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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Tue, 08/08/2017 - 14:30
Related Articles

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Breast Cancer Res. 2016 Jun 21;18(1):64

Authors: Zeng C, Guo X, Long J, Kuchenbaecker KB, Droit A, Michailidou K, Ghoussaini M, Kar S, Freeman A, Hopper JL, Milne RL, Bolla MK, Wang Q, Dennis J, Agata S, Ahmed S, Aittomäki K, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Arun BK, Arver B, Bacot F, Barrowdale D, Baynes C, Beeghly-Fadiel A, Benitez J, Bermisheva M, Blomqvist C, Blot WJ, Bogdanova NV, Bojesen SE, Bonanni B, Borresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Broeks A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldes T, Campbell I, Carpenter J, Chang-Claude J, Choi JY, Claes KB, Clarke C, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, De Leeneer K, Devilee P, Diez O, Domchek SM, Doody M, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Dworniczak B, Egan K, Eilber U, Einbeigi Z, Ejlertsen B, Ellis S, Frost D, Lalloo F, EMBRACE, Fasching PA, Figueroa J, Flyger H, Friedlander M, Friedman E, Gambino G, Gao YT, Garber J, García-Closas M, Gehrig A, Damiola F, Lesueur F, Mazoyer S, Stoppa-Lyonnet D, behalf of GEMO Study Collaborators, Giles GG, Godwin AK, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Haiman CA, Hallberg E, Hamann U, Hansen TV, Hart S, Hartikainen JM, Hartman M, Hassan N, Healey S, Hogervorst FB, Verhoef S, HEBON, Hendricks CB, Hillemanns P, Hollestelle A, Hulick PJ, Hunter DJ, Imyanitov EN, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jaworska-Bieniek K, Jensen UB, John EM, Joly Beauparlant C, Jones M, Kabisch M, Kang D, Karlan BY, Kauppila S, Kerin MJ, Khan S, Khusnutdinova E, Knight JA, Konstantopoulou I, Kraft P, Kwong A, Laitman Y, Lambrechts D, Lazaro C, Le Marchand L, Lee CN, Lee MH, Lester J, Li J, Liljegren A, Lindblom A, Lophatananon A, Lubinski J, Mai PL, Mannermaa A, Manoukian S, Margolin S, Marme F, Matsuo K, McGuffog L, Meindl A, Menegaux F, Montagna M, Muir K, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Newcomb PA, Nord S, Nussbaum RL, Offit K, Olah E, Olopade OI, Olswold C, Osorio A, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Peeters S, Peissel B, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Presneau N, Radice P, Rahman N, Ramus SJ, Rashid MU, Rennert G, Rhiem K, Rudolph A, Salani R, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Schoemaker MJ, Schürmann P, Seynaeve C, Shen CY, Shrubsole MJ, Shu XO, Sigurdson A, Singer CF, Slager S, Soucy P, Southey M, Steinemann D, Swerdlow A, Szabo CI, Tchatchou S, Teixeira MR, Teo SH, Terry MB, Tessier DC, Teulé A, Thomassen M, Tihomirova L, Tischkowitz M, Toland AE, Tung N, Turnbull C, van den Ouweland AM, van Rensburg EJ, Ven den Berg D, Vijai J, Wang-Gohrke S, Weitzel JN, Whittemore AS, Winqvist R, Wong TY, Wu AH, Yannoukakos D, Yu JC, Pharoah PD, Hall P, Chenevix-Trench G, KConFab, AOCS Investigators, Dunning AM, Simard J, Couch FJ, Antoniou AC, Easton DF, Zheng W

Abstract
BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.
RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.
CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

PMID: 27459855 [PubMed - indexed for MEDLINE]

Salt intake and eating habits of school-aged children.

Tue, 08/08/2017 - 14:30
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Salt intake and eating habits of school-aged children.

