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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]

Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.

Tue, 08/22/2017 - 12:50

Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.

Radiother Oncol. 2017 Aug 16;:

Authors: Tonlaar N, Galoforo S, Thibodeau BJ, Ahmed S, Wilson TG, Yumpo Cardenas P, Marples B, Wilson GD

Abstract
BACKGROUND AND PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge where new treatments are required to supplement the current-standard-of care of concurrent chemoradiation. The PI3K/AKT/MTOR pathway has been identified from several next generation DNA sequencing studies to be commonly altered and activated in HNSCC.
MATERIAL AND METHODS: In this study we investigated the activity of PF-04691502, an orally active ATP-competitive, dual inhibitor of PI3K and mTOR, in combination with a clinically relevant fractionated radiation treatment in two contrasting, well characterized, low passage HNSCC models.
RESULTS: We found that PF-04691502 combined synergistically with radiation in the UT-SCC-14 model derived from a primary cancer but was ineffective in the UT-SCC-15 model which was derived from a nodal recurrence. Further examination of the status of key signaling pathways combined with next generation DNA sequencing of a panel of 160 cancer-associated genes revealed crucial differences between the two models that could account for the differential effect. The UT-SCC-15 cell line was characterized by a higher mutational burden, an excess of variants in the PI3K/AKT/MTOR pathway, increased constitutive activity of PI3K, AKT1 and 2 and MTOR and an inability to inhibit key phosphorylation events in response to the treatments.
CONCLUSION: This study clearly highlights the promise of agents such as PF-04691502 in selected HNSCCs but also emphasizes the need for molecular characterization and alternative treatment strategies in non-responsive HNSCCs.

PMID: 28823407 [PubMed - as supplied by publisher]

Protective Effects of Cryoprotectants and Lyoprotectants on the Survival of Persipeptide Producing Streptomyces zagrosensis UTMC 1154.

Sat, 08/19/2017 - 13:43

Protective Effects of Cryoprotectants and Lyoprotectants on the Survival of Persipeptide Producing Streptomyces zagrosensis UTMC 1154.

Biopreserv Biobank. 2017 Aug 18;:

Authors: Mohammadipanah F, Parvizi L, Hamedi J, Azizmohseni F

Abstract
Streptomyces sp. are bacteria recognized as the producers of more than half of the known bioactive compounds. Developing appropriate preservation methods for industrial strains of Streptomyces is necessary, as continuous subculture could have significant negative effects on their characteristics, including their potential to produce secondary metabolites. The effects of two common preservation methods on a bioactive metabolite producer, Streptomyces zagrosensis UTMC 1154, were studied. In the cryopreservation method, glycerol and dimethyl sulfoxide (DMSO) were evaluated as cryoprotectants. Three different suspending fluids including skimmed milk, sucrose+gelatin and Mist. dessicans were compared as the freeze-drying methods. Freeze-dried samples were stored at 4°C for 6 months and at 37°C for 1 and 2 weeks in an accelerated storage stability study, which approximately correspond to storage at 4°C for 10 and 20 years, respectively. Frozen samples were stored at -20°C, -70°C and in the vapor phase of liquid nitrogen for 6 months. Skimmed milk and DMSO were the most efficient protectants for survival and functional maintenance of the strain during the lyophilization and cryopreservation processes (p < 0.05), respectively. The survival rate of S. zagrosensis was 95.0% and 99.3% after 6 months of preservation by using skimmed milk as lyoprotectant and DMSO as the cryoprotectant, respectively. The obtained results showed that cryopreservation is the method of choice for long-term preservation of S. zagrosensis. Cryopreservation also led to only 1%-3% reduction in the biological activity of the strain after 6 months preservation in vapor phase of the liquid nitrogen.

PMID: 28820614 [PubMed - as supplied by publisher]

Retrospectively assessed physical work environment during working life and risk of sickness absence and labour market exit among older workers.

Sat, 08/19/2017 - 13:43

Retrospectively assessed physical work environment during working life and risk of sickness absence and labour market exit among older workers.

Occup Environ Med. 2017 Aug 17;:

Authors: Sundstrup E, Hansen ÅM, Mortensen EL, Poulsen OM, Clausen T, Rugulies R, Møller A, Andersen LL

