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RORγt(+) Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.

Tue, 08/29/2017 - 13:19
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RORγt(+) Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.

Cancer Res. 2017 Mar 01;77(5):1083-1096

Authors: Irshad S, Flores-Borja F, Lawler K, Monypenny J, Evans R, Male V, Gordon P, Cheung A, Gazinska P, Noor F, Wong F, Grigoriadis A, Fruhwirth GO, Barber PR, Woodman N, Patel D, Rodriguez-Justo M, Owen J, Martin SG, Pinder SE, Gillett CE, Poland SP, Ameer-Beg S, McCaughan F, Carlin LM, Hasan U, Withers DR, Lane P, Vojnovic B, Quezada SA, Ellis P, Tutt AN, Ng T

Abstract
Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt(+) group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt(+)ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083-96. ©2017 AACR.

PMID: 28082403 [PubMed - indexed for MEDLINE]

The heritable basis of gene-environment interactions in cardiometabolic traits.

Tue, 08/29/2017 - 13:19
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The heritable basis of gene-environment interactions in cardiometabolic traits.

Diabetologia. 2017 Mar;60(3):442-452

Authors: Poveda A, Chen Y, Brändström A, Engberg E, Hallmans G, Johansson I, Renström F, Kurbasic A, Franks PW

Abstract
AIMS/HYPOTHESIS: Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions.
METHODS: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software.
RESULTS: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h (2)) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction.
CONCLUSIONS/INTERPRETATION: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.

PMID: 28004149 [PubMed - indexed for MEDLINE]

Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease.

Sun, 08/27/2017 - 12:37

Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease.

Mov Disord. 2017 Aug 26;:

Authors: Trezzi JP, Galozzi S, Jaeger C, Barkovits K, Brockmann K, Maetzler W, Berg D, Marcus K, Betsou F, Hiller K, Mollenhauer B

Abstract
OBJECTIVE: The purpose of this study was to profile cerebrospinal fluid (CSF) from early-stage PD patients for disease-related metabolic changes and to determine a robust biomarker signature for early-stage PD diagnosis.
METHODS: By applying a non-targeted and mass spectrometry-driven approach, we investigated the CSF metabolome of 44 early-stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age- and gender-matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tübingen cohort).
RESULTS: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers-mannose, threonic acid, and fructose-and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800.
CONCLUSION: We identified PD-specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early-stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early-stage PD. © 2017 International Parkinson and Movement Disorder Society.

PMID: 28843022 [PubMed - as supplied by publisher]

Procoagulant imbalance in premenopausal women with chronic migraine.

Sun, 08/27/2017 - 12:37
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Procoagulant imbalance in premenopausal women with chronic migraine.

Neurology. 2017 Aug 25;:

Authors: Ferroni P, Barbanti P, Aurilia C, Egeo G, Fofi L, La Farina F, Valente MG, De Marchis ML, Spila A, Palmirotta R, Della-Morte D, Guadagni F

PMID: 28842452 [PubMed - as supplied by publisher]

C4 Nephritic Factors in C3 Glomerulopathy: A Case Series.

Sat, 08/26/2017 - 18:10
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C4 Nephritic Factors in C3 Glomerulopathy: A Case Series.

Am J Kidney Dis. 2017 Aug 22;:

Authors: Zhang Y, Meyer NC, Fervenza FC, Lau W, Keenan A, Cara-Fuentes G, Shao D, Akber A, Fremeaux-Bacchi V, Sethi S, Nester CM, Smith RJH

Abstract
BACKGROUND: C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases.
STUDY DESIGN: Case series.
SETTING & PARTICIPANTS: 168 patients with C3G (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G biobank.
OUTCOMES: Patient-purified immunoglobulin Gs were tested for C4 nephritic factors (C4NeFs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement.
MEASUREMENTS: C4NeFs were detected using a modified hemolytic assay.
RESULTS: C4NeFs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. C4NeFs were associated with dysregulation of C3 and C5 convertases, and they appear to stabilize these convertases in a dose-dependent manner. C4NeFs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein. The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4NeFs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls.
LIMITATIONS: In addition to C4NeFs, 2 patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3NeFs).
CONCLUSIONS: The finding of C4NeFs in a small percentage of patients with C3G highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients.

