Maternal Serum Meteorin Levels and the Risk of Preeclampsia

BACKGROUND: Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker. METHODS AND FINDINGS: Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included. CONCLUSIONS: The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia

PD-L1 Expression in Endometrial Carcinoma Cells and Intratumoral Immune Cells Differences Across Histologic and TCGA-based Molecular Subgroups

Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1/PD-L1 immunotherapy. We evaluated the expression of PD-L1 in carcinoma cells (Ca) and immune cells (ICs) across histopathologic and The Cancer Genome Atlas (TCGA) molecular subgroups of endometrial carcinoma (EC). Our study included 842 patients with EC. Direct sequencing of polymerase epsilon (POLE) exonuclease domain hot spots and conventional immunohistochemistry (MLH1, PMS2, MSH2, MSH6, p53) were conducted to identify TCGA classification-based molecular subgroups of EC: POLE-mutated, mismatch repair deficient, no specific molecular profile, and p53 aberrant. Multiplex immunohistochemistry was performed to evaluate PD-L1 expression in Ca and tumor-infiltrating ICs. PD-L1 expression in Ca and in ICs was detected in 8.6% and 27.7% of the cases, respectively. A combined positive score (CPS) was >= 1% in 19.4% of the samples. PD-L1 positivity in Ca and ICs, and CPS correlated with tumor T-cell density (P= 1% (P=0.037) positivity compared with early disease. In conclusion, PD-L1 expression profiles differ between molecular subclasses, histologic subtypes, and disease stage of EC. Prospective studies are needed to explore the predictive value of various PD-L1 scoring systems within the subgroups of EC. CPS presents methodological advantages over cell type-specific scoring systems.Peer reviewe

Clinical Significance of Colonic Diverticulosis Associated with Bowel Symptoms and Colon Polyp

This study was done to evaluate prospectively the clinical significance of colonic diverticulosis. In the 1,030 consecutive outpatients undergoing colonoscopy, the information on the demographics, the patterns of bowel symptoms, and the prevalence of colon polyp were analyzed according to the presence of colonic diverticulosis. The mean age of 1,030 patients were 52.2 yr and 59.3% were male. The prevalence of diverticulosis was 19.7% (203/1,030). Of 203 diverticulosis patients 85.2% were in proximal group, 5.4% in distal group and 9.4% in both group. Six (3.0%) patients were found to have diverticulitis. Multivariate logistic regression analysis showed that an old age, diabetes and the presence of polyp were significant factors associated with proximal or both diverticulosis. A significant difference was demonstrated between the patients of distal diverticular group and the controls for the symptom frequency scores within the previous 4 weeks. The items, which showed difference, were hard stool, urgency, flatus, chest discomfort and frequent urination. In conclusion, old age, diabetes and the presence of colon polyp were associated with proximal diverticulosis. The temporal symptoms were more frequent in distal diverticulosis than in proximal diverticulosis in the study subjects

ANKRD54 preferentially selects Bruton's Tyrosine Kinase (BTK) from a Human Src-Homology 3 (SH3) domain library

Bruton's Tyrosine Kinase (BTK) is a cytoplasmic protein tyrosine kinase with a fundamental role in B-lymphocyte development and activation. The nucleocytoplasmic shuttling of BTK is specifically modulated by the Ankyrin Repeat Domain 54 (ANKRD54) protein and the interaction is known to be exclusively SH3-dependent. To identify the spectrum of the ANKRD54 SH3-interactome, we applied phage-display screening of a library containing all the 296 human SH3 domains. The BTK-SH3 domain was the prime interactor. Quantitative western blotting analysis demonstrated the accuracy of the screening procedure. Revealing the spectrum and specificity of ANKRD54-interactome is a critical step toward functional analysis in cells and tissues.Peer reviewe

CXCR2 Signaling Protects Oligodendrocytes and Restricts Demyelination in a Mouse Model of Viral-Induced Demyelination

BACKGROUND: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis. METHODOLOGY/PRINCIPAL FINDINGS: JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV-induced apoptosis, readily activating caspase 3 and down regulating Bcl-2. CONCLUSION/SIGNIFICANCE: These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS

Antiviral mode of action of bovine dialyzable leukocyte extract against human immunodeficiency virus type 1 infection