Hypertens Res. 2016 Nov;39(11):812-817

Authors: Ohta Y, Iwayama K, Suzuki H, Sakata S, Hayashi S, Iwashima Y, Takata A, Kawano Y

Abstract
Salt restriction is important for the prevention and treatment of hypertension; however, salt consumption is still high in Japan. Improvements in dietary habits, including salt reduction in childhood, may contribute to the prevention of hypertension. The aim of the present study was to investigate the salt intake of school-aged children and the relationship between their diet diary and actual salt intake. The subjects comprised 580 schoolchildren (471 elementary school pupils and 109 junior high school pupils) who wanted to evaluate their salt intake in Kuji, a northeast coastal area in Japan. We estimated salt intake using spot urine samples and a formula. Lifestyle was assessed using a questionnaire. We also evaluated the salt intake and the lifestyles of 440 parents. The estimated salt intakes of elementary school pupils, junior high school pupils and their parents were 7.1±1.5, 7.6±1.5 and 8.0±1.7 g per day, respectively. The proportion of lower-grade children who achieved the recommended salt intake was low. In the multivariate analysis, the estimated salt intake of school-aged children correlated with their age, estimated salt intake of their parents and the menu priorities of the household. The estimated salt intake of the parents was associated with female gender, obesity, age and the habitual consumption of bread and noodles. In conclusion, the estimated salt intake of school-aged children positively correlated with the estimated salt intake of their parents, and the proportion of lower-grade children who achieved the recommended salt intake was low. Guidance on salt restriction for children and their parents may reduce the salt intake of school-aged children.

PMID: 27357057 [PubMed - indexed for MEDLINE]

Magnolol suppresses the proliferation and invasion of cholangiocarcinoma cells via inhibiting the NF-κB signaling pathway.

Sun, 08/06/2017 - 13:16

Magnolol suppresses the proliferation and invasion of cholangiocarcinoma cells via inhibiting the NF-κB signaling pathway.

Biomed Pharmacother. 2017 Aug 02;94:474-480

Authors: Zhang FH, Ren HY, Shen JX, Zhang XY, Ye HM, Shen DY

Abstract
BACKGROUND: Magnolol has shown the potential anticancer properties against a variety of cancers. However, the role of magnolol in cholangiocarcinoma (CCA) cells is unknown. In this study, we assessed the effect of magnolol on the CCA cells.
METHODS: CCA cells were treated with magnolol in the absence or presence of TNFα, the activator for NF-κB. After co-incubation with magnolol, cell proliferation and growth were examined by MTT, colony formation and xenograft tumors; cell cycle was analyzed by flow cytometry; cell migration and invasion were detected by wound healing and transwell assays; the expression of PCNA, Ki67, CyclinD1, MMP-2, MMP-7 and MMP-9 and NF-κB pathway were evaluated by using Western blot.
RESULTS: Magnolol inhibited the abilities of CCA cell growth, migration and invasion accompanying with a decreased expression of PCNA, Ki67, MMP-2, MMP-7 and MMP-9 (all P<0.05).
TREATMENT: with magnolol induced cell cycle arrest in G1 phase with a downregulation of cell cycle protein CyclinD1 (all P<0.05). In addition, magnolol suppressed the expression of p-IκBα and p-P65 and the effect of magnolol on CCA cells could be inhibited by TNFα.
CONCLUSIONS: Magnolol could inhibit the growth, migration and invasion of CCA cells through regulation of NF-κB pathway, and these data indicate that magnolol is a potential candidate for treating of CCA.

PMID: 28779709 [PubMed - as supplied by publisher]

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

Sun, 08/06/2017 - 13:16
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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

Gut. 2017 Aug 04;:

Authors: Alberts R, de Vries EMG, Goode EC, Jiang X, Sampaziotis F, Rombouts K, Böttcher K, Folseraas T, Weismüller TJ, Mason AL, Wang W, Alexander G, Alvaro D, Bergquist A, Björkström NK, Beuers U, Björnsson E, Boberg KM, Bowlus CL, Bragazzi MC, Carbone M, Chazouillères O, Cheung A, Dalekos G, Eaton J, Eksteen B, Ellinghaus D, Färkkilä M, Festen EAM, Floreani A, Franceschet I, Gotthardt DN, Hirschfield GM, Hoek BV, Holm K, Hohenester S, Hov JR, Imhann F, Invernizzi P, Juran BD, Lenzen H, Lieb W, Liu JZ, Marschall HU, Marzioni M, Melum E, Milkiewicz P, Müller T, Pares A, Rupp C, Rust C, Sandford RN, Schramm C, Schreiber S, Schrumpf E, Silverberg MS, Srivastava B, Sterneck M, Teufel A, Vallier L, Verheij J, Vila AV, Vries B, Zachou K, International PSC Study Group, The UK PSC Consortium, Chapman RW, Manns MP, Pinzani M, Rushbrook SM, Lazaridis KN, Franke A, Anderson CA, Karlsen TH, Ponsioen CY, Weersma RK

Abstract
OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.
DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.
RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.
CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

PMID: 28779025 [PubMed - as supplied by publisher]

Diagnosis of monogenic liver diseases in childhood by Next-Generation Sequencing.