PMID: 28838767 [PubMed - as supplied by publisher]

Glycosaminoglycans are involved in bacterial adherence to lung cells.

Sat, 08/26/2017 - 18:10
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Glycosaminoglycans are involved in bacterial adherence to lung cells.

BMC Infect Dis. 2017 May 02;17(1):319

Authors: Rajas O, Quirós LM, Ortega M, Vazquez-Espinosa E, Merayo-Lloves J, Vazquez F, García B

Abstract
BACKGROUND: Lower respiratory infections are among the top ten causes of death worldwide. Since pathogen to cell adhesion is a crucial step in the infection progress, blocking the interaction between eukaryotic receptors and bacterial ligands may enable the pathogenesis process to be stopped. Cell surface glycosaminoglycans (GAGs) are known to be mediators in the adhesion of diverse bacteria to different cell types, making it of interest to examine their involvement in the attachment of various pathogenic bacteria to lung cells, including epithelial cells and fibroblasts.
METHODS: The function of cell surface GAGs in bacterial adhesion was studied by reducing their levels through inhibiting their biosynthesis and enzymatic degradation, as well as in binding competition experiments with various species of GAGs. The participation of the different bacterial adhesins in attachment was evaluated through competition with two peptides, both containing consensus heparin binding sequences. Blocking inhibition assays using anti-syndecans and the enzymatic removal of glypicans were conducted to test their involvement in bacterial adhesion. The importance of the fine structure of GAGs in the interaction with pathogens was investigated in competition experiments with specifically desulfated heparins.
RESULTS: The binding of all bacteria tested decreased when GAG levels in cell surface of both lung cells were diminished. Competition experiments with different types of GAGs showed that heparan sulfate chains are the main species involved. Blocking or removal of cell surface proteoglycans evidenced that syndecans play a more important role than glypicans. The binding was partially inhibited by peptides including heparin binding sequences. Desulfated heparins also reduced bacterial adhesion to different extents depending on the bacterium and the sulfated residue, especially in fibroblast cells.
CONCLUSIONS: Taken together, these data demonstrate that the GAG chains of the cell surface are involved in the adhesion of bacterial adhesins to lung cells. Heparan sulfate seems to be the main species implicated, and binding is dependent on the sulfation pattern of the molecule. These data could facilitate the development of new anti-infective strategies, enabling the development of new procedures for blocking the interaction between pathogens and lung cells more effectively.

PMID: 28464847 [PubMed - indexed for MEDLINE]

Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.

Sat, 08/26/2017 - 18:10
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Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.

Nucleic Acids Res. 2017 Apr 20;45(7):4131-4141

Authors: Zangari J, Ilie M, Rouaud F, Signetti L, Ohanna M, Didier R, Roméo B, Goldoni D, Nottet N, Staedel C, Gal J, Mari B, Mograbi B, Hofman P, Brest P

Abstract
Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223-3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA.

PMID: 27994032 [PubMed - indexed for MEDLINE]

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

Sat, 08/26/2017 - 18:10
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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

