information that facilitates shared decision making in clinical practice

Oncogenic role of connective tissue growth factor is associated with canonical TGF-β cascade in colorectal cancer

TGF-β signaling pathways promote tumour development and control several downstream genes such as CTGF and MMPs. This study aimed to investigate the association between CTGF and MMP-1 mRNA expressions with clinicopathological status and survival rate in colorectal cancer patients. We investigated expression levels of CTGF and MMP-1 genes in paraffin-embedded tumours and adjacent normal tissue blocks (ADJ) by Real Time-PCR. Then, the expression of Smad2 and Smad4 proteins in the TGF-β canonical pathway was evaluated by immunohistochemistry. Finally, the correlation between CTGF, MMP-1, and the canonical TGF-β-signalling pathway with the clinicopathological features was investigated. Expression levels of MMP-1and CTGF were higher in tumours compared with adjacent normal tissues. Overexpression levels of MMP-1 and CTGF were associated with lymph node metastasis, distant metastasis, tumour histopathological grading, advanced stage, and poor survival (p 0.05). Additionally, a significant association between the upregulation of MMP-1 and tumour location was noted. Upregulation of Smad2 and Smad4 proteins were also significantly correlated with lymph node metastasis, distant metastasis, advanced stage, and poor survival (p 0.0001). This study showed that canonical TGF-β signalling regulates both CTGF and MMP-1 expression and CRC progression. Moreover, TGF-β signalling and its downstream genes could be used as novel biomarkers and novel approaches for targeted therapy in CRC

Molecular characterization and sterol profiles identify nonsynonymous mutations in ERG2 as a major mechanism conferring reduced susceptibility to amphotericin B in candida kefyr

The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 patients in Kuwait and identified by phenotypic and molecular methods were analyzed. An Etest was initially used to identify isolates with rs-AMB. Specific mutations in ERG2 and ERG6 involved in ergosterol biosynthesis were detected by PCR sequencing. Twelve selected isolates were also tested by the SensiTitre Yeast One (SYO), and total cell sterols were evaluated by gas chromatography-mass spectrometry and ERG3 and ERG11 sequencing. Eight isolates from 8 patients showed rs-AMB by Etest, including 2 isolates with additional resistance to fluconazole or to all three antifungals. SYO correctly identified 8 of 8 rs-AMB isolates. A nonsynonymous mutation in ERG2 was detected in 6 of 8 rs-AMB isolates but also in 3 of 73 isolates with a wild-type AMB pattern. One rs-AMB isolate contained a deletion (frameshift) mutation in ERG2. One or more nonsynonymous mutations was detected in ERG6 in 11 of 81 isolates with the rs-AMB or wild-type AMB pattern. Among 12 selected isolates, 2 and 2 isolates contained a nonsynonymous mutation(s) in ERG3 and ERG11, respectively. Ergosterol was undetectable in 7 of 8 rs-AMB isolates, and the total cell sterol profiles were consistent with loss of ERG2 function in 6 rs-AMB isolates and loss of ERG3 activity in another rs-AMB isolate. Our data showed that ERG2 is a major target conferring rs-AMB in clinical C. kefyr isolates

A Structurally Simple Vaccine Candidate Reduces Progression and Dissemination of Triple-Negative Breast Cancer

The Tn antigen is a well-known tumor-associated carbohydrate determinant, often incorporated in glycopeptides to develop cancer vaccines. Herein, four copies of a conformationally constrained mimetic of the antigen TnThr (GalNAc-Thr) were conjugated to the adjuvant CRM197, a protein licensed for human use. The resulting vaccine candidate, mime[4]CRM elicited a robust immune response in a triple-negative breast cancer mouse model, correlated with high frequency of CD4+ T cells and low frequency of M2-type macrophages, which reduces tumor progression and lung metastasis growth. Mime[4]CRM-mediated activation of human dendritic cells is reported, and the proliferation of mime[4]CRM-specific T cells, in cancer tissue and peripheral blood of patients with breast cancer, is demonstrated. The locked conformation of the TnThr mimetic and a proper presentation on the surface of CRM197 may explain the binding of the conjugate to the anti-Tn antibody Tn218 and its efficacy to fight cancer cells in mice

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3