Sat, 08/05/2017 - 13:53

Diagnosis of monogenic liver diseases in childhood by Next-Generation Sequencing.

Clin Genet. 2017 Aug 04;:

Authors: Stalke A, Skawran B, Auber B, Illig T, Schlegelberger B, Junge N, Goldschmidt I, Leiskau C, von Neuhoff N, Baumann U, Pfister ED

Abstract
Next-Generation Sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients we detected pathogenic or likely pathogenic variants in ten different genes. We present six novel variants. 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symptoms or presented with additional signs. In another 13 out of 135 cases, we detected variants of unknown significance (VUS) in nine different genes. Only two of these patients showed characteristic phenotypes conclusive with the detected variants, whereas 11 patients showed unspecific or atypical phenotypes. Our multi-gene panel is a fast and comprehensive tool to diagnose inherited pediatric hepatopathies. We also illustrate the challenge of dealing with genetic variants and highlight arising clinical questions, especially in patients with atypical phenotypes.

PMID: 28776642 [PubMed - as supplied by publisher]

Social and Communicative Functions of Informed Consent Forms in East Asia and Beyond.

Sat, 08/05/2017 - 13:53
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Social and Communicative Functions of Informed Consent Forms in East Asia and Beyond.

Front Genet. 2017;8:99

Authors: Yoshizawa G, Sasongko TH, Ho CH, Kato K

Abstract
The recent research and technology development in medical genomics has raised new issues that are profoundly different from those encountered in traditional clinical research for which informed consent was developed. Global initiatives for international collaboration and public participation in genomics research now face an increasing demand for new forms of informed consent which reflect local contexts. This article analyzes informed consent forms (ICFs) for genomic research formulated by four selected research programs and institutes in East Asia - the Medical Genome Science Program in Japan, Universiti Sains Malaysia Human Research Ethics Committee in Malaysia, and the Taiwan Biobank and the Taipei Medical University- Joint Institutional Review Board in Taiwan. The comparative text analysis highlights East Asian contexts as distinct from other regions by identifying communicative and social functions of consent forms. The communicative functions include re-contact options and offering interactive support for research participants, and setting opportunities for family or community engagement in the consent process. This implies that informed consent cannot be validated solely with the completion of a consent form at the initial stage of the research, and informed consent templates can facilitate interactions between researchers and participants through (even before and after) the research process. The social functions consist of informing participants of possible social risks that include genetic discrimination, sample and data sharing, and highlighting the role of ethics committees. Although international ethics harmonization and the subsequent coordination of consent forms may be necessary to maintain the quality and consistency of consent process for data-intensive international research, it is also worth paying more attention to the local values and different settings that exist where research participants are situated for research in medical genomics. More than simply tools to gain consent from research participants, ICFs function rather as a device of social communication between research communities and civic communities in liaison with intermediary agents like ethics committees, genetic counselors, and public biobanks and databases.

PMID: 28775738 [PubMed]

Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo.

Sat, 08/05/2017 - 13:53
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Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo.

Eur Respir J. 2017 Aug;50(2):

Authors: Lehmann M, Korfei M, Mutze K, Klee S, Skronska-Wasek W, Alsafadi HN, Ota C, Costa R, Schiller HB, Lindner M, Wagner DE, Günther A, Königshoff M

Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor prognosis and limited therapeutic options. The incidence of IPF increases with age, and ageing-related mechanisms such as cellular senescence have been proposed as pathogenic drivers. The lung alveolar epithelium represents a major site of tissue injury in IPF and senescence of this cell population is probably detrimental to lung repair. However, the potential pathomechanisms of alveolar epithelial cell senescence and the impact of senolytic drugs on senescent lung cells and fibrosis remain unknown. Here we demonstrate that lung epithelial cells exhibit increased P16 and P21 expression as well as senescence-associated β-galactosidase activity in experimental and human lung fibrosis tissue and primary cells.Primary fibrotic mouse alveolar epithelial type (AT)II cells secreted increased amounts of senescence-associated secretory phenotype (SASP) factors in vitro, as analysed using quantitative PCR, mass spectrometry and ELISA. Importantly, pharmacological clearance of senescent cells by induction of apoptosis in fibrotic ATII cells or ex vivo three-dimensional lung tissue cultures reduced SASP factors and extracellular matrix markers, while increasing alveolar epithelial markers.These data indicate that alveolar epithelial cell senescence contributes to lung fibrosis development and that senolytic drugs may be a viable therapeutic option for IPF.

PMID: 28775044 [PubMed - in process]

Heart failure is associated with depletion of core intestinal microbiota.

Sat, 08/05/2017 - 13:53
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Heart failure is associated with depletion of core intestinal microbiota.

ESC Heart Fail. 2017 Aug;4(3):282-290

Authors: Luedde M, Winkler T, Heinsen FA, Rühlemann MC, Spehlmann ME, Bajrovic A, Lieb W, Franke A, Ott SJ, Frey N

Abstract
AIMS: In spite of current medical treatment approaches, mortality of chronic heart failure (HF) remains high and novel treatment modalities are thus urgently needed. A recent theory proposes a possible impact of the intestinal microbiome on the incidence and clinical course of heart failure. This study sought to systematically investigate, if there are specific changes of the intestinal microbiome in heart failure patients.
METHODS AND RESULTS: The intestinal microbiome of 20 patients with heart failure with reduced ejection fraction due to ischemic or dilated cardiomyopathy was investigated by applying high-throughput sequencing of the bacterial 16S rRNA gene. Microbial profiles were compared to those of matched controls in which heart failure was ruled out by clinical assessment and NT-proBNP serum levels (n = 20). According to the Shannon diversity index (which measures the intra-individual alpha-diversity) based on the distribution of operational taxonomic units (OTUs), HF cases showed a nominally significantly lower diversity index compared to controls (Pnom.  = 0.01), and testing for genera abundance showed a tendency towards a decreased alpha diversity of HF patients. Beta-diversity measures (inter-individual diversity) revealed a highly significant separation of HF cases and controls, (e.g. Pweighted UniFracv  = 0.004). Assessing the individual abundance of core measurable microbiota (CMM), a significant decrease of Coriobacteriaceae, Erysipelotrichaceae and Ruminococcaceae was observed on the family level. In line with that, Blautia, Collinsella, uncl. Erysipelotrichaceae and uncl. Ruminococcaceae showed a significant decrease in HF cases compared to controls on the genus level.
CONCLUSIONS: Heart failure patients showed a significantly decreased diversity of the intestinal microbiome as well as a downregulation of key intestinal bacterial groups. Our data point to an altered intestinal microbiome as a potential player in the pathogenesis and progression of heart failure.

PMID: 28772054 [PubMed]

Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy.

Sat, 08/05/2017 - 13:53
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Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy.

Circ Cardiovasc Genet. 2017 Aug;10(4):e001544

Authors: Haitjema S, Kofink D, van Setten J, van der Laan SW, Schoneveld AH, Eales J, Tomaszewski M, de Jager SCA, Pasterkamp G, Asselbergs FW, den Ruijter HM