J Med Genet. 2016 May;53(5):298-309

Authors: Easton DF, Lesueur F, Decker B, Michailidou K, Li J, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Dennis J, Ahmad J, Thompson ER, Damiola F, Pertesi M, Voegele C, Mebirouk N, Robinot N, Durand G, Forey N, Luben RN, Ahmed S, Aittomäki K, Anton-Culver H, Arndt V, Australian Ovarian Cancer Study Group, Baynes C, Beckman MW, Benitez J, Van Den Berg D, Blot WJ, Bogdanova NV, Bojesen SE, Brenner H, Chang-Claude J, Chia KS, Choi JY, Conroy DM, Cox A, Cross SS, Czene K, Darabi H, Devilee P, Eriksson M, Fasching PA, Figueroa J, Flyger H, Fostira F, García-Closas M, Giles GG, Glendon G, González-Neira A, Guénel P, Haiman CA, Hall P, Hart SN, Hartman M, Hooning MJ, Hsiung CN, Ito H, Jakubowska A, James PA, John EM, Johnson N, Jones M, Kabisch M, Kang D, kConFab Investigators, Kosma VM, Kristensen V, Lambrechts D, Li N, Lifepool Investigators, Lindblom A, Long J, Lophatananon A, Lubinski J, Mannermaa A, Manoukian S, Margolin S, Matsuo K, Meindl A, Mitchell G, Muir K, NBCS Investigators, Nevelsteen I, van den Ouweland A, Peterlongo P, Phuah SY, Pylkäs K, Rowley SM, Sangrajrang S, Schmutzler RK, Shen CY, Shu XO, Southey MC, Surowy H, Swerdlow A, Teo SH, Tollenaar RA, Tomlinson I, Torres D, Truong T, Vachon C, Verhoef S, Wong-Brown M, Zheng W, Zheng Y, Nevanlinna H, Scott RJ, Andrulis IL, Wu AH, Hopper JL, Couch FJ, Winqvist R, Burwinkel B, Sawyer EJ, Schmidt MK, Rudolph A, Dörk T, Brauch H, Hamann U, Neuhausen SL, Milne RL, Fletcher O, Pharoah PD, Campbell IG, Dunning AM, Le Calvez-Kelm F, Goldgar DE, Tavtigian SV, Chenevix-Trench G

Abstract
BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

PMID: 26921362 [PubMed - indexed for MEDLINE]

Oversight of Genomic Data Sharing: What Roles for Ethics and Data Access Committees?

Fri, 08/25/2017 - 13:05

Oversight of Genomic Data Sharing: What Roles for Ethics and Data Access Committees?

Biopreserv Biobank. 2017 Aug 24;:

Authors: Shabani M, Dove ES, Murtagh M, Knoppers BM, Borry P

Abstract
Discussions regarding responsible genomic data sharing often center around ethical and legal issues such as the consent, privacy, and confidentiality of individuals, families, and communities. To ensure the ethical grounds of genomic data sharing, oversight by both research ethics and Data Access Committees (DACs) across the research lifecycle is warranted. In this article, we review these oversight practices and argue that they reveal a compelling need to clarify the scope of ethical considerations by oversight bodies and to delineate core elements such as "objectionable" data uses. Ethical oversight of genomic data sharing would be considerably improved if the relevant ethical considerations by research ethics and DACs were coordinated. We therefore suggest several mechanisms to achieve greater clarification of ethical considerations by these committees, as well as greater communication and coordination between both to ensure robust and sustained ethical oversight of genomic data sharing.

PMID: 28836815 [PubMed - as supplied by publisher]

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results.

Fri, 08/25/2017 - 13:05
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Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results.

Int J Cardiovasc Imaging. 2017 Aug 23;:

Authors: Suinesiaputra A, Sanghvi MM, Aung N, Paiva JM, Zemrak F, Fung K, Lukaschuk E, Lee AM, Carapella V, Kim YJ, Francis J, Piechnik SK, Neubauer S, Greiser A, Jolly MP, Hayes C, Young AA, Petersen SE

Abstract
UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland-Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV -6.4 ± 9.0 ml, 0.853 (mean ± SD of the differences, ICC) EDV -3.0 ± 11.6 ml, 0.937; SV 3.4 ± 9.8 ml, 0.855; and EF 3.5 ± 5.1%, 0.586. Although LV mass was consistently overestimated (29.9 ± 17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future.

PMID: 28836039 [PubMed - as supplied by publisher]

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery.

