Elevated expression of serine protease HtrA1 in preeclampsia and its role in trophoblast cell migration and invasion

Objective: Aberrant expression of developmentally regulated genes during placental development could affect fetal growth and contribute to preeclampsia. Expression of serine protease HtrA1 is developmentally regulated with the highest expression in decidua capsularis, compared with ectoplacental cone, and with the highest expression during later stages of pregnancy, compared with early stages. This study was designed to determine the expression of HtrA1 in placental tissues from control and preeclamptic pregnancies and to determine the effect of HtrA1 expression in trophoblast cell migration and invasion. Study Design: HtrA1 expression was assessed by immunohistochemistry in placentas from gestational age-matched preeclamptic and control pregnancies. HtrA1 expression in extravillous trophoblast cells, HTR-8/SVneo, was assessed by immunoblotting and immunofluorescence microscopy. Finally, the effect of ectopic expression of HtrA1 on cell migration and invasion was determined in HTR-8/SVneo cells. Results: Higher expression of HtrA1 was detected in placental tissues collected from patients with early-onset preeclampsia, compared with those from gestational age-matched control samples. Moreover, ectopic expression of HtrA1 significantly attenuates HTR-8/SVneo cell migration and invasion. Conclusion: Higher expression of HtrA1 is associated with early-onset preeclampsia and may affect trophoblast cell migration and invasion. © 2008 Mosby, Inc. All rights reserved

Unique cellular and mitochondrial defects mediate FK506-induced islet β-cell dysfunction

OBJECTIVE: Determine biological mechanisms involved in post transplantation diabetes mellitus caused by the immunosuppressant FK506. METHODS: INS-1 cells and isolated rat islets were incubated with vehicle or FK506 and harvested at 24 hr intervals. Cells were assessed for viability, apoptosis, proliferation, cell insulin secretion and content. Gene expression studies by microarray analysis, qPCR and motifADE analysis of the microarray data identified potential FK506-mediated pathways and regulatory motifs. Mitochondrial functions, including cell respiration, mitochondrial content and bioenergetics were assessed. RESULTS: Cell replication, viability, insulin secretion, oxygen consumption, and mitochondrial content were decreased (p < 0.05) 1.2-, 1.27-, 1.77-, 1.32-, and 1.43-fold, respectively after 48 hr FK506 treatment. Differences increased with time. FK506 (50 ng/ml) and Cyclosporine A (800 ng/ml) had comparable effects. FK 506 significantly decreased mitochondrial content and mitochondrial bioenergetics and showed a trend towards decreased oxygen consumption in isolated islets. Cell apoptosis and proliferation, mitochondrial DNA copy number and ATP/ADP ratios were not significantly affected. Pathway analysis of microarray data showed FK506 modification of pathways involving ATP metabolism, membrane trafficking and cytoskeleton remodeling. PGC1-α mRNA was down-regulated by FK506. MotifADE identified nuclear factor of activated T-cells (NFAT), an important mediator of β cell survival and function, as a potential factor mediating both up- and down-regulation of gene expression. CONCLUSIONS: At pharmacologically relevant concentrations FK506 decreases insulin secretion and reduces mitochondrial density and function without changing apoptosis rates, suggesting that post transplantation diabetes induced by FK506 may be mediated by its effects on mitochondrial function

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 7 10 '21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 7 10 '10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 7 10 '8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 7 10 '13 and 3.63 7 10 '11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL. \ua9 2014 Nature America, Inc. All rights reserved

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science. © The Author(s) 2019. Published by Oxford University Press