Single-nucleotide polymorphisms in PSCA and the risk of breast cancer in a Chinese population.

This study explored the associations between common PSCA single-nucleotide polymorphisms (rs2294008, rs2978974, and rs2976392) and breast cancer among 560 breast cancer cases and 583 controls (Chinese Han women). We found rs2294008 was significantly associated with a high risk of breast cancer (homozygote model, odds ratio [OR]: 1.67, 95% confidence interval [CI]: 1.06–2.59; recessive, OR: 1.64, 95% CI: 1.06–2.53). And stratification by menopausal status revealed an association of the minor allele of rs2294008 with breast cancer risk among premenopausal (homozygote model, OR: 2.41, 95% CI: 1.03–5.66; recessive, OR: 2.80, 95 % CI: 1.21–6.47) and postmenopausal women (allele model, OR: 1.29, 95% CI: 1.01–1.65). Rs2978974 influenced the breast cancer risk among postmenopausal women in heterozygote model (OR: 1.47, 95% CI: 1.05–2.07). When stratified by clinicopathologic features, the T allele of rs2294008 was associated with progesterone receptor status (homozygote model, OR: 1.98, 95% CI: 1.08–3.63; recessive, OR: 1.87, 95% CI: 1.04–3.37), and the rs2976392 polymorphism was associated with high lymph node metastasis risk in homozygote model (OR: 2.09, 95%CI: 1.01–4.31). Further haplotype analysis suggested that Trs2294008 Ars2976392 Grs2978974haplotype enhances breast cancer risk (OR:1.52, 95%CI:1.23-1.89, P\u3c0.001). Therefore, among Chinese Han women, the PSCArs2294008, rs2978974, and rs2976392 minor alleles are associated with increased breast cancer risk especially in progesterone receptor positive breast cancer patients, with breast cancer risk in postmenopausal women, and with high lymph node metastasis risk, respectively. Moreover, Trs2294008 Ars2976392 Grs2978974 haplotype was associated with significantly increased risk of breast cancer

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition.

The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression

Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?

OBJECTIVE: To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. DESIGN: A nested case-control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. SETTING: A multicentre study in 16 academic medical centres in the USA. POPULATION: Low-risk nulliparous women. METHODS: Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9-12, 15-18 and 23-26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. MAIN OUTCOME MEASURES: Change in PlGF, sFlt-1 and sEng. RESULTS: Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64-99), 77% (95% CI 50-93) and 77% (95% CI 50-93) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. CONCLUSION: Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia

Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P \u3c 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P \u3c 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P \u3c 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES(-/-) knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES(-/-)), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8(+) and double-negative CD3(+)CD4(-)CD8(-) T cells in perivascular space and reduced vascular oxidative stress while FoxP3(+) T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = -0.3, P \u3c 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P \u3c 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.-Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension

Household Clustering of Escherichia coli Sequence Type 131 Clinical and Fecal Isolates According to Whole Genome Sequence Analysis

Background. Within-household sharing of strains from the resistance-associated H30R1 and H30Rx subclones of Escherichia coli sequence type 131 (ST131) has been inferred based on conventional typing data, but has been assessed minimally using whole genome sequence (WGS) analysis. Methods. Thirty-three clinical and fecal isolates of ST131-H30R1 and ST131-H30Rx, from 20 humans and pets in six households, underwent WGS analysis for comparison with 52 published ST131 genomes. Phylogenetic relationships were inferred using a bootstrapped maximum likelihood tree based on core genome sequence polymorphisms. Accessory traits were compared between phylogenetically similar isolates. Results. In the WGS-based phylogeny, isolates clustered strictly by household, in clades that were distributed widely across the phylogeny, interspersed between H30R1 and H30Rx comparison genomes. For only one household did the core genome phylogeny place epidemiologically unlinked isolates together with household isolates, but even there multiple differences in accessory genome content clearly differentiated these two groups. The core genome phylogeny supported within-household strain sharing, fecal-urethral urinary tract infection pathogenesis (with the entire household potentially providing the fecal reservoir), and instances of host-specific microevolution. In one instance the household\u27s index strain persisted for 6 years before causing a new infection in a different household member. Conclusions. Within-household sharing of E. coli ST131 strains was confirmed extensively at the genome level, as was long-term colonization and repeated infections due to an ST131-H30Rx strain. Future efforts toward surveillance and decolonization may need to address not just the affected patient but also other human and animal household members

Cancer Genomics and Biology 2015 – Meeting Report

The Cancer Genomics and Biology 2015 meeting embodied a three way collaboration among colleagues from the Global Cancer Genomics Consortium (GCGC), the Unifaith Cancer Institute China and Jiujiang University of China. The meeting marks the fifth and the last meeting of GCGC, which was formed in 2010. Previous four GCGC meetings have been held at the Tata Memorial Center- Mumbai, Institute of Molecular Medicine-Lisbon, and Graduate Medical School Kyoto University-Kyoto. In contrast to the genomic themes of the previous meetings, the 2015 conference theme was at the interface of laboratory and translation research and emerging therapeutics as reflected in the shared interests of all three collaborative entities – Cancer Genomics and Biology 2015. This year’s conference was co-organized by the Jiujiang University at the Run Run Shaw building, Jiujiang University, Jiujiang City, China, on November 13 and 14, 2015. The conference attracted over 174 participants with 13 platform presentations. Scientific sessions included a plenary and five platform scientific sessions with themes ranging from biomarkers, stem cells and markers of the tumor microenvironment, proteomics and epigenetics, big data, to hormone and expression profiles. The meeting concluded with closing remarks by conference co-chairs emphasizing with the need to broaden membership across the globe, establishing priorities, and redrafting a white paper to launch a new consortium

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links.

