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Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Sat, 08/12/2017 - 15:04
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Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Nature. 2017 03 30;543(7647):714-718

Authors: Ju YS, Martincorena I, Gerstung M, Petljak M, Alexandrov LB, Rahbari R, Wedge DC, Davies HR, Ramakrishna M, Fullam A, Martin S, Alder C, Patel N, Gamble S, O'Meara S, Giri DD, Sauer T, Pinder SE, Purdie CA, Borg Å, Stunnenberg H, van de Vijver M, Tan BK, Caldas C, Tutt A, Ueno NT, van 't Veer LJ, Martens JW, Sotiriou C, Knappskog S, Span PN, Lakhani SR, Eyfjörd JE, Børresen-Dale AL, Richardson A, Thompson AM, Viari A, Hurles ME, Nik-Zainal S, Campbell PJ, Stratton MR

Abstract
Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

PMID: 28329761 [PubMed - indexed for MEDLINE]

Use of the 22C3 anti-PD-L1 antibody to determine PD-L1 expression in multiple automated immunohistochemistry platforms.

Fri, 08/11/2017 - 14:12
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Use of the 22C3 anti-PD-L1 antibody to determine PD-L1 expression in multiple automated immunohistochemistry platforms.

PLoS One. 2017;12(8):e0183023

Authors: Ilie M, Khambata-Ford S, Copie-Bergman C, Huang L, Juco J, Hofman V, Hofman P

Abstract
BACKGROUND: For non-small cell lung cancer (NSCLC), treatment with pembrolizumab is limited to patients with tumours expressing PD-L1 assessed by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx (Dako, Inc.) companion diagnostic test, on the Dako Autostainer Link 48 (ASL48) platform. Optimised protocols are urgently needed for use of the 22C3 antibody concentrate to test PD-L1 expression on more widely available IHC autostainers.
METHODS: We evaluated PD-L1 expression using the 22C3 antibody concentrate in the three main commercially available autostainers Dako ASL48, BenchMark ULTRA (Ventana Medical Systems, Inc.), and Bond-III (Leica Biosystems) and compared the staining results with the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform. Several technical conditions for laboratory-developed tests (LDTs) were evaluated in tonsil specimens and a training set of three NSCLC samples. Optimised protocols were then validated in 120 NSCLC specimens.
RESULTS: Optimised protocols were obtained on both the VENTANA BenchMark ULTRA and Dako ASL48 platforms. Significant expression of PD-L1 was obtained on tissue controls with the Leica Bond-III autostainer when high concentrations of the 22C3 antibody were used. It therefore was not tested on the 120 NSCLC specimens. An almost 100% concordance rate for dichotomized tumour proportion score (TPS) results was observed between TPS ratings using the 22C3 antibody concentrate on the Dako ASL48 and VENTANA BenchMark ULTRA platforms relative to the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform. Interpathologist agreement was high on both LDTs and the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform.
CONCLUSION: Availability of standardized protocols for determining PD-L1 expression using the 22C3 antibody concentrate on the widely available Dako ASL48 and VENTANA BenchMark ULTRA IHC platforms will expand the number of laboratories able to determine eligibility of patients with NSCLC for treatment with pembrolizumab in a reliable and concordant manner.

PMID: 28797130 [PubMed - in process]

Replication and characterization of CADM2 and MSRA genes on human behavior.

Fri, 08/11/2017 - 14:12
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Replication and characterization of CADM2 and MSRA genes on human behavior.

Heliyon. 2017 Jul;3(7):e00349

Authors: Boutwell B, Hinds D, 23andMe Research Team, Tielbeek J, Ong KK, Day FR, Perry JRB

Abstract
Progress identifying the genetic determinants of personality has historically been slow, with candidate gene studies and small-scale genome-wide association studies yielding few reproducible results. In the UK Biobank study, genetic variants in CADM2 and MSRA were recently shown to influence risk taking behavior and irritability respectively, representing some of the first genomic loci to be associated with aspects of personality. We extend this observation by performing a personality "phenome-scan" across 16 traits in up to 140,487 participants from 23andMe for these two genes. Genome-wide heritability estimates for these traits ranged from 5-19%, with both CADM2 and MSRA demonstrating significant effects on multiple personality types. These associations covered all aspects of the big five personality domains, including specific facet traits such as compliance, altruism, anxiety and activity/energy. This study both confirms and extends the original observations, highlighting the role of genetics in aspects of mental health and behavior.