Fri, 08/25/2017 - 13:05
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MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery.

Sci Rep. 2017 Aug 23;7(1):9262

Authors: Krauskopf J, de Kok TM, Hebels DG, Bergdahl IA, Johansson A, Spaeth F, Kiviranta H, Rantakokko P, Kyrtopoulos SA, Kleinjans JC

Abstract
Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

PMID: 28835693 [PubMed - in process]

Horse spermatogonial stem cell cryopreservation: feasible protocols and potential biotechnological applications.

Thu, 08/24/2017 - 14:12
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Horse spermatogonial stem cell cryopreservation: feasible protocols and potential biotechnological applications.

Cell Tissue Res. 2017 Aug 22;:

Authors: Costa GMJ, Avelar GF, Lacerda SMSN, Figueiredo AFA, Tavares AO, Rezende-Neto JV, Martins FGP, França LR

Abstract
The establishment of proper conditions for spermatogonial stem cells (SSCs) cryopreservation and storage represents an important biotechnological approach for the preservation of the genetic stock of valuable animals. This study demonstrates the effects of different cryopreservation protocols on the survival rates and phenotypic expression of SSCs in horses. The cells were enzymatically isolated from testes of eight adult horses. After enrichment and characterization of germ cells in the suspension, the feasibility of several cryopreservation protocols were evaluated. Three different cryomedia compositions, associated with three different methods of freezing (vitrification, slow-freezing and fast-freezing) were evaluated. Based on the rates of viable SSCs found before and after thawing, as well as the number of recovered cells after cryopreservation, the best results were obtained utilizing the DMSO-based cryomedia associated with the slow-freezing method. In addition, when isolated cells were cultured in vitro, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and immunofluorescence analysis indicated that the cryopreserved cells were as metabolically active as the fresh cells and were also expressing typical SSCs proteins (VASA, NANOS2 and GFRA1). Therefore, our results indicate that equine SSCs can be cryopreserved without impairment of structure, function, or colony-forming abilities.

PMID: 28831567 [PubMed - as supplied by publisher]

Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.

Thu, 08/24/2017 - 14:12
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Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.

Sci Rep. 2017 Aug 22;7(1):9065

Authors: Hsieh CL, Liu CM, Chen HA, Yang ST, Shigemura K, Kitagawa K, Yamamichi F, Fujisawa M, Liu YR, Lee WH, Chen KC, Shen CN, Lin CC, Chung LWK, Sung SY

Abstract
Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

PMID: 28831065 [PubMed - in process]

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Thu, 08/24/2017 - 14:12
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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Hum Mol Genet. 2016 Sep 01;25(17):3863-3876

Authors: Wyszynski A, Hong CC, Lam K, Michailidou K, Lytle C, Yao S, Zhang Y, Bolla MK, Wang Q, Dennis J, Hopper JL, Southey MC, Schmidt MK, Broeks A, Muir K, Lophatananon A, Fasching PA, Beckmann MW, Peto J, Dos-Santos-Silva I, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guénel P, Truong T, Bojesen SE, Nordestgaard BG, González-Neira A, Benitez J, Neuhausen SL, Brenner H, Dieffenbach AK, Meindl A, Schmutzler RK, Brauch H, GENICA Network, Nevanlinna H, Khan S, Matsuo K, Ito H, Dörk T, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kosma VM, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu AH, Van Den Berg D, Lambrechts D, Wildiers H, Chang-Claude J, Rudolph A, Radice P, Peterlongo P, Couch FJ, Olson JE, Giles GG, Milne RL, Haiman CA, Henderson BE, Dumont M, Teo SH, Wong TY, Kristensen V, Zheng W, Long J, Winqvist R, Pylkäs K, Andrulis IL, Knight JA, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Klevebring D, Czene K, Hooning MJ, van den Ouweland AM, Darabi H, Shu XO, Gao YT, Cox A, Blot W, Signorello LB, Shah M, Kang D, Choi JY, Hartman M, Miao H, Hamann U, Jakubowska A, Lubinski J, Sangrajrang S, McKay J, Toland AE, Yannoukakos D, Shen CY, Wu PE, Swerdlow A, Orr N, Simard J, Pharoah PD, Dunning AM, Chenevix-Trench G, Hall P, Bandera E, Amos C, Ambrosone C, Easton DF, Cole MD

