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Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo.

Sat, 01/13/2018 - 12:41
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Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo.

Oncotarget. 2016 May 03;7(18):26374-87

Authors: Chen CH, Liu YM, Pan SL, Liu YR, Liou JP, Yen Y

Abstract
In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers.

PMID: 27029060 [PubMed - indexed for MEDLINE]

Human Tumor Tissue-Based 3D In Vitro Invasion Assays.

Thu, 01/11/2018 - 12:48

Human Tumor Tissue-Based 3D In Vitro Invasion Assays.

Methods Mol Biol. 2018;1731:213-221

Authors: Åström P, Heljasvaara R, Nyberg P, Al-Samadi A, Salo T

Abstract
Here we describe a protocol to utilize human benign leiomyoma tissue in in vitro 3D model that enables an assessment of cell invasion. The chapter also describes detailed instructions for image analysis to quantify the results. Leiomyoma is a benign tumor of the uterus which mimics authentic components of the tumor microenvironment including fibroblasts, vessels, collagen fibers, and extracellular protein composition. The leiomyoma invasion model represents a superior 3D model for cell invasion studies compared to the other non-human organotypic models.

PMID: 29318556 [PubMed - in process]

Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.

Thu, 01/11/2018 - 12:48

Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.

Transl Psychiatry. 2018 Jan 10;8(1):9

Authors: Hall LS, Adams MJ, Arnau-Soler A, Clarke TK, Howard DM, Zeng Y, Davies G, Hagenaars SP, Maria Fernandez-Pujals A, Gibson J, Wigmore EM, Boutin TS, Hayward C, Scotland G, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Porteous DJ, Deary IJ, Thomson PA, Haley CS, McIntosh AM

Abstract
Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.

PMID: 29317602 [PubMed - in process]

PD-L1 expression in basaloid squamous cell lung carcinoma: Relationship to PD-1+ and CD8+ tumor-infiltrating T cells and outcome.

Thu, 01/11/2018 - 12:48
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PD-L1 expression in basaloid squamous cell lung carcinoma: Relationship to PD-1+ and CD8+ tumor-infiltrating T cells and outcome.

Mod Pathol. 2016 Dec;29(12):1552-1564

Authors: Ilie M, Falk AT, Butori C, Chamorey E, Bonnetaud C, Long E, Lassalle S, Zahaf K, Vénissac N, Mouroux J, Cohen C, Brambilla E, Marquette CH, Hofman V, Hofman P

Abstract
PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell carcinoma. However, the expression pattern of PD-L1 and the presence of CD8+ and PD-1+ tumor-infiltrating T cells in the basaloid variant of squamous cell carcinoma remain unknown. immunohistochemistry analysis of PD-L1 expression, with three recently validated monoclonal antibodies used in clinical trials (clones SP142, SP263, and 28-8), and detection of CD8+ and PD-1+ tumor-infiltrating T cells was performed on whole-tissue sections from 56 patients following surgery for basaloid squamous cell carcinoma. Data were correlated to clinicopathological parameters and outcome. Fair to poor concordance was observed between the SP142 vs SP263 clones, and SP142 vs 28-8 (κ range, 0.018-0.412), while the 28-8 and SP263 demonstrated a strong correlation in both the tumor cell and immune cell compartments (κ=0.883, and κ=0.721). Expression of PD-L1 correlated with a high content of CD8+ and PD-1+ tumor-infiltrating T cells when using SP142 (P=0.012; P=0.022), but not with SP263 or 28-8 (P=0.314; P=0.611). In the multivariate analysis, we found significantly better disease-free and overall survival rates for high PD-L1 expression with SP142, CD8+ and PD-1+ tumor-infiltrating T cells (P=0.003; P=0.007). No significant prognosis value was observed for SP263 and 28-8 clones, except a correlation between improved overall survival and SP263 in the univariate analysis (P=0.039), not confirmed in the multivariate model. In conclusion, we report that the expression of PD-L1 and the content of CD8+ and PD-1+ tumor-infiltrating T cells is an independent indicator of better outcome in basaloid squamous cell carcinoma patients, although the observed effect is dependent on the PD-L1 immunohistochemistry assay.

