Irradiation effects in oxide glasses doped with transition and rare-earth elements

International audienceThe effect of -irradiation on silicate and aluminoborosilicate glasses doped with transition metals (TM) and rare earth (RE) elements has been studied using Electron Paramagnetic Resonance (EPR), Raman and luminescence spectroscopy. Irradiation leads to the reduction of both Cr and Mn ions in both types of glass matrix. It is shown that even small amounts of TM dopants completely block defect production, as occurs under irradiation in non-doped glasses. As well, TM doping results in the disappearance of structural changes in the glass (densification, polymerization increase and Na migration) for doses of ~ 10 Gy. Unlike TM-doped matrices, incorporation of RE ions into aluminoborosilicate glass blocks neither defect production nor structural changes in glass matrices during irradiation. Simultaneously, we observe a reduction of RE ions, most clearly demonstrated for Ce ions in aluminoborosilicate glasses. We propose that the relative stability of the different charge states of the RE ions is linked to the efficiency of the reduction process, and therefore to the evolution of the glass structure during irradiation

KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer

Abstract Purpose: KRAS mutation is a common canonical mutation in colorectal cancer, found at differing frequencies in all consensus molecular subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Expression analysis of immune genes/signatures was performed using The Cancer Genome Atlas (TCGA) RNA-seq and the KFSYSCC microarray datasets. Multivariate analysis included KRAS status, CMS, tumor location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-class II, and CXCL10 was analyzed by digital IHC. Results: The Th1-centric co-ordinate immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS-mutant colorectal cancer in both datasets. Cytotoxic T cells, neutrophils, and the IFNγ pathway were suppressed in KRAS-mutant samples. The expressions of STAT1 and CXCL10 were reduced at the mRNA and protein levels. In multivariate analysis, KRAS mutation, CMS2, and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS-mutant colorectal cancer: KRAS-mutant CMS2 samples have the lowest CIRC expression, reduced expression of the IFNγ pathway, STAT1 and CXCL10, and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to KRAS wild-type CMS2 samples in the TCGA. These trends held in the KFSYSCC dataset. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in colorectal cancer, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of colorectal cancer. Clin Cancer Res; 24(1); 224–33. ©2017 AACR.</jats:p

Krüppel-like Factor 4 Regulates Intestinal Epithelial Cell Morphology and Polarity

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays a vital role in regulating cell lineage differentiation during development and maintaining epithelial homeostasis in the intestine. In normal intestine, KLF4 is predominantly expressed in the differentiated epithelial cells. It has been identified as a tumor suppressor in colorectal cancer. KLF4 knockout mice demonstrated a decrease in number of goblet cells in the colon, and conditional ablation of KLF4 from the intestinal epithelium led to altered epithelial homeostasis. However, the role of KLF4 in differentiated intestinal cells and colon cancer cells, as well as the mechanism by which it regulates homeostasis and represses tumorigenesis in the intestine is not well understood. In our study, KLF4 was partially depleted in the differentiated intestinal epithelial cells by a tamoxifen-inducible Cre recombinase. We found a significant increase in the number of goblet cells in the KLF4-deleted small intestine, suggesting that KLF4 is not only required for goblet cell differentiation, but also required for maintaining goblet cell numbers through its function in inhibiting cell proliferation. The number and position of Paneth cells also changed. This is consistent with the KLF4 knockout study using villin-Cre [1]. Through immunohistochemistry (IHC) staining and statistical analysis, we found that a stem cell and/or tuft cell marker, DCAMKL1, and a proliferation marker, Ki67, are affected by KLF4 depletion, while an enteroendocrine cell marker, neurotensin (NT), was not affected. In addition, we found KLF4 depletion altered the morphology and polarity of the intestinal epithelial cells. Using a three-dimensional (3D) intestinal epithelial cyst formation assay, we found that KLF4 is essential for cell polarity and crypt-cyst formation in human colon cancer cells. These findings suggest that, as a tumor suppressor in colorectal cancer, KLF4 affects intestinal epithelial cell morphology by regulating proliferation, differentiation and polarity of the cells

The anti-proliferative role of metformin in non-diabetic female patients with breast cancer: systematic review and meta-analysis of randomized control trials