Abstract
Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10(-19)) and identify 13 additional linked variants (r(2 )>( )0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10(-15) - 5.6 × 10(-17)). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

PMID: 27402876 [PubMed - indexed for MEDLINE]

Dietary and lifestyle determinants of acrylamide and glycidamide hemoglobin adducts in non-smoking postmenopausal women from the EPIC cohort.

Thu, 08/24/2017 - 14:12
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Dietary and lifestyle determinants of acrylamide and glycidamide hemoglobin adducts in non-smoking postmenopausal women from the EPIC cohort.

Eur J Nutr. 2017 Apr;56(3):1157-1168

Authors: Obón-Santacana M, Lujan-Barroso L, Freisling H, Cadeau C, Fagherazzi G, Boutron-Ruault MC, Kaaks R, Fortner RT, Boeing H, Ramón Quirós J, Molina-Montes E, Chamosa S, Castaño JM, Ardanaz E, Khaw KT, Wareham N, Key T, Trichopoulou A, Lagiou P, Naska A, Palli D, Grioni S, Tumino R, Vineis P, De Magistris MS, Bueno-de-Mesquita HB, Peeters PH, Wennberg M, Bergdahl IA, Vesper H, Riboli E, Duell EJ

Abstract
PURPOSE: Acrylamide was classified as 'probably carcinogenic' to humans in 1994 by the International Agency for Research on Cancer. In 2002, public health concern increased when acrylamide was identified in starchy, plant-based foods, processed at high temperatures. The purpose of this study was to identify which food groups and lifestyle variables were determinants of hemoglobin adduct concentrations of acrylamide (HbAA) and glycidamide (HbGA) in 801 non-smoking postmenopausal women from eight countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
METHODS: Biomarkers of internal exposure were measured in red blood cells (collected at baseline) by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) . In this cross-sectional analysis, four dependent variables were evaluated: HbAA, HbGA, sum of total adducts (HbAA + HbGA), and their ratio (HbGA/HbAA). Simple and multiple regression analyses were used to identify determinants of the four outcome variables. All dependent variables (except HbGA/HbAA) and all independent variables were log-transformed (log2) to improve normality. Median (25th-75th percentile) HbAA and HbGA adduct levels were 41.3 (32.8-53.1) pmol/g Hb and 34.2 (25.4-46.9) pmol/g Hb, respectively.
RESULTS: The main food group determinants of HbAA, HbGA, and HbAA + HbGA were biscuits, crackers, and dry cakes. Alcohol intake and body mass index were identified as the principal determinants of HbGA/HbAA. The total percent variation in HbAA, HbGA, HbAA + HbGA, and HbGA/HbAA explained in this study was 30, 26, 29, and 13 %, respectively.
CONCLUSIONS: Dietary and lifestyle factors explain a moderate proportion of acrylamide adduct variation in non-smoking postmenopausal women from the EPIC cohort.

PMID: 26850269 [PubMed - indexed for MEDLINE]

Improvement of a Simple and Cost-Effective Passive Cooling Rate-Controlled Device for Cell/Tissue Cryopreservation.

Wed, 08/23/2017 - 14:59
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Improvement of a Simple and Cost-Effective Passive Cooling Rate-Controlled Device for Cell/Tissue Cryopreservation.