PMID: 27562497 [PubMed - indexed for MEDLINE]

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

Wed, 01/10/2018 - 12:59

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

Alzheimers Dement. 2018 Jan 06;:

Authors: van der Lee SJ, Teunissen CE, Pool R, Shipley MJ, Teumer A, Chouraki V, Melo van Lent D, Tynkkynen J, Fischer K, Hernesniemi J, Metspalu A, Singh-Manoux A, Verhoeven A, Willemsen G, de Leeuw FA, Wagner H, van Dongen J, Hertel J, Budde K, Willems van Dijk K, Weinhold L, Ikram MA, Pietzner M, Perola M, Wagner M, Friedrich N, Slagboom PE, Scheltens P, Yang Q, Gertzen RE, Egert S, Li S, Hankemeier T, van Beijsterveldt CEM, Ramachandran V, Maier W, Peeters CFW, Jörgen Grabe H, Ramirez A, Seshadri S, Haller T, Kivimäki M, Salomaa V, Demirkan A, Boomsma D, van der Flier WM, Amin N, van Duijn CM

Abstract
INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions.
METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined.
RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors.
DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.

PMID: 29316447 [PubMed - as supplied by publisher]

Circulating Anti-Müllerian Hormone and Breast Cancer Risk: A Study in Ten Prospective Cohorts.

Wed, 01/10/2018 - 12:59

Circulating Anti-Müllerian Hormone and Breast Cancer Risk: A Study in Ten Prospective Cohorts.

Int J Cancer. 2018 Jan 08;:

Authors: Ge W, Clendenen TV, Afanasyeva Y, Koenig KL, Agnoli C, Brinton LA, Dorgan JF, Eliassen AH, Falk RT, Hallmans G, Hankinson SE, Hoffman-Bolton J, Key TJ, Krogh V, Nichols HB, Sandler DP, Schoemaker MJ, Sluss PM, Sund M, Swerdlow AJ, Visvanathan K, Liu M, Zeleniuch-Jacquotte A

Abstract
A strong positive association has been observed between circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case-control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme-linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (ptrend across quartiles < 0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top versus bottom quartile of AMH was 1.60 (95% CI = 1.31-1.94). Though the test for interaction was not statistically significant (pinteraction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: ORQ4-Q1 = 1.96, 95% CI = 1.46-2.64, ptrend <0.0001; ER+/PR-: ORQ4-Q1 = 0.82, 95% CI = 0.40-1.68, ptrend = 0.51; ER-/PR+: ORQ4-Q1 = 3.23, 95% CI =0.48-21.9, ptrend = 0.26; ER-/PR-: ORQ4-Q1 = 1.15, 95% CI = 0.63-2.09, ptrend = 0.60. The association was observed for both pre- (ORQ4-Q1 = 1.35, 95% CI= 1.05-1.73) and post-menopausal (ORQ4-Q1 =1.61, 95% CI = 1.03 - 2.53) breast cancer (pinteraction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH. This article is protected by copyright. All rights reserved.

PMID: 29315564 [PubMed - as supplied by publisher]

ISBER President's Message: The Intent of the ISBER Best Practices Fourth Edition.

Wed, 01/10/2018 - 12:59

ISBER President's Message: The Intent of the ISBER Best Practices Fourth Edition.

Biopreserv Biobank. 2018 Jan 09;:

Authors: Kozlakidis Z

PMID: 29314870 [PubMed - as supplied by publisher]

Calcium and vitamin D supplementation are not associated with risk of incident ischaemic cardiac events or death: findings from the UK Biobank cohort.

Wed, 01/10/2018 - 12:59

Calcium and vitamin D supplementation are not associated with risk of incident ischaemic cardiac events or death: findings from the UK Biobank cohort.

J Bone Miner Res. 2018 Jan 04;:

Authors: Harvey NC, D'Angelo S, Paccou J, Curtis EM, Edwards M, Raisi-Estabragh Z, Walker-Bone K, Petersen SE, Cooper C