Abstract
BACKGROUND: Recent studies found an immune regulatory role for Y chromosome and a relationship between loss of Y chromosome (LOY) in blood cells and a higher risk of cancer and mortality. Given involvement of immune cells in atherosclerosis, we hypothesized that LOY is associated with the severity of atherosclerotic plaque characteristics and outcome in men undergoing carotid endarterectomy.
METHODS AND RESULTS: LOY was quantified in blood and plaque from raw intensity genotyping data in men within the Athero-Express biobank study. Plaques were dissected, and the culprit lesions used for histology and the measurement of inflammatory proteins. We tested LOY for association with (inflammatory) atherosclerotic plaque phenotypes and cytokines and assessed the association of LOY with secondary events during 3-year follow-up. Of 366 patients with carotid endarterectomy, 61 exhibited some degree of LOY in blood. LOY was also present in atherosclerotic plaque lesions (n=8/242, 3%). LOY in blood was negatively associated with age (β=-0.03/10 y; r(2)=0.07; P=1.6×10(-7)) but not with cardiovascular disease severity at baseline. LOY in blood was associated with a larger atheroma size (odds ratio, 2.15; 95% confidence interval, 1.06-4.76; P=0.04); however, this association was not significant after correction for multiple testing. LOY was independently associated with secondary major cardiovascular events (hazard ratio=2.28; 95% confidence interval, 1.11-4.67; P=0.02) in blood when corrected for confounders.
CONCLUSIONS: In this hypothesis-generating study, LOY in blood is independently associated with secondary major cardiovascular events in a severely atherosclerotic population. Our data could indicate that LOY affects secondary outcome via other mechanisms than inflammation in the atherosclerotic plaque.

PMID: 28768751 [PubMed - in process]

SLC3A2, antigen of mAb 3G9, promotes migration and invasion by upregulating of mucins in gastric cancer.

Thu, 08/03/2017 - 13:32
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SLC3A2, antigen of mAb 3G9, promotes migration and invasion by upregulating of mucins in gastric cancer.

Oncotarget. 2017 Jul 25;:

Authors: Wang S, Han H, Hu Y, Yang W, Lv Y, Wang L, Zhang L, Ji J

Abstract
Solute carrier family 3 member 2 (SLC3A2) has been reported to be highly expressed in a variety of carcinomas. However, the function of SLC3A2 in gastric carcinoma (GC) has not been well explored. Monoclonal antibody (mAb) 3G9, generated from immunogen of various human GC cell lines, has been shown to bind to GC tissues specifically. In this study, we identified the target antigen of mAb 3G9 as SLC3A2, and detected the expression profile of SLC3A2 in a panel of gastric cancer cell lines and GC tumor tissues. We found that the increased expression of SLC3A2 was associated with serosal invasion in GC patients. Knockout of SLC3A2 suppressed the migration and invasion of BGC-823 cells in vitro and in vivo, whereas overexpression of SLC3A2 in NCI-N87 cells promoted the migration and invasion in vitro and in vivo. Mechanistic investigations suggested that MUC1, MUC16 and MUC5B were the downstream genes of SLC3A2 in GC cells. Taken together, our data suggested that SLC3A2 promoted the aggressive phenotype of GC by upregulating several mucin genes expression and may serve as a potential biomarker for diagnosis and target therapy.

PMID: 28768242 [PubMed - as supplied by publisher]

rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis.

Thu, 08/03/2017 - 13:32
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rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis.

Oncotarget. 2017 Jul 18;:

Authors: Chen WC, Wang WC, Lu HF, Okada Y, Chang WP, Chou YH, Chang HH, Huang JD, Chen DY, Chang WC

Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands, and may share some common genetic factors with other autoimmune disorders, such as ankylosing spondylitis (AS). Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in the Taiwanese population. In this study, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population. Based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project, we observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odds ratio (OR) = 0.6, p = 3.0 x 10-6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compare to other subjects (OR = 0.09, p = 5.6 x 10-3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2. In summary, this study replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.

PMID: 28767437 [PubMed - as supplied by publisher]

Echinacoside's nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin.

Thu, 08/03/2017 - 13:32
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Echinacoside's nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin.

J Cell Mol Med. 2017 Aug 02;:

Authors: Zhang Y, Long H, Zhou F, Zhu W, Ruan J, Zhao Y, Lu Y

Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6-hydroxydopamine (6-OHDA)-induced endoplasmic reticulum stress (ERS) in vivo and in vitro. ECH rescued cell viability in damaged cells and decreased 6-OHDA-induced reactive oxygen species accumulation in vitro. It also rescued tyrosine hydroxylase and dopamine transporter expression in the striatum, and decreased α-synuclein aggregation following 6-OHDA treatment in vivo. The validated mechanism of ECH activity was the reduction in the 6-OHDA-induced accumulation of seipin (Berardinelli-Seip congenital lipodystrophy 2). Seipin has been shown to be a key molecule related to motor neuron disease and was tightly associated with ERS in a series of in vivo studies. ECH attenuated seipinopathy by promoting seipin degradation via ubiquitination. ERS was relieved by ECH through the Grp94/Bip-ATF4-CHOP signal pathway.