PMID: 28795158 [PubMed]

Population-based biobank participants' preferences for receiving genetic test results.

Fri, 08/11/2017 - 14:12
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Population-based biobank participants' preferences for receiving genetic test results.

J Hum Genet. 2017 Aug 10;:

Authors: Yamamoto K, Hachiya T, Fukushima A, Nakaya N, Okayama A, Tanno K, Aizawa F, Tokutomi T, Hozawa A, Shimizu A

Abstract
There are ongoing debates on issues relating to returning individual research results (IRRs) and incidental findings (IFs) generated by genetic research in population-based biobanks. To understand how to appropriately return genetic results from biobank studies, we surveyed preferences for returning IRRs and IFs among participants of the Tohoku Medical Megabank Project (TMM). We mailed a questionnaire to individuals enrolled in the TMM cohort study (Group 1; n=1031) and a group of Tohoku region residents (Group 2; n=2314). The respondents were required to be over 20 years of age. Nearly 90% of Group 1 participants and over 80% of Group 2 participants expressed a preference for receiving their genetic test results. Furthermore, over 60% of both groups preferred to receive their genetic results 'from a genetic specialist.' A logistic regression analysis revealed that engaging in 'health-conscious behaviors' (such as regular physical activity, having a healthy diet, intentionally reducing alcohol intake and/or smoking and so on) was significant, positively associated with preferring to receive their genetic test results (odds ratio=2.397 (Group 1) and 1.897 (Group 2)). Our findings provided useful information and predictors regarding the return of IRRs and IFs in a population-based biobank.Journal of Human Genetics advance online publication, 10 August 2017; doi:10.1038/jhg.2017.81.

PMID: 28794501 [PubMed - as supplied by publisher]

Independent and joint associations of grip strength and adiposity with all-cause and cardiovascular disease mortality in 403,199 adults: the UK Biobank study.

Fri, 08/11/2017 - 14:12
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Independent and joint associations of grip strength and adiposity with all-cause and cardiovascular disease mortality in 403,199 adults: the UK Biobank study.

Am J Clin Nutr. 2017 Aug 09;:

Authors: Kim Y, Wijndaele K, Lee DC, Sharp SJ, Wareham N, Brage S

Abstract
Background: Higher grip strength (GS) is associated with lower mortality risk. However, whether this association is independent of adiposity is uncertain.Objective: The purpose of this study was to examine the associations between GS, adiposity, and mortality.Design: The UK Biobank study is an ongoing prospective cohort of >0.5 million UK adults aged 40-69 y. Baseline data collection (2006-2010) included measurements of GS and adiposity indicators, including body mass index (BMI; in kg/m(2)). Age- and sex-specific GS quintiles were used. BMI was classified according to clinical cutoffs.Results: Data from 403,199 participants were included in analyses. Over a median 7.0-y of follow-up, 8287 all-cause deaths occurred. The highest GS quintile had 32% (95% CI: 26%, 38%) and 25% (95% CI: 16%, 33%) lower all-cause mortality risks for men and women, respectively, compared with the lowest GS quintile, after adjustment for confounders and BMI. Obesity class II (BMI ≥35) was associated with a greater all-cause mortality risk. The highest GS quintile and obesity class II category showed relatively higher all-cause mortality hazards (not statistically significant in men) than the highest GS quintile and the normal weight category; however, the increased risk was relatively lower than the risk for the lowest GS quintile and obesity class II category. All-cause mortality risks were generally lower for obese but stronger individuals than for nonobese but weaker individuals. Similar patterns of associations were observed for cardiovascular mortality.Conclusions: Lower grip strength and excess adiposity are both independent predictors of higher mortality risk. The higher mortality risk associated with excess adiposity is attenuated, although not completely attenuated, by greater GS. Interventions and policies should focus on improving the muscular strength of the population regardless of their degree of adiposity.