Biopreserv Biobank. 2017 Aug 22;:

Authors: Huang Y, Wang J, Zhou X, Peng J, Zhang Z, Shen L, Gao F, Cao Y

Abstract
The currently used commercial cooling-rate control device is the liquid nitrogen controlled rate freezer (LNF), which has some shortcomings such as high cost, high liquid nitrogen consumption, and potential operational risks in quality control. Based on thermophysical properties of new materials, we improved, manufactured, and optimized a reliable yet simple device named the "passive cooling rate-controlled device (PCD)" with real-time temperature tracing. In this study, using the improved PCD we cryopreserved human umbilical vein endothelial cells (HUVECs) and compared the results with a standard commercial CryoMed LNF. The temperature profiles and cooling rates of the HUVEC samples in a cryopreservation solution (with dimethyl sulfoxide [DMSO] in 10% v/v concentration) were measured and automatically recorded by the PCD during the controlled cooling process. This study and experimental results showed that the HUVEC survival rates after cryopreservation using the PCD have no significant difference from those using the CryoMed LNF and that the improved PCD is a user-friendly, reliable, and low-cost device to ensure an optimal slow cooling rate ranging from -0.5 to -1°C/min for the cryopreservation. Considering the advantages of low cost, durability, reliability, and no liquid nitrogen consumption for the cooling process, it is concluded that the PCD is an excellent controlled cooling device to achieve a desired optimal cooling rate for cell/tissue cryopreservation.

PMID: 28829621 [PubMed - as supplied by publisher]

New anionic carbosilane dendrons functionalized with a DO3A ligand at the focal point for the prevention of HIV-1 infection.

Wed, 08/23/2017 - 14:59
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New anionic carbosilane dendrons functionalized with a DO3A ligand at the focal point for the prevention of HIV-1 infection.

Antiviral Res. 2017 Aug 18;:

Authors: Moreno S, Sepúlveda-Crespo D, de la Mata FJ, Gómez R, Muñoz-Fernández MÁ

Abstract
Novel third-generation polyanionic carbosilane dendrons with sulfonate or carboxylate end-groups and functionalized with a DO3A ligand at the focal point, and their corresponding copper complexes, have been prepared as antiviral compounds to prevent HIV-1 infection. The topology enables the compound to have an excellent chelating agent, DO3A, while keeping anionic peripheral groups for a therapeutic action. In this study, the cytotoxicity and anti-HIV-1 abilities of carboxylate- (5) or sulfonate-terminated (6) dendrons containing DO3A and their copper complexes (7 or 8) were evaluated. All compounds showed low cytotoxicity and demonstrated potent and broad-spectrum anti-HIV-1 activity in vitro. We also assessed the mode of antiviral action on the inhibition of HIV-1 through a panel of different in vitro antiviral assays. Our results show that copper-free dendron 6 protects the epithelial monolayer from short-term cell disruption. Copper-free dendrons 5 and 6 exert anti-HIV-1 activity at an early stage of the HIV-1 lifecycle by binding to the envelope glycoproteins of HIV-1 and by interacting with the CD4 cell receptor and blocking the binding of gp120 to CD4, and consequently HIV-1 entry. These findings show that copper-free dendrons 5 and 6 have a high potency against HIV-1 infection, confirming their non-specific ability and suggesting that these compounds deserve further study as potential candidate microbicides to prevent HIV-1 transmission.

PMID: 28827122 [PubMed - as supplied by publisher]

Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe.

Wed, 08/23/2017 - 14:59
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Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe.

J Alzheimers Dis. 2017 Aug 17;:

Authors: Miller AM, Balasa M, Blennow K, Gardiner M, Rutkowska A, Scheltens P, Teunissen CE, Visser PJ, Winblad B, Waldemar G, Lawlor B

Abstract
BACKGROUND: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.
OBJECTIVE: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.
METHODS: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe; their biomarker platform preferences, lumbar puncture methodologies, and application of reference values and cut-offs for CSF analysis.
RESULTS: 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% performed lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis. 43% report using normal reference ranges derived from publications.
CONCLUSION: Variations in attitude and practice relating to CSF biomarkers, widely recognized as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centers. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application to further their use for the diagnostic evaluation of dementia.