The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC. On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction

Urinary estrogen metabolites and self-reported infertility in women infected with Schistosoma haematobium

Background Schistosomiasis is a neglected tropical disease, endemic in 76 countries, that afflicts more than 240 million people. The impact of schistosomiasis on infertility may be underestimated according to recent literature. Extracts of Schistosoma haematobium include estrogen-like metabolites termed catechol-estrogens that down regulate estrogen receptors alpha and beta in estrogen responsive cells. In addition, schistosome derived catechol-estrogens induce genotoxicity that result in estrogen-DNA adducts. These catechol estrogens and the catechol-estrogen-DNA adducts can be isolated from sera of people infected with S. haematobium. The aim of this study was to study infertility in females infected with S. haematobium and its association with the presence of schistosome-derived catechol-estrogens. Methodology/Principal Findings A cross-sectional study was undertaken of female residents of a region in Bengo province, Angola, endemic for schistosomiasis haematobia. Ninety-three women and girls, aged from two (parents interviewed) to 94 years were interviewed on present and previous urinary, urogenital and gynecological symptoms and complaints. Urine was collected from the participants for egg-based parasitological assessment of schistosome infection, and for liquid chromatography diode array detection electron spray ionization mass spectrometry (LC/UV-DAD/ESI-MSn) to investigate estrogen metabolites in the urine. Novel estrogen-like metabolites, potentially of schistosome origin, were detected in the urine of participants who were positive for eggs of S. haematobium, but not detected in urines negative for S. haematobium eggs. The catechol-estrogens/ DNA adducts were significantly associated with schistosomiasis (OR 3.35; 95% CI 2.32–4.84; P≤0.001). In addition, presence of these metabolites was positively associated with infertility (OR 4.33; 95% CI 1.13–16.70; P≤0.05). Conclusions/Significance Estrogen metabolites occur widely in diverse metabolic pathways. In view of the statistically significant association between catechol-estrogens/ DNA adducts and self-reported infertility, we propose that an estrogen-DNA adduct mediated pathway in S. haematobium-induced ovarian hormonal deregulation could be involved. In addition, the catechol-estrogens/ DNA adducts described here represent potential biomarkers for schistosomiasis haematobia

Predicting Risk of End-Stage Liver Disease in Antiretroviral-Treated HIV/Hepatitis C Virus-Coinfected Patients

Background. End-stage liver disease (ESLD) is an important cause of morbidity among HIV/hepatitis C virus (HCV)-coinfected patients. Quantifying the risk of this outcome over time could help determine which coinfected patients should be targeted for risk factor modification and HCV treatment. We evaluated demographic, clinical, and laboratory variables to predict risk of ESLD in HIV/HCV-coinfected patients receiving antiretroviral therapy (ART). Methods. We conducted a retrospective cohort study among 6,016 HIV/HCV-coinfected patients who received ART within the Veterans Health Administration between 1997 and 2010. The main outcome was incident ESLD, defined by hepatic decompensation, hepatocellular carcinoma, or liver-related death. Cox regression was used to develop prognostic models based on baseline demographic, clinical, and laboratory variables, including FIB-4 and aspartate aminotransferase-to-platelet ratio index, previously validated markers of hepatic fibrosis. Model performance was assessed by discrimination and decision curve analysis. Results. Among 6,016 HIV/HCV patients, 532 (8.8%) developed ESLD over a median of 6.6 years. A model comprising FIB-4 and race had modest discrimination for ESLD (c-statistic, 0.73) and higher net benefit than alternative strategies of treating no or all coinfected patients at relevant risk thresholds. For FIB-4 \u3e3.25, ESLD risk ranged from 7.9% at 1 year to 26.0% at 5 years among non-blacks and from 2.4% at 1 year to 14.0% at 5 years among blacks. Conclusions. Race and FIB-4 provided important predictive information on ESLD risk among HIV/HCV patients. Estimating risk of ESLD using these variables could help direct HCV treatment decisions among HIV/HCV-coinfected patients

Erratum: Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype (The American Journal of Human Genetics (2019) 105(3) (616–624), (S0002929719303052), (10.1016/j.ajhg.2019.08.002))

© 2019 The Author(s) (The American Journal of Human Genetics 105, 616–624; September 5, 2019) In the originally published version of this article, the first author, Chikashi Tereo, had footnotes indicating affiliations with the first seven institutions. The correct affiliations are the first six plus footnote 17, indicating equal contribution. This error has been corrected here and online, and the authors and copyeditor express their regret for the mistake