PMID: 28793990 [PubMed - as supplied by publisher]

Performance of gout definitions for genetic epidemiological studies: analysis of UK Biobank.

Fri, 08/11/2017 - 14:12
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Performance of gout definitions for genetic epidemiological studies: analysis of UK Biobank.

Arthritis Res Ther. 2017 Aug 09;19(1):181

Authors: Cadzow M, Merriman TR, Dalbeth N

Abstract
BACKGROUND: Many different combinations of available data have been used to identify gout cases in large genetic studies. The aim of this study was to determine the performance of case definitions of gout using the limited items available in multipurpose cohorts for population-based genetic studies.
METHODS: This research was conducted using the UK Biobank Resource. Data, including genome-wide genotypes, were available for 105,421 European participants aged 40-69 years without kidney disease. Gout definitions and combinations of these definitions were identified from previous epidemiological studies. These definitions were tested for association with 30 urate-associated single-nucleotide polymorphisms (SNPs) by logistic regression, adjusted for age, sex, waist circumference, and ratio of waist circumference to height. Heritability estimates under an additive model were generated using GCTA version 1.26.0 and PLINK version 1.90b3.32 by partitioning the genome.
RESULTS: There were 2066 (1.96%) cases defined by self-report of gout, 1652 (1.57%) defined by urate-lowering therapy (ULT) use, 382 (0.36%) defined by hospital diagnosis, 1861 (1.76%) defined by hospital diagnosis or gout-specific medications and 2295 (2.18%) defined by self-report of gout or ULT use. Association with gout at experiment-wide significance (P < 0.0017) was observed for 13 SNPs with gout using the self-report of gout or ULT use definition, 12 SNPs using the self-report of gout definition, 11 SNPs using the hospital diagnosis or gout-specific medication definition, 10 SNPs using ULT use definition and 3 SNPs using hospital diagnosis definition. Heritability estimates ranged from 0.282 to 0.308 for all definitions except hospital diagnosis (0.236).
CONCLUSIONS: Of the limited items available in multipurpose cohorts, the case definition of self-report of gout or ULT use has high sensitivity and precision for detecting association in genetic epidemiological studies of gout.

PMID: 28793914 [PubMed - in process]

The effects of climate factors on scabies. A 14-year population-based study in Taiwan.

Fri, 08/11/2017 - 14:12
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The effects of climate factors on scabies. A 14-year population-based study in Taiwan.

Parasite. 2016;23:54

Authors: Liu JM, Wang HW, Chang FW, Liu YP, Chiu FH, Lin YC, Cheng KC, Hsu RJ

Abstract
Scabies is a common infectious disease and can cause severe outbreaks if not controlled quickly. Besides personal contact history, environmental factors are also important. This study analyzed the effects of environmental climate factors on the incidence of scabies in Taiwan. We conducted a 14-year nationwide population-based study: a total of 14,883 patients with scabies infestation were enrolled. Monthly climate data were collected from Taiwan's Central Weather Bureau, including data on temperature, relative humidity, total rainfall, total rain days, and total sunshine hours. The linear relationships between these climate factors and scabies infestations or other risk factors were examined by Pearson's correlation analysis. Overall, the incidence of scabies was negatively correlated with temperature (γ = -0.152, p < 0.001), while being positively correlated with humidity (γ = 0.192, p < 0.001). This useful information may provide evidence for lowering humidity at nursing facilities, hospitals, and military camps with scabies infestations, which may help to reduce its spread and prevent outbreaks.

PMID: 27905271 [PubMed - indexed for MEDLINE]

Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank.