Abstract
We investigated associations between calcium/vitamin D supplementation and incident cardiovascular events/deaths in a UK population-based cohort. UK Biobank is a large prospective cohort comprising 502,637 men and women aged 40-69 years at recruitment. Supplementation with calcium/vitamin D was self-reported, and information on incident hospital admission (ICD-10) for ischaemic heart disease (IHD), myocardial infarction (MI) any cardiovascular event, and subsequent death, was obtained from linkage to national registers. Cox Proportional Hazards models were used to investigate longitudinal relationships between calcium/vitamin D supplementation and hospital admission for men/women, controlling for covariates. 475,255 participants (median age 58years, 55.8% women) had complete data on calcium/vitamin D supplementation. 33,437 participants reported taking calcium supplements; 19,089 vitamin D; 10,007 both. In crude and adjusted analyses, there were no associations between use of calcium supplements and risk of incident hospital admission with either IHD, MI or any cardiovascular event, or subsequent death. Thus, for example, in unadjusted models, the hazard ratio (HR) for admission with myocardial infarction was 0.97 (95%CI:0.79,1.20; p = 0.79) amongst women taking calcium supplementation. Corresponding HR for men: 1.16 (95%CI:0.92,1.46;p = 0.22). After full adjustment, HR(95%CI) were 0.82 (0.62,1.07), p = 0.14 amongst women and 1.12 (0.85,1.48), p = 0.41 amongst men. Adjusted HR(95%CI) for admission with IHD were 1.05 (0.92,1.19), p = 0.50 amongst women and 0.97 (0.82,1.15), p = 0.77 amongst men. Results were similar for any cardiovascular admission and for vitamin D and combination supplementation. There were no associations with death, and in women, further adjustment for HRT use did not alter the associations. In this very large prospective cohort, there was no evidence that use of calcium/vitamin D supplementation was associated with increased risk of hospital admission or death following ischaemic or non-ischaemic cardiovascular events. This article is protected by copyright. All rights reserved.

PMID: 29314248 [PubMed - as supplied by publisher]

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Wed, 01/10/2018 - 12:59

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Nat Commun. 2017 Jul 12;8:16015

Authors: Willems SM, Wright DJ, Day FR, Trajanoska K, Joshi PK, Morris JA, Matteini AM, Garton FC, Grarup N, Oskolkov N, Thalamuthu A, Mangino M, Liu J, Demirkan A, Lek M, Xu L, Wang G, Oldmeadow C, Gaulton KJ, Lotta LA, Miyamoto-Mikami E, Rivas MA, White T, Loh PR, Aadahl M, Amin N, Attia JR, Austin K, Benyamin B, Brage S, Cheng YC, Cięszczyk P, Derave W, Eriksson KF, Eynon N, Linneberg A, Lucia A, Massidda M, Mitchell BD, Miyachi M, Murakami H, Padmanabhan S, Pandey A, Papadimitriou I, Rajpal DK, Sale C, Schnurr TM, Sessa F, Shrine N, Tobin MD, Varley I, Wain LV, Wray NR, Lindgren CM, MacArthur DG, Waterworth DM, McCarthy MI, Pedersen O, Khaw KT, Kiel DP, GEFOS Any-Type of Fracture Consortium, Pitsiladis Y, Fuku N, Franks PW, North KN, van Duijn CM, Mather KA, Hansen T, Hansson O, Spector T, Murabito JM, Richards JB, Rivadeneira F, Langenberg C, Perry JRB, Wareham NJ, Scott RA

Abstract
Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

PMID: 29313844 [PubMed - in process]

Recombination Is Responsible for the Increased Recovery of Drug-Resistant Mutants with Hypermutated Genomes in Resting Yeast Diploids Expressing APOBEC Deaminases.

Wed, 01/10/2018 - 12:59
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Recombination Is Responsible for the Increased Recovery of Drug-Resistant Mutants with Hypermutated Genomes in Resting Yeast Diploids Expressing APOBEC Deaminases.

Front Genet. 2017;8:202

Authors: Lada AG, Stepchenkova EI, Zhuk AS, Kliver SF, Rogozin IB, Polev DE, Dhar A, Pavlov YI