Abstract
OBJECTIVE: To determine the prospective association between retrospectively assessed physical work environment during working life and prospectively assessed sickness absence and labour market exit among older workers.
METHODS: Using Cox regression analyses we estimated the 4-year to 6-year prospective risk of register-based long-term sickness absence (LTSA), disability pension, early retirement and unemployment from exposure to different physical work environmental factors during working life among 5076 older workers (age 49-63 at baseline) from the Copenhagen Aging and Midlife Biobank cohort.
RESULTS: Very hard physical work throughout working life was a risk factor for LTSA (HR 1.66,95% CI 1.32 to 2.07), disability pension (HR 2.21,95% CI 1.04 to 4.72) and early retirement (HR 1.57,95% CI 1.13 to 2.17). Both short-term (<10 years) and long-term (≥20 years) exposures to lifting or carrying of heavy burdens predicted the risk of LTSA (HRs 1.49-1.56) and disability pension (HRs 2.26-3.29). In contrast, exposure to dust was associated with LTSA and disability pension only following 20 or more exposure years.
CONCLUSIONS: Retrospectively assessed hard physical work during working life and exposure to several factors in the physical work environment, especially heavy lifting, were important for labour market exit and sickness absence. This study underscores the importance of reducing physical work exposures throughout the working life course for preventing sickness absence and premature exit from the labour market.

PMID: 28819019 [PubMed - as supplied by publisher]

Transparency of Biobank Access in Canada: An Assessment of Industry Access and the Availability of Information on Access Policies and Resulting Research.

Sat, 08/19/2017 - 13:43

Transparency of Biobank Access in Canada: An Assessment of Industry Access and the Availability of Information on Access Policies and Resulting Research.

J Empir Res Hum Res Ethics. 2017 Aug 01;:1556264617723137

Authors: Gibson SG, Axler RE, Lemmens T

Abstract
A key issue impacting public trust in biobanks is how these resources are utilized, including who is given access to biobank data and samples. To assess the conditions under which researchers are given access to Canadian biobanks, we reviewed websites and contacted Canadian biobanks to determine the availability of information on access policies and procedures; research resulting from access biobank data and samples; and conditions on private industry access to biobanks. We also conducted expert interviews with key Canadian stakeholders ( n = 11) to obtain their perspectives on biobank transparency and access policies. Among 21 Canadian biobanks, there was wide variation in the access information made publicly available, and the majority of these allowed access by industry applicants. Biobanks should be governed by the principles of transparency, accountability, and accessibility, and attention must be given to the conditions around the commercialization of biobank-based research.

PMID: 28818009 [PubMed - as supplied by publisher]

Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice.

Sat, 08/19/2017 - 13:43
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Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice.

Oncotarget. 2017 Feb 21;8(8):13059-13072

Authors: Sommer J, Mahli A, Freese K, Schiergens TS, Kuecuekoktay FS, Teufel A, Thasler WE, Müller M, Bosserhoff AK, Hellerbrand C

Abstract
Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis.Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal β-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression.

PMID: 28055957 [PubMed - indexed for MEDLINE]

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Thu, 08/17/2017 - 16:00
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Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Transl Psychiatry. 2017 Aug 15;7(8):e1205

Authors: Wigmore EM, Clarke TK, Howard DM, Adams MJ, Hall LS, Zeng Y, Gibson J, Davies G, Fernandez-Pujals AM, Thomson PA, Hayward C, Smith BH, Hocking LJ, Padmanabhan S, Deary IJ, Porteous DJ, Nicodemus KK, McIntosh AM

Abstract
Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

PMID: 28809859 [PubMed - in process]

A Five-year Surveillance of Carbapenemase-producing Klebsiella pneumoniae in a Pediatric Hospital in China Reveals Increased Predominance of NDM-1.

Thu, 08/17/2017 - 16:00
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A Five-year Surveillance of Carbapenemase-producing Klebsiella pneumoniae in a Pediatric Hospital in China Reveals Increased Predominance of NDM-1.

Biomed Environ Sci. 2017 Aug;30(8):562-569

Authors: Dong F, Lu J, Wang Y, Shi J, Zhen JH, Chu P, Zhen Y, Han SJ, Guo YL, Song WQ

Abstract
OBJECTIVE: To characterize carbapenem (CPM)-non-susceptible Klebsiella pneumoniae (K. pneumoniae) and carbape-nemase produced by these strains isolated from Beijing Children's Hospital based on a five-year surveillance.
METHODS: The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonix100 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis.
RESULTS: In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 (53.1%) strains carried the blaIMP gene, and IMP-4 and IMP-8 were detected in 92 (96.8%) and 3 (3.2%) IMP-producing isolates, respectively. 65 (36.3%) strains carried the blaNDM-1 gene. 6 (3.4%) strains carried the blaKPC gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 (NDM-1) producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%.
CONCLUSION: High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children's Hospital. The production of IMP-4 and NDM-1 metallo-β-lactamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.

PMID: 28807096 [PubMed - in process]

Improvement of myocardial infarction risk prediction via inflammation-associated metabolite biomarkers.

Thu, 08/17/2017 - 16:00
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Improvement of myocardial infarction risk prediction via inflammation-associated metabolite biomarkers.