PMID: 28767194 [PubMed - as supplied by publisher]

5'-tRNA-halves are dysregulated in clear cell renal cell carcinoma.

Thu, 08/03/2017 - 13:32
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5'-tRNA-halves are dysregulated in clear cell renal cell carcinoma.

J Urol. 2017 Jul 29;:

Authors: Zhao C, Tolkach Y, Schmidt D, Kristiansen G, Müller SC, Ellinger J

Abstract
PURPOSE: tRNA fragments are dysregulated in various malignancies. Our study was designed to determine the expression of four 5'-tRNA-halves in tissue and serum of clear cell renal cell carcinoma (ccRCC) patients.
MATERIALS AND METHODS: Tissue and serum samples of patients with ccRCC and non-malignant disease were collected prospectively in our Biobank. We isolated total RNA from 95 ccRCC and 50 normal renal tissues as well as serum RNA from 27 patients with ccRCC and 13 with non-malignant urological diseases. In order to determine specifically the expression of 5'-tRNA halves, we dephosphorylated and ligated an adaptor nucleotide to the 3'-end of the tRNA halves. The expression levels of four 5'-tRNA-halves (5'-tRNA-Arg-CCT, 5'-tRNA-Glu-CTC, 5'-tRNA-Leu-CAG, 5'-tRNA-Lys-TTT) were then measured by TaqMan-based qRT-PCR.
RESULTS: All studied 5'-tRNA-halves were downregulated in ccRCC tissues indicating a potential role as tumor suppressor. Furthermore, we noticed a decreased expression of 5'-tRNA-halves in patients with adverse clinicopathological parameters: All 5'-tRNA-halves were expressed at lower levels in in non-organ confined ccRCC and 5'-tRNA-Lys-TTT halves were inversely correlated with ISUP Grade. 5'-tRNA-Arg-CCT, 5'-tRNA-Glu-CTC and 5'-tRNA-Lys-TTT halves were circulating at lower levels in ccRCC patients compared to control subjects indicating its relevance as non-invasive biomarker.
CONCLUSIONS: 5'-tRNA halves have the potential as diagnostic and prognostic biomarker for patients with ccRCC. The 5'-tRNA-halves may act in a tumor suppressive manner which requires further research to confirm.

PMID: 28765068 [PubMed - as supplied by publisher]

Relationship between plasma bilirubin level and oxidative stress markers in HIV-infected patients on atazanavir- vs. efavirenz-based antiretroviral therapy.

Thu, 08/03/2017 - 13:32
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Relationship between plasma bilirubin level and oxidative stress markers in HIV-infected patients on atazanavir- vs. efavirenz-based antiretroviral therapy.

HIV Med. 2016 Oct;17(9):653-61

Authors: Estrada V, Monge S, Gómez-Garre MD, Sobrino P, Masiá M, Berenguer J, Portilla J, Viladés C, Martínez E, Blanco JR, CoRIS and the HIV Biobank integrated in the Spanish AIDS Research Network

Abstract
OBJECTIVES: Chronic oxidative stress (OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UDP-glucuronosyl-transferase 1A1 (UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line antiretroviral therapy (ART).
METHODS: A multicentre, prospective cohort study of HIV-infected patients who started first-line ART with either ATV/r or EFV was conducted. Lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO) and oxidized low-density lipoprotein (oxLDL) were measured for 145 patients in samples obtained at baseline and after at least 9 months of ART during which the initial regimen was maintained and the patient was virologically suppressed. The change in OS markers was modelled using multiple linear regressions adjusting for baseline values and confounders.
RESULTS: After adjustment for baseline variables, patients on ATV/r had a significantly greater decrease in Lp-PLA2 [estimated difference -16.3; 95% confidence interval (CI) -31.4, -1.25; P = 0.03] and a significantly smaller increase in OxLDL (estimated difference -21.8; 95% CI -38.0, -5.6; P < 0.01) relative to those on EFV, whereas changes in MPO were not significantly different (estimated difference 1.2; 95% CI -14.3, 16.7; P = 0.88). Adjusted changes in bilirubin were significantly greater for the ATV/r group than for the EFV group (estimated difference 1.33 mg/dL; 95% CI 1.03, 1.52 mg/dL; P < 0.01). Changes in bilirubin and changes in OS markers were significantly correlated.
CONCLUSIONS: When compared with EFV, ATV/r-based therapy was associated with lower levels of oxidative stress biomarkers, which was in part attributable to increased bilirubin levels.