Thu, 08/10/2017 - 12:30

Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank.

Addiction. 2017 Aug 09;:

Authors: Taylor AE, Davey Smith G, Munafò MR

Abstract
AIMS: To evaluate the utility of coffee-related genetic variants as proxies for coffee consumption in Mendelian randomisation studies, by examining their association with non-alcoholic beverage consumption (including subtypes of coffee and tea) and a range of sociodemographic and lifestyle factors.
DESIGN: Observational study of the association of genetic risk scores for coffee consumption with different types of non-alcoholic beverage consumption.
SETTING: UK general population PARTICIPANTS: Individuals of European ancestry aged 40-70 years from the UK Biobank between 2006 and 2010 (N = 114,316).
MEASUREMENTS: Genetic risk scores were constructed using two, four and eight independent single nucleotide polymorphisms (SNPs) identified in genomewide association studies (GWAS) of coffee consumption. Drinks were self-reported in a baseline questionnaire (all participants) and in detailed 24 dietary recall questionnaires in a subset (N = 48,692).
FINDINGS: Genetic risk scores explained up to 0.38%, 0.19% and 0.76% of the variance in coffee, tea and combined coffee and tea consumption respectively. Genetic risk scores demonstrated positive associations with both caffeinated and decaffeinated coffee and tea consumption, and with most subtypes of coffee consumption, but only with standard tea consumption. There was no clear evidence for positive associations with most other non-alcoholic beverages, but higher genetic risk for coffee consumption was associated with lower daily water consumption. The genetic risk scores were associated with increased alcohol consumption, but not consistently with other sociodemographic and lifestyle factors.
CONCLUSIONS: Coffee-related genetic risk scores could be used as instruments for combined coffee and tea consumption in Mendelian randomisation studies. However, associations observed with alcohol consumption require further investigation to determine whether these are due to causal effects of coffee and tea consumption, or biological pleiotropy.

PMID: 28793181 [PubMed - as supplied by publisher]

The Final Common Rule: Implications for Biobanks.

Thu, 08/10/2017 - 12:30

The Final Common Rule: Implications for Biobanks.

Biopreserv Biobank. 2017 Aug;15(4):283-284

Authors: Bledsoe MJ

PMID: 28792843 [PubMed - in process]

Prognostic value of a 25-gene assay in patients with gastric cancer after curative resection.

Thu, 08/10/2017 - 12:30
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Prognostic value of a 25-gene assay in patients with gastric cancer after curative resection.

Sci Rep. 2017 Aug 08;7(1):7515

Authors: Wang X, Liu Y, Niu Z, Fu R, Jia Y, Zhang L, Shao D, Du H, Hu Y, Xing X, Cheng X, Li L, Guo T, Li Z, Ji Q, Zhang L, Ji J

Abstract
This study aimed to develop and validate a practical, reliable assay for prognosis and chemotherapy benefit prediction compared with conventional staging in Gastric cancer (GC). Twenty-three candidate genes with significant correlation between quantitative hybridization and microarray results plus 2 reference genes were selected to form a 25-gene prognostic classifier, which can classify patients into 3 distinct groups of different risk of mortality obtained by analyzing microarray data from 78 frozen tumor specimens. The 25-gene assay was associated with overall survival in both training (P = 0.017) and testing cohort (P = 0.005) (462 formalin-fixed paraffin-embedded samples). The risk prediction in stages I + II is significantly better than that in stages III. Analysis demonstrated that this 25-gene signature is an independent prognostic predictor and show higher prognostic accuracy than conventional TNM staging in early stage patients. Moreover, only high-risk patients in stage I + II were found benefit from adjuvant chemotherapy (P = 0.043), while low-risk patients in stage III were not found benefit from adjuvant chemotherapy. In conclusion, our results suggest that this 25-gene assay can reliably identify patients with different risk for mortality after surgery, especially for stage I + II patients, and might be able to predict patients who benefit from chemotherapy.