Heart. 2017 Aug;103(16):1278-1285

Authors: Ward-Caviness CK, Xu T, Aspelund T, Thorand B, Montrone C, Meisinger C, Dunger-Kaltenbach I, Zierer A, Yu Z, Helgadottir IR, Harris TB, Launer LJ, Ganna A, Lind L, Eiriksdottir G, Waldenberger M, Prehn C, Suhre K, Illig T, Adamski J, Ruepp A, Koenig W, Gudnason V, Emilsson V, Wang-Sattler R, Peters A

Abstract
OBJECTIVE: The comprehensive assaying of low-molecular-weight compounds, for example, metabolomics, provides a unique tool to uncover novel biomarkers and understand pathways underlying myocardial infarction (MI). We used a targeted metabolomics approach to identify biomarkers for MI and evaluate their involvement in the pathogenesis of MI.
METHODS AND RESULTS: Using three independent, prospective cohorts (KORA S4, KORA S2 and AGES-REFINE), totalling 2257 participants without a history of MI at baseline, we identified metabolites associated with incident MI (266 cases). We also investigated the association between the metabolites and high-sensitivity C reactive protein (hsCRP) to understand the relation between these metabolites and systemic inflammation. Out of 140 metabolites, 16 were nominally associated (p<0.05) with incident MI in KORA S4. Three metabolites, arginine and two lysophosphatidylcholines (LPC 17:0 and LPC 18:2), were selected as biomarkers via a backward stepwise selection procedure in the KORA S4 and were significant (p<0.0003) in a meta-analysis comprising all three studies including KORA S2 and AGES-REFINE. Furthermore, these three metabolites increased the predictive value of the Framingham risk score, increasing the area under the receiver operating characteristic score in KORA S4 (from 0.70 to 0.78, p=0.001) and AGES-REFINE study (from 0.70 to 0.76, p=0.02), but was not observed in KORA S2. The metabolite biomarkers attenuated the association between hsCRP and MI, indicating a potential link to systemic inflammatory processes.
CONCLUSIONS: We identified three metabolite biomarkers, which in combination increase the predictive value of the Framingham risk score. The attenuation of the hsCRP-MI association by these three metabolites indicates a potential link to systemic inflammation.

PMID: 28255100 [PubMed - indexed for MEDLINE]

Human epididymis protein 4 immunostaining of malignant ascites differentiates cancer of Müllerian origin from gastrointestinal cancer.

Thu, 08/17/2017 - 16:00
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Human epididymis protein 4 immunostaining of malignant ascites differentiates cancer of Müllerian origin from gastrointestinal cancer.

Cancer. 2017 Mar;125(3):197-204

Authors: Stiekema A, Van de Vijver KK, Boot H, Broeks A, Korse CM, van Driel WJ, Kenter GG, Lok CA

Abstract
BACKGROUND: An accurate diagnosis of cancer of Müllerian origin is required before the initiation of treatment. An overlap in clinical presentation and cytological, histological, or imaging studies with other nongynecological tumors does occur. Therefore, immunocytochemistry markers are used to determine tumor origin. Human epididymis protein 4 (HE4) is overexpressed in tissue of epithelial ovarian cancer (EOC). It has shown to be a sensitive and specific serum marker for EOC and to be of value for the differentiation between EOC and ovarian metastases of gastrointestinal origin. The objective of the current study was to evaluate HE4 immunocytochemistry in malignant ascites for differentiation between cancer of Müllerian origin, including EOC, and adenocarcinomas of the gastrointestinal tract.
METHODS: Cytological specimens of 115 different adenocarcinomas (45 EOCs, 46 cases of gastric cancer, and 24 cases of colorectal cancer) were stained for HE4, paired box 8 (PAX8), and other specific markers.
RESULTS: 91% of the ascites samples from patients with EOC stained for both HE4 and PAX8. The 4 samples without HE4 staining were a clear cell carcinoma, a low-grade serous adenocarcinoma, an undifferentiated adenocarcinoma, and a neuroendocrine carcinoma. All high-grade serous adenocarcinomas (n = 37, 100%) stained with HE4, compared with 94% that stained positively for PAX8. In cases of gastric or colorectal cancer, 25% and 21% of cases, respectively, stained positive for HE4. No PAX8 staining was observed in colorectal or gastric adenocarcinomas.
CONCLUSIONS: HE4 staining in ascites is feasible and appears to have a high sensitivity for high-grade serous ovarian cancer. HE4 is a useful addition to the current panel of immunocytochemistry markers for the diagnosis of EOC and for differentiation with gastrointestinal adenocarcinomas. Cancer Cytopathol 2017;125:197-204. © 2016 American Cancer Society.

PMID: 28199067 [PubMed - indexed for MEDLINE]