PMID: 26935006 [PubMed - indexed for MEDLINE]

Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells.

Tue, 08/01/2017 - 22:36
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Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells.

Ann N Y Acad Sci. 2017 Jul 31;:

Authors: Lin HY, Hsieh MT, Cheng GY, Lai HY, Chin YT, Shih YJ, Nana AW, Lin SY, Yang YSH, Tang HY, Chiang IJ, Wang K

Abstract
Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin αv β3 for nonpeptide hormones. Interaction between hormones and integrin αv β3 can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin αv β3 . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin αv β3 blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. .

PMID: 28759712 [PubMed - as supplied by publisher]

Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank.

Tue, 08/01/2017 - 22:36
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Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank.

Nat Genet. 2017 Jul 31;:

Authors: Cortes A, Dendrou CA, Motyer A, Jostins L, Vukcevic D, Dilthey A, Donnelly P, Leslie S, Fugger L, McVean G

Abstract
Genetic discovery from the multitude of phenotypes extractable from routine healthcare data can transform understanding of the human phenome and accelerate progress toward precision medicine. However, a critical question when analyzing high-dimensional and heterogeneous data is how best to interrogate increasingly specific subphenotypes while retaining statistical power to detect genetic associations. Here we develop and employ a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Our method displays a more than 20% increase in power to detect genetic effects over other approaches and identifies new associations between classical human leukocyte antigen (HLA) alleles and common immune-mediated diseases (IMDs). By applying the approach to genetic risk scores (GRSs), we show the extent of genetic sharing among IMDs and expose differences in disease perception or diagnosis with potential clinical implications.

PMID: 28759005 [PubMed - as supplied by publisher]

Neurocardiology: Cardiovascular Changes and Specific Brain Region Infarcts.

Tue, 08/01/2017 - 22:36
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Neurocardiology: Cardiovascular Changes and Specific Brain Region Infarcts.

Biomed Res Int. 2017;2017:5646348

Authors: Zou R, Shi W, Tao J, Li H, Lin X, Yang S, Hua P

Abstract
There are complex and dynamic reflex control networks between the heart and the brain, including cardiac and intrathoracic ganglia, spinal cord, brainstem, and central nucleus. Recent literature based on animal model and clinical trials indicates a close link between cardiac function and nervous systems. It is noteworthy that the autonomic nervous-based therapeutics has shown great potential in the management of atrial fibrillation, ventricular arrhythmia, and myocardial remodeling. However, the potential mechanisms of postoperative brain injury and cardiovascular changes, particularly heart rate variability and the presence of arrhythmias, are not understood. In this chapter, we will describe mechanisms of brain damage undergoing cardiac surgery and focus on the interaction between cardiovascular changes and damage to specific brain regions.

PMID: 28758117 [PubMed - in process]

Tumor Organoids as a Pre-clinical Cancer Model for Drug Discovery.

Tue, 08/01/2017 - 22:36
Related Articles

Tumor Organoids as a Pre-clinical Cancer Model for Drug Discovery.

Cell Chem Biol. 2017 Jul 27;:

Authors: Weeber F, Ooft SN, Dijkstra KK, Voest EE

Abstract
Tumor organoids are 3D cultures of cancer cells that can be derived on an individual patient basis with a high success rate. This creates opportunities to build large biobanks with relevant patient material that can be used to perform drug screens and facilitate drug development. The high take rate will also allow side-by-side comparison to evaluate the translational potential of this model system to the patient. These tumors-in-a-dish can be established for a variety of tumor types including colorectal, pancreas, stomach, prostate, and breast cancers. In this review, we highlight what is currently known about tumor organoid culture, the advantages and challenges of the model system, compare it with other pre-clinical cancer models, and evaluate its value for drug development.