PMID: 28790411 [PubMed - in process]

Genome-wide copy number variation analysis identified deletions in SFMBT1 associated with fasting plasma glucose in a Han Chinese population.

Thu, 08/10/2017 - 12:30
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Genome-wide copy number variation analysis identified deletions in SFMBT1 associated with fasting plasma glucose in a Han Chinese population.

BMC Genomics. 2017 Aug 08;18(1):591

Authors: Chung RH, Chiu YF, Hung YJ, Lee WJ, Wu KD, Chen HL, Lin MW, Chen YI, Quertermous T, Hsiung CA

Abstract
BACKGROUND: Fasting glucose and fasting insulin are glycemic traits closely related to diabetes, and understanding the role of genetic factors in these traits can help reveal the etiology of type 2 diabetes. Although single nucleotide polymorphisms (SNPs) in several candidate genes have been found to be associated with fasting glucose and fasting insulin, copy number variations (CNVs), which have been reported to be associated with several complex traits, have not been reported for association with these two traits. We aimed to identify CNVs associated with fasting glucose and fasting insulin.
RESULTS: We conducted a genome-wide CNV association analysis for fasting plasma glucose (FPG) and fasting plasma insulin (FPI) using a family-based genome-wide association study sample from a Han Chinese population in Taiwan. A family-based CNV association test was developed in this study to identify common CNVs (i.e., CNVs with frequencies ≥ 5%), and a generalized estimating equation approach was used to test the associations between the traits and counts of global rare CNVs (i.e., CNVs with frequencies <5%). We found a significant genome-wide association for common deletions with a frequency of 5.2% in the Scm-like with four mbt domains 1 (SFMBT1) gene with FPG (association p-value = 2×10(-4) and an adjusted p-value = 0.0478 for multiple testing). No significant association was observed between global rare CNVs and FPG or FPI. The deletions in 20 individuals with DNA samples available were successfully validated using PCR-based amplification. The association of the deletions in SFMBT1 with FPG was further evaluated using an independent population-based replication sample obtained from the Taiwan Biobank. An association p-value of 0.065, which was close to the significance level of 0.05, for FPG was obtained by testing 9 individuals with CNVs in the SFMBT1 gene region and 11,692 individuals with normal copies in the replication cohort.
CONCLUSIONS: Previous studies have found that SNPs in SFMBT1 are associated with blood pressure and serum urate concentration, suggesting that SFMBT1 may have functional implications in some metabolic-related traits.

PMID: 28789618 [PubMed - in process]

Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition.

Thu, 08/10/2017 - 12:30
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Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition.

Biol Psychiatry. 2017 Feb 01;81(3):243-251

Authors: Takayanagi Y, Yoshida M, Takashima A, Takanami K, Yoshida S, Nishimori K, Nishijima I, Sakamoto H, Yamagata T, Onaka T

Abstract
BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined.
METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala.
RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice.
CONCLUSIONS: The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits.

PMID: 26803341 [PubMed - indexed for MEDLINE]

Time trends and exposure determinants of lead and cadmium in the adult population of northern Sweden 1990-2014.

Wed, 08/09/2017 - 13:47

Time trends and exposure determinants of lead and cadmium in the adult population of northern Sweden 1990-2014.