Abstract
DNA editing deaminases (APOBECs) are implicated in generation of mutations in somatic cells during tumorigenesis. APOBEC-dependent mutagenesis is thought to occur during transient exposure of unprotected single-stranded DNA. Mutations frequently occur in clusters (kataegis). We investigated mechanisms of mutant generation in growing and resting diploid yeast expressing APOBEC from sea lamprey, PmCDA1, whose kataegistic effect was previously shown to be associated with transcription. We have found that the frequency of canavanine-resistant mutants kept raising after growth cessation, while the profile of transcription remained unchanged. Surprisingly, the overall number of mutations in the genomes did not elevate in resting cells. Thus, mutations were accumulated during vigorous growth stage with both intense replication and transcription. We found that the elevated recovery of can1 mutant clones in non-growing cells is the result of loss of heterozygosity (LOH) leading to clusters of homozygous mutations in the chromosomal regions distal to the reporter gene. We confirmed that recombination frequency in resting cells was elevated by orders of magnitude, suggesting that cells were transiently committed to meiotic levels of recombination, a process referred to in yeast genetics as return-to-growth. In its extreme, on day 6 of starvation, a few mutant clones were haploid, likely resulting from completed meiosis. Distribution of mutations along chromosomes indicated that PmCDA1 was active during ongoing recombination events and sometimes produced characteristic kataegis near initial breakpoints. AID and APOBEC1 behaved similar to PmCDA1. We conclude that replication, transcription, and mitotic recombination contribute to the recovered APOBEC-induced mutations in resting diploids. The mechanism is relevant to the initial stages of oncogenic transformation in terminally differentiated cells, when recombination may lead to the LOH exposing recessive mutations induced by APOBECs in cell's history and to acquisition of new mutations near original break.

PMID: 29312434 [PubMed]

Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care.

Wed, 01/10/2018 - 12:59
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Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care.

Scand J Rheumatol. 2018 Jan 09;:1-4

Authors: Glintborg B, Kringelbach T, Bolstad N, Warren DJ, Eng G, Sørensen IJ, Loft AG, Hendricks O, Hansen I, Linauskas A, Nordin H, Kristensen S, Lindegaard H, Jensen DV, Goll GL, Høgdall E, Gehin J, Enevold C, Nielsen CH, Krogh NS, Johansen JS, Hetland ML

PMID: 29310493 [PubMed - as supplied by publisher]

Prevalence and risk of diabetes based on family history in the Shanghai High-Risk Diabetic Screen (SHiDS) study.

Wed, 01/10/2018 - 12:59
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Prevalence and risk of diabetes based on family history in the Shanghai High-Risk Diabetic Screen (SHiDS) study.

Diabet Med. 2016 Dec;33(12):1705-1711

Authors: Zhang Y, Chen H, Lu H, Shen Y, Chen R, Fang P, Du X, Bao Y, Wang C, Jia W

Abstract
AIMS: To evaluate the prevalence and risk of diabetes based on family history in high-risk subjects and also to evaluate insulin sensitivity and insulin secretion in these subjects.
METHODS: Data were analysed from 9756 participants in the Shanghai High-Risk Diabetic Screen (SHiDS) Project. Family history of diabetes was classified according to parental and sibling diabetes status. The prevalence and odds ratios were calculated for each grouping after adjusting for other risk factors. Insulin resistance and sensitivity were evaluated using oral glucose tolerance test-derived indices that were validated by hyperinsulinaemic-euglycaemic and hyperglycaemic clamps.
RESULTS: A total of 30.4% of the subjects had a family history of diabetes in a first-degree relative. The proportions of subjects with a father, mother or sibling with diabetes were 7.5, 11.9 and 5.5%, respectively. The prevalence rates of diabetes in subjects with sibling history, maternal history or paternal history of diabetes were 39.3, 38.3 and 36.4%, respectively. Sibling history was a strong risk factor for diabetes (odds ratio 1.53, 95% CI 1.27-1.84; P < 0.05). Insulin secretion was significantly lower in those with a maternal or sibling history of diabetes; however, insulin sensitivity was not significantly different among subjects with a family history of diabetes.
CONCLUSIONS: Sibling history of diabetes was more strongly associated with diabetes risk than parental history among high-risk subjects. Subjects with a sibling or maternal history of diabetes had significantly lower insulin secretion. Sibling history is an important and independent risk factor for diabetes even among multi-risk populations. Those with a sibling history of diabetes warrant intensive care and follow-up screening.