PMID: 28757181 [PubMed - as supplied by publisher]

A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma.

Sun, 07/30/2017 - 14:42

A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma.

Clin Endocrinol (Oxf). 2017 Jul 29;:

Authors: Shen CT, Zhang Y, Liu YM, Yin S, Zhang XY, Wei WJ, Sun ZK, Song HJ, Qiu ZL, Wang CR, Luo QY

Abstract
BACKGROUND: Although the incidence rate for thyroid cancer seems to have begun stabilizing in recent years, an increased rate of advanced stage of this disease has been reported. Additionally, distant metastasis is one of the most important prognostic factors of patients with papillary thyroid carcinoma (PTC). Unfortunately, the underlying mechanisms of distant metastasis as well as cell status like metabolism changes in distant metastatic tumors have not been clearly elucidated.
OBJECTIVE: To identify serum metabolic signature of distant metastatic PTC. DESIGN, PATIENTS AND MEASUREMENTSIN: this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) was used to analyze the serum from 77 patients diagnosed with PTC (37 in distant metastasis group and 40 in ablation group). Principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA)scores plots were used to analyze the data.
RESULTS: PCA and OPLS-DA analyses demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group. A total of 31 metabolites were identified which are related to amino acid, lipid, glucose, vitamin metabolism and diet/gut microbiota interaction. Pathway analysis showed 'alanine, aspartate and glutamate metabolism' and 'inositol phosphate metabolism' were the most relevant pathways.
CONCLUSION: Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis. Potential metabolic aberration in distant metastatic PTC could be involved in different biologic behaviors of tumor cells including proliferation, invasion/migration, and immune escape. Diet/gut microbiota produced metabolites could play an important role in these effects. This work may provide new clues to find the underlying mechanisms regarding to the distant metastasis of PTC as well as potential adjuvant therapy targets. This article is protected by copyright. All rights reserved.

PMID: 28755525 [PubMed - as supplied by publisher]

The Stockholm-3 (STHLM3) Model can Improve Prostate Cancer Diagnostics in Men Aged 50-69 yr Compared with Current Prostate Cancer Testing.

Sun, 07/30/2017 - 14:42
Related Articles

The Stockholm-3 (STHLM3) Model can Improve Prostate Cancer Diagnostics in Men Aged 50-69 yr Compared with Current Prostate Cancer Testing.

Eur Urol Focus. 2016 Nov 23;:

Authors: Eklund M, Nordström T, Aly M, Adolfsson J, Wiklund P, Brandberg Y, Thompson J, Wiklund F, Lindberg J, Presti JC, StLezin M, Clements M, Egevad L, Grönberg H

Abstract
Prostate cancer screening is associated with low specificity, unnecessary biopsies, and overdiagnosis. We have previously shown that the Stockholm-3 model (S3M) can reduce biopsies compared with using prostate-specific antigen (PSA) ≥3ng/ml as an indication for biopsy. Urologists in today's current prostate cancer testing (CPT) have access to numerous variables in addition to PSA (eg, age, ethnicity, family history, free PSA, PSA velocity, digital rectal examination, and prostate volume) to support biopsy decisions. We estimated the number of prostate cancers diagnosed and prostate biopsies performed if S3M replaced CPT in Stockholm, Sweden, by comparing biopsy results in 56 282 men who underwent PSA testing according to CPT in Stockholm in 2011 with the 47 688 men enrolled in the STHLM3 validation cohort 2012-2015. With the same sensitivity as CPT to diagnose Gleason score ≥7 prostate cancer, S3M was estimated to reduce the number of men biopsied by 53% (95% confidence interval [CI]: 41-65%), avoid 76% (95% CI: 67-81%) of negative biopsies, and reduce Gleason score 6 cancers by 23% (95% CI: 6-40%). S3M has the potential to improve prostate cancer diagnostics by better selecting men with high risk of GS ≥7 prostate cancer.
PATIENT SUMMARY: We modeled the effect the Stockholm-3 model would have on prostate cancer diagnostics if it replaced current clinical practice. We found that Stockholm-3 model may substantially reduce the number of biopsies, while maintaining the same sensitivity to diagnose clinically significant prostate cancer.

PMID: 28753803 [PubMed - as supplied by publisher]