PMID: 28826189 [PubMed - as supplied by publisher]

Ketogenic Diet and Other Dietary Intervention Strategies in the Treatment of Cancer.

Wed, 08/23/2017 - 14:59
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Ketogenic Diet and Other Dietary Intervention Strategies in the Treatment of Cancer.

Curr Med Chem. 2017;24(12):1170-1185

Authors: Vergati M, Krasniqi E, Monte GD, Riondino S, Vallone D, Guadagni F, Ferroni P, Roselli M

Abstract
Pre-clinical and clinical studies have investigated the role of a dysregulated metabolism in the sustainability of tumor initiation and progression. One of the most familiar metabolic alterations encountered in several types of cancers is the upregulation of glycolysis, which is also maintained in conditions of normal oxygen tension (aerobic glycolysis, Warburg effect) while oxidative phosphorylation is apparently reduced. As a result, cancer cells convert most incoming glucose to lactate. Although more rapid, adenosine triphosphate (ATP) production by glycolysis is less efficient in terms of ATP generated per unit of glucose consumed than oxidative phosphorylation. The consequence is that tumor cells require an abnormally higher rate of glucose compared to the normal counterpart. New evidence shows that other metabolic substrates such as glutamine may also have an important role in cancer metabolism. Ketogenic diet (KD) replaces all but non-starchy vegetable carbohydrates with low to moderate amounts of proteins and high amounts of monounsaturated and polyunsaturated fats. The rationale of KD is valid both because it lowers carbohydrate uptake possibly leading to cancer cell starvation and apoptosis and, at the same time, increases the levels of ketone bodies available for energy production in normal cells but not in cancer cells which have an allegedly downregulated oxidative phosphorylation. For this reason, several authors speculate on the possibility to evaluate KD as a novel approach in the treatment of cancer. In this review we will assess the data supporting the use of such alimentary regimen and its impact on tumor development and progression.

PMID: 28093985 [PubMed - indexed for MEDLINE]

Systematic Evaluation of Corticosteroid Use in Obese and Non-obese Individuals: A Multi-cohort Study.

Tue, 08/22/2017 - 12:50

Systematic Evaluation of Corticosteroid Use in Obese and Non-obese Individuals: A Multi-cohort Study.

Int J Med Sci. 2017;14(7):615-621

Authors: Savas M, Wester VL, Staufenbiel SM, Koper JW, van den Akker ELT, Visser JA, van der Lely AJ, Penninx BWJH, van Rossum EFC

Abstract
Background: Although the use of corticosteroids has been linked to high incidence of weight gain, no data are available concerning the differences in corticosteroid use between a diverse obese population and non-obese individuals. The main purpose of this study was to systematically explore the use of corticosteroids in obese subjects compared to non-obese controls. In addition, we also explored self-reported marked weight gain within obese subjects. Methods: Two hundred seventy-four obese outpatients (median [range] BMI: 40.1 kg/m(2) [30.5-67.0]), and 526 non-obese controls (BMI: 24.1 kg/m(2) [18.6-29.9]) from two different Dutch cohort studies were included. Corticosteroid use at the time of clinic or research site visit for up to the preceding three months was recorded in detail. Medical records and clinical data were evaluated with regard to age and body mass index in relation to corticosteroid use, single or multiple type use, and administration forms. Results: Recent corticosteroid use was nearly twice as high for obese subjects than for non-obese controls (27.0% vs. 11.9% and 14.8%, both P<.001). Largest differences were found for use of local corticosteroids, in particular inhaled forms, and simultaneous use of multiple types. Marked weight gain was self-reported during corticosteroid use in 10.5% of the obese users. Conclusion: Corticosteroid use, especially the inhaled agents, is higher in obese than in non-obese individuals. Considering the potential systemic effects of also local corticosteroids, caution is warranted on the increasing use in the general population and on its associations with weight gain.

PMID: 28824292 [PubMed - in process]