Background. Usage of metformin in non-diabetic womenwith breast cancer is neither a common approachnor a conventional treatment modality. Metforminand chemotherapy have a high phenotypic variationin complete response rate among diabetic patientswith different types of cancer. Although the resultson salvage therapy were contradictory, we carried outa meta-analysis to evaluate the effect of the additionof metformin to conventional treatment on the prognosisin non-diabetic women who have breast cancer. Methods. A consummate literature search of Pub-Med, EMBASE, grey literature, and web of sciencewas conducted until 7th of March 2020. A total of 11randomized control trials were included in this metaanalysisincluding references related to metformin,breast cancer, and prognosis. The search was limited toEnglish language and human studies, including referencesrelated to metformin, breast cancer, and prognosis.We performed the meta-analysis using a randomand fixed-effects model, with hazard ratios and 95%confidence intervals (95% CI) as effect measures. Results. A total of 11 randomized control trials consistingof 1681 breast cancer patients without diabetesincluding 841 ones which received metformintreatementversus 840 ones not treated with metformin.The meta-analysis found that metformin has beenlinked with anti-proliferative role (HR 0.63, 95% CI0.59–0.71). Subgroup analysis showed an increased averageprogression of free survival which demonstratesthat metformin improves overall survival by 65% aftercorrecting for hormone-receptor/gene expression (HR0.35, 95% CI 0.15–0.84). Taking metformin as treatmentof breast cancer has been related to extendedsurvival rate. Conclusion. This meta-analysis supports the potentialrole of metformin in the management of cancer, as itmay increase progression free survival among nondiabeticpatients with breast cancer. More clinical trialsare needed for further exploration of metformin role,and to determine whether improvements in cancercare can be achieved with adding metformin to reducemortality or to improve overall survival in patients withbreast cancer

Effect of Sm-, Gd- codoping on structural modifications in aluminoborosilicate glasses under beta-irradiation

Two series of Sm-, Gd-codoped aluminoborosilicate glasses with different total rare earth content have been studied in order to examine the codoping effect on the structural modifications of beta-irradiated glasses. The data obtained by Electron Paramagnetic Resonance spectroscopy indicated that relative amount of Gd3+ ions located in network former position reveals non-linear dependence on Sm/Gd ratio. Besides, codoping leads to the evolution of the EPR signal attributed to defects created by irradiation: superhyperfine structure of boron oxygen hole centres EPR line becomes less noticeable and resolved with increase of Gd amount. This fact manifests that Gd3+ ions are mainly diluted in vicinity of the boron network. By Raman spectroscopy, we showed that the structural changes induced by the irradiation also reveal non-linear behaviour with Sm/Gd ratio. In fact, the shift of the Si-O-Si bending vibration modes has a clear minimum for the samples containing equal amount of Sm and Gd (50:50) in both series of the investigated glasses. In contrast, for single doped glass there is no influence of dopant's content on Si-O-Si shift (in case of Gd) or its diminution (in case of Sm) occurs which is explained by the reduction process influence. At the same time, no noticeable effect of codoping on Sm3+ intensity as well as on Sm2+ emission or on Sm reduction process was observed

Effects of Lipoic Acid Supplementation on Activities of Cyclooxygenases and Levels of Prostaglandins E 2 and F 2 Metabolites, in the Offspring of Rats with Streptozotocin-Induced Diabetes

Background. Our aim was to evaluate the protective effect of lipoic acid (LA) on fetal outcome of diabetic mothers. Methods. Diabetes was induced in female rats using streptozotocin and rats were made pregnant. Pregnant control (group 1; = 9; and group 2; = 7) or pregnant diabetic (group 3; = 10; and group 4; = 8) rats were treated daily with either LA (groups 2 and 4) or vehicle (groups 1 and 3) between gestational days 0 and 15. On day 15 of gestation, the fetuses, placentas, and membranes were dissected, examined morphologically, and then homogenized, to measure cyclooxygenase (COX) activities and metabolisms of prostaglandin (PG) E 2 (PGEM) and PGF 2 (PGFM) levels. The level of total glutathione was measured in the maternal liver and plasma and in all fetuses. Results. Supplementation of diabetic rats with LA was found to significantly ( &lt; 0.05) reduce resorption rates in diabetic rats and led to a significant ( &lt; 0.05) increase in liver, plasma, and fetuses total glutathione from LA-TD rats as compared to those from V-TD. Decreased levels of PGEM and elevated levels of PGFM in the fetuses, placentas, and membranes were characteristic of experimental diabetic gestation associated with malformation. The levels of PGEM in malformed fetuses from LA-TD mothers was significantly ( &lt; 0.05) higher than those in malformed fetuses from V-TD rats. Conclusions. LA treatment did not completely prevent the occurrence of malformations. Thus, other factors may be involved in the pathogenesis of the diabetesinduced congenital malformations

Protocol for evaluating a workplace intervention within the framework of consultations for suffering at work in French-speaking Switzerland.