PMID: 26511673 [PubMed - indexed for MEDLINE]

Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Tue, 01/09/2018 - 12:05

Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Hum Mol Genet. 2018 Jan 03;:

Authors: Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, Bradfield JP, Kreiner-Møller E, Huikari V, Metrustry S, Lunetta KL, Painter JN, Hottenga JJ, Allard C, Barton SJ, Espinosa A, Marsh JA, Potter C, Zhang G, Ang W, Berry DJ, Bouchard L, Das S, Early Growth Genetics (EGG) Consortium, Hakonarson H, Heikkinen J, Helgeland Ø, Hocher B, Hofman A, Inskip HM, Jones SE, Kogevinas M, Lind PA, Marullo L, Medland SE, Murray A, Murray JC, Njølstad PR, Nohr EA, Reichetzeder C, Ring SM, Ruth KS, Santa-Marina L, Scholtens DM, Sebert S, Sengpiel V, Tuke MA, Vaudel M, Weedon MN, Willemsen G, Wood AR, Yaghootkar H, Muglia LJ, Bartels M, Relton CL, Pennell CE, Chatzi L, Estivill X, Holloway JW, Boomsma DI, Montgomery GW, Murabito JM, Spector TD, Power C, Järvelin MR, Bisgaard H, Grant SF, Sørensen TI, Jaddoe VW, Jacobsson B, Melbye M, McCarthy MI, Hattersley AT, Hayes MG, Frayling TM, Hivert MF, Felix JF, Hyppönen E, Lowe WL, Evans DM, Lawlor DA, Feenstra B, Freathy RM

Abstract
Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

PMID: 29309628 [PubMed - as supplied by publisher]

Oversight of EU medical data transfers - an administrative law perspective on cross-border biomedical research administration.

Tue, 01/09/2018 - 12:05
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Oversight of EU medical data transfers - an administrative law perspective on cross-border biomedical research administration.

Health Technol (Berl). 2017;7(4):389-400

Authors: Reichel J

Abstract
The notion of privacy has long had a central role in human rights law, not least in connection to health and medicine. International, regional and national bodies have enacted a number of binding and non-binding document for physicians and researchers to adhere to, in order to protect the autonomy, dignity and privacy of patients and research subjects. With the development of new technologies, the right to privacy has gained a new perspective; the right to protection of personal data within information and communication technologies. The right to data protection has been attributed an increasing importance within EU law. Accordingly, the use of health data in medical research in general and in biobank-related medical research in particular, has made data protection law highly relevant. In medical research involving biobanks, transferring human biological samples and/or individual health data is taking place on a daily basis. These transfers involve several oversight bodies, institutional review boards (IRBs), research ethics committees, or even data protection authorities. This article investigates the role of these national oversight bodies in the transfer of health data in cross-border research, from an EU law point of view. A special focus is laid on transfer of health data for research purposes from the EU to the US, in the light of the recently enacted EU-US Privacy Shield. The main question posed is how American oversight bodies for medical research can be expected to handle the increasingly strict EU requirements for the processing of health data in medical research review.

PMID: 29308345 [PubMed]

The built environment and obesity in UK Biobank: right project, wrong data?

Tue, 01/09/2018 - 12:05
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The built environment and obesity in UK Biobank: right project, wrong data?

Lancet Public Health. 2018 Jan;3(1):e4-e5

Authors: Monsivais P, Burgoine T

PMID: 29307387 [PubMed - in process]

Associations between fast food and physical activity environments and adiposity in mid-life: cross-sectional, observational evidence from UK Biobank.

Tue, 01/09/2018 - 12:05
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Associations between fast food and physical activity environments and adiposity in mid-life: cross-sectional, observational evidence from UK Biobank.

Lancet Public Health. 2018 Jan;3(1):e24-e33

Authors: Mason KE, Pearce N, Cummins S

Abstract
BACKGROUND: The built environment might be associated with development of obesity and related disorders. We examined whether neighbourhood exposure to fast-food outlets and physical activity facilities were associated with adiposity in UK adults.
METHODS: We used cross-sectional observational data from UK Biobank. Participants were aged 40-70 years and attended 21 assessment centres between 2006 and 2010. Using linked data on environments around each participant's residential address, we examined whether density of physical activity facilities and proximity to fast-food outlets were associated with waist circumference, body-mass index (BMI), and body fat percentage. We used multilevel linear regression models adjusted for potential confounders, and conducted several sensitivity analyses.
FINDINGS: Complete case sample sizes were 401 917 (waist circumference models), 401 435 (BMI), and 395 640 (body fat percentage). Greater density of physical activity facilities within 1000 m of home was independently associated with smaller waist circumference and lower BMI and body fat percentage. Compared with people with no nearby facilities, those with at least six facilities close to home had 1·22 cm smaller waist circumference (95% CI -1·64 to -0·80), 0·57 kg/m2 lower BMI (-0·74 to -0·39), and 0·81 percentage points lower body fat (-1·03 to -0·59). Living further from a fast-food outlet was weakly associated with waist circumference and BMI, mostly among women. Compared with people living fewer than 500 m from a fast-food outlet, those living at least 2000 m away had 0·26 cm smaller waist circumference (-0·52 to 0·01).
INTERPRETATION: This study shows strong associations between high densities of physical activity facilities and lower adiposity for adults in mid-life. We observed weaker associations for access to fast food, but these are likely to be underestimated owing to limitations of the food environment measure. Policy makers should consider interventions aimed at tackling the obesogenic built environment.
FUNDING: Commonwealth Scholarship Commission, Wellcome Trust Institutional Strategic Support Fund.