<p>Abstract</p> <p>Background</p> <p>Bovine dialyzable leukocyte extract (bDLE) is derived from immune leukocytes obtained from bovine spleen. DLE has demonstrated to reduce transcription of Human Immunodeficiency Virus Type 1 (HIV-1) and inactivate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Therefore, we decided to clarify the mode of antiviral action of bDLE on the inhibition of HIV-1 infection through a panel of antiviral assays.</p> <p>Results</p> <p>The cytotoxicity, HIV-1 inhibition activity, residual infectivity of bDLE in HIV-1, time of addition experiments, fusion inhibition of bDLE for fusogenic cells and the duration of cell protection even after the removal of bDLE were all assessed in order to discover more about the mode of the antiviral action.</p> <p>HIV-1 infectivity was inhibited by bDLE at doses that were not cytotoxic for HeLa-CD4-LTR-β-gal cells. Pretreatment of HIV-1 with bDLE did not decrease the infectivity of these viral particles. Cell-based fusion assays helped to determine if bDLE could inhibit fusion of Env cells against CD4 cells by membrane fusion and this cell-based fusion was inhibited only when CD4 cells were treated with bDLE. Infection was inhibited in 80% compared with the positive (without EDL) at all viral life cycle stages in the time of addition experiments when bDLE was added at different time points. Finally, a cell-protection assay against HIV-1 infection by bDLE was performed after treating host cells with bDLE for 30 minutes and then removing them from treatment. From 0 to 7 hours after the bDLE was completely removed from the extracellular compartment, HIV-1 was then added to the host cells. The bDLE was found to protect the cells from HIV-1 infection, an effect that was retained for several hours.</p> <p>Conclusions</p> <p>bDLE acted as an antiviral compound and prevented host cell infection by HIV-1 at all viral life cycle stages. These cell protection effects lingered for hours after the bDLE was removed. Interestingly, bDLE inhibited fusion of fusogenic cells by acting only on CD4 cells. bDLE had no virucidal effect, but could retain its antiviral effect on target cells after it was removed from the extracellular compartment, protecting the cells from infection for hours.</p> <p>bDLE, which has no reported side effects or toxicity in clinical trials, should therefore be further studied to determine its potential use as a therapeutic agent in HIV-1 infection therapy, in combination with known antiretrovirals.</p

Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population

The vitamin D receptor (VDR) is an essential protein related to bone metabolism. Some VDR alleles are differentially distributed among ethnic populations and display variable patterns of linkage disequilibrium (LD). In this study, 200 unrelated Brazilians were genotyped using 21 VDR single nucleotide polymorphisms (SNPs) and 28 ancestry informative markers. The patterns of LD and haplotype distribution were compared among Brazilian and the HapMap populations of African (YRI), European (CEU) and Asian (JPT+CHB) origins. Conditional regression and haplotype-specific analysis were performed using estimates of individual genetic ancestry in Brazilians as a quantitative trait. Similar patterns of LD were observed in the 5′ and 3′ gene regions. However, the frequency distribution of haplotype blocks varied among populations. Conditional regression analysis identified haplotypes associated with European and Amerindian ancestry, but not with the proportion of African ancestry. Individual ancestry estimates were associated with VDR haplotypes. These findings reinforce the need to correct for population stratification when performing genetic association studies in admixed populations

TNFA and IL10 Gene Polymorphisms are not Associated with Periodontitis in Brazilians

IL-10 and TNF-α are cytokines that have complex and opposing roles in the inflammatory responses. G/A polymorphisms at position –1082 of IL10 and –308 of TNFA genes have been reported to influence the expression of IL-10 and TNF-α, respectively. The aim of this study was to investigate the association between the IL10 (-1082) and TNFA (- 308) gene polymorphisms with different clinical forms or severity of periodontitis in a sample of Brazilian individuals. DNA was obtained from oral swabs of 165 Brazilian individuals, which were divided into three groups: individuals with chronic periodontitis, aggressive periodontitis and individuals without clinical evidence of periodontitis. Evaluation of IL10 and TNFA polymorphisms was performed by RFLP analysis. Statistical analysis of data was performed using the χ2 likelihood ratio and Fisher`s exact test. No significant differences in the genotype and allele distribution of either IL10 or TNFA were observed among individuals with different clinical forms or with different degrees of severity of periodontitis. Moreover, combined analysis of IL10 and TNFA polymorphisms did not show any association with periodontal status. As conclusion, the IL10 and TNFA gene promoter polymorphisms investigated are not associated with different clinical forms of periodontitis or with severity of the disease in the Brazilian population polymorphisms