Psychosocial suffering involves diverse human, social and economic costs. Some 34.4% of workers in Switzerland report chronic stress related to their jobs. Medical consultations for suffering at work aim to maintain-or renew-patients' abilities to make decisions and act following a diagnosis of psychological suffering related to their work; they also aim to help workers return to their workstations or remain there. Workplace interventions by consulting occupational physicians can go beyond the subjective issues: they can be offered to employees, in anticipation of a return to work when this appears feasible from the outset. To qualitatively evaluate perceptions of workplace interventions and identify their effects by collecting the verbatim statements of employees and their employers. Qualitative single-centre study of workplace interventions conducted by the Consultation Service for Suffering at Work's occupational physicians for patients seen between January 2015 to December 2017. Nineteen workplace interventions took place, out of 184 different consultations. The verbatim statements of employees and their employers will be collected over a variable timeframe, using semi-structured face-to-face interviews. These will then be recorded, transcribed and analysed. Fourteen patients refused the workplace intervention. Their professional path will be collected for comparison and exploratory purposes. This exploratory research project will provide a better understanding of the issues surrounding work-related psychological suffering and of which strategies support patients most effectively

Rituximab as monotherapy for the treatment of chronic active antibody-mediated rejection after kidney transplantation.

Chronic active antibody-mediated rejection (caAMR) is a major cause of allograft loss after kidney transplantation (1). The BANFF 2013 classification redefined caAMR by the presence of donor-specific anti-HLA antibodies (DSA) together with immuno-histopathological evidence for active vascular lesions of the endothelium (C4d deposits, glomerulitis, peritubular capillaritis) as well as evidence of chronic tissue injury (transplant glomerulopathy, peritubular capillary basement membrane multilayering or arterial intimal fibrosis) (2,3). Humoral immunity, detected by the presence of DSA, and B cells are considered pivotal in the development of caAMR. Gosset et al. showed that circulating DSA are responsible for accelerated allograft fibrosis independently of acute AMR (1). This article is protected by copyright. All rights reserved

Zebrafish Krüppel-Like Factor 4a Represses Intestinal Cell Proliferation and Promotes Differentiation of Intestinal Cell Lineages

BACKGROUND:Mouse krüppel-like factor 4 (Klf4) is a zinc finger-containing transcription factor required for terminal differentiation of goblet cells in the colon. However, studies using either Klf4(-/-) mice or mice with conditionally deleted Klf4 in their gastric epithelia showed different results in the role of Klf4 in epithelial cell proliferation. We used zebrafish as a model organism to gain further understanding of the role of Klf4 in the intestinal cell proliferation and differentiation. METHODOLOGY/PRINCIPAL FINDINGS:We characterized the function of klf4a, a mammalian klf4 homologue by antisense morpholino oligomer knockdown. Zebrafish Klf4a shared high amino acid similarities with human and mouse Klf4. Phylogenetic analysis grouped zebrafish Klf4a together with both human and mouse Klf4 in a branch with high bootstrap value. In zebrafish, we demonstrate that Klf4a represses intestinal cell proliferation based on results of BrdU incorporation, p-Histone 3 immunostaining, and transmission electron microscopy analyses. Decreased PepT1 expression was detected in intestinal bulbs of 80- and 102-hours post fertilization (hpf) klf4a morphants. Significant reduction of alcian blue-stained goblet cell number was identified in intestines of 102- and 120-hpf klf4a morphants. Embryos treated with γ-secretase inhibitor showed increased klf4a expression in the intestine, while decreased klf4a expression and reduction in goblet cell number were observed in embryos injected with Notch intracellular domain (NICD) mRNA. We were able to detect recovery of goblet cell number in 102-hpf embryos that had been co-injected with both klf4a and Notch 1a NICD mRNA. CONCLUSIONS/SIGNIFICANCE:This study provides in vivo evidence showing that zebrafih Klf4a is essential for the repression of intestinal cell proliferation. Zebrafish Klf4a is required for the differentiation of goblet cells and the terminal differentiation of enterocytes. Moreover, the regulation of differentiation of goblet cells in zebrafish intestine by Notch signaling at least partially mediated through Klf4a