PMID: 29307385 [PubMed - in process]

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

Tue, 01/09/2018 - 12:05
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Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.

Radiother Oncol. 2017 Sep;124(3):504-512

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 - indexed for MEDLINE]

Using Genotype-Based Recall to Estimate the Effects of AMY1 Copy Number Variation in Substrate Metabolism.

Tue, 01/09/2018 - 12:05
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Using Genotype-Based Recall to Estimate the Effects of AMY1 Copy Number Variation in Substrate Metabolism.

Diabetes. 2016 11;65(11):3240-3242

Authors: Franks PW, Renström F

PMID: 27959860 [PubMed - indexed for MEDLINE]

Sleep behavior and depression: Findings from the China Kadoorie Biobank of 0.5 million Chinese adults.

Mon, 01/08/2018 - 12:40

Sleep behavior and depression: Findings from the China Kadoorie Biobank of 0.5 million Chinese adults.

J Affect Disord. 2017 Dec 28;229:120-124

Authors: Sun X, Zheng B, Lv J, Guo Y, Bian Z, Yang L, Chen Y, Fu Z, Guo H, Liang P, Chen Z, Chen J, Yu C, Li L, China Kadoorie Biobank (CKB) Collaborative Group

Abstract
BACKGROUND: Mixed results have shown the association between sleep behavior and depression, but evidence relating the joint effect of sleep duration and sleep disturbances is limited, especially in Chinese population.
METHODS: A total of 512,891 adults aged 30-79 years from China Kadoorie Biobank (CKB) were included. Depression was defined by Composite International Diagnostic Inventory-short form (CIDI-SF). Sleep duration and sleep disturbances, including difficulty initiating and maintaining sleep (DIMS), early morning awakening (EMA), daytime dysfunction (DDF) and any sleep disturbances (ASD), were obtained by a self-reported questionnaire. Logistic regression was applied to examine the association between sleep behavior and depression.
RESULTS: About 23.1% of participants reported short sleep duration (≤ 6h), and 5.1% reported long sleep duration (> 9h). Compared with normal sleep duration (7-9h), both groups were associated greater likelihood of having depression (short sleep: OR = 2.32, 95%CI: 2.14-2.51; long sleep: OR = 1.56, 96%CI: 1.34-1.81). Participants reported sleep disturbances were significantly associated with depression (odds ratios ranged from 3.31 to 4.17). Moreover, the associations tended to be stronger for those who reported both abnormal sleep duration and sleep disturbances (p for interactions < 0.05), especially for those who slept long.
LIMITATIONS: The cross-sectional nature of the study design limits the interpretation of the results.
CONCLUSIONS: Abnormal sleep duration and sleep disturbances were associated with depression. The associations were stronger for abnormal sleep duration accompanied with sleep disturbances, especially for a long duration. More attention should be paid on these persons in clinical practice.

PMID: 29306691 [PubMed - as supplied by publisher]

Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

Sun, 01/07/2018 - 14:40
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Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

Acta Neuropathol. 2018 Jan 05;:

Authors: Verginelli F, Perconti S, Vespa S, Schiavi F, Prasat SC, Lanuti P, Cama A, Tramontana L, Esposito DL, Guarnieri S, Sheu A, Pantalone MR, Florio R, Morgano A, Rossi C, Bologna G, Marchisio M, D'Argenio A, Taschin E, Visone R, Opocher G, Veronese A, Paties CT, Rajasekhar VK, Söderberg-Nauclér C, Sanna M, Lotti LV, Mariani-Costantini R

Abstract
Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles' heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization.

PMID: 29305721 [PubMed - as supplied by publisher]