Environ Res. 2017 Aug 05;159:111-117

Authors: Wennberg M, Lundh T, Sommar JN, Bergdahl IA

Abstract
INTRODUCTION: This study follows cadmium and lead concentrations in blood in the adult population in northern Sweden over 24 years.
MATERIAL AND METHODS: Concentrations of lead and cadmium were measured in single whole blood samples (B-Pb and B-Cd) from 619 men and 926 women participating in the Northern Sweden WHO MONICA Study on one occasion 1990-2014. Associations with smoking and dietary factors were investigated. Consumption of moose meat was asked for in 2014.
RESULTS: In the adult population in northern Sweden, the median B-Pb in 2014 was 11.0µg/L in young (25-35 years) men and 9.69µg/L in young women. In an older age-group (50-60 years), the median B-Pb was 15.1µg/L in men and 13.1µg/L in women. B-Pb decreased from 1990 to 2009, after which time no further decrease was observed. B-Pb was higher in smokers than in non-smokers. In never-smokers, positive associations were found between B-Pb and consumption of wine and brewed coffee (women only) in 2004-2014. Higher B-Pb with consumption of moose meat was demonstrated in men, but not in women. B-Cd was essentially stable over the whole period, but an increase in B-Cd, of 3% per year, was detected in never-smoking women between 2009 and 2014. In 2014, median B-Cd in never-smokers in the four groups was; 0.11µg/L in younger men, 0.15µg/L in younger women, 0.14µg/L in older men, and 0.21µg/L in older women. B-Cd was higher in smokers than in non-smokers. The only positive association between B-Cd and food items in 2004-2014 was with consumption of brewed coffee (men only).
CONCLUSIONS: The lack of a decrease in B-Cd from 1990 to 2014 and the absence of a further decrease in B-Pb after 2009 are unsatisfactory considering the health risks these metals pose in the general population at current concentrations.

PMID: 28787621 [PubMed - as supplied by publisher]

PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma.

Wed, 08/09/2017 - 13:47
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PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma.

Sci Rep. 2017 Aug 07;7(1):7391

Authors: Otani Y, Ishida J, Kurozumi K, Oka T, Shimizu T, Tomita Y, Hattori Y, Uneda A, Matsumoto Y, Michiue H, Tomida S, Matsubara T, Ichikawa T, Date I

Abstract
Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.

PMID: 28785028 [PubMed - in process]

Pregnancy, pregnancy loss, and the risk of cardiovascular disease in Chinese women: findings from the China Kadoorie Biobank.

Wed, 08/09/2017 - 13:47
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Pregnancy, pregnancy loss, and the risk of cardiovascular disease in Chinese women: findings from the China Kadoorie Biobank.

BMC Med. 2017 Aug 08;15(1):148

Authors: Peters SAE, Yang L, Guo Y, Chen Y, Bian Z, Tian X, Chang L, Zhang S, Liu J, Wang T, Chen J, Li L, Woodward M, Chen Z, China Kadoorie Biobank collaboration group

Abstract
BACKGROUND: Pregnancy and pregnancy loss may be linked to cardiovascular disease (CVD). However, the evidence is still inconsistent, especially in East Asians, whose reproductive patterns differ importantly from those in the West. We examined the associations of pregnancy, miscarriage, induced abortion, and stillbirth with CVD incidence among Chinese women.
METHODS: In 2004-2008, the nationwide China Kadoorie Biobank recruited 302,669 women aged 30-79 years from ten diverse localities. During 7 years of follow-up, 43,968 incident cases of circulatory disease, 14,440 of coronary heart disease, and 19,925 of stroke (including 11,430 ischaemic and 2170 haemorrhagic strokes), were recorded among 289,573 women without prior CVD at baseline. Cox regression yielded multiple adjusted hazard ratios (HRs) for CVD risks associated with pregnancy outcomes.
RESULTS: Overall, 99% of women had been pregnant, and among them 10%, 53%, and 7% reported having a history of miscarriage, induced abortion, and stillbirth, respectively. Each additional pregnancy was associated with an adjusted HR of 1.03 (95% confidence interval, CI: 1.02; 1.04) for circulatory disease. A history of miscarriage, induced abortion, and stillbirth, respectively, were associated with adjusted HRs of 1.04 (1.01; 1.07), 1.04 (1.02; 1.07), and 1.07 (1.03; 1.11) for circulatory disease. The relationship was stronger with recurrent pregnancy loss; adjusted HRs for each additional loss being 1.04 (1.00; 1.09) for miscarriage, 1.02 (1.01; 1.04) for induced abortion, and 1.04 (1.00; 1.08) for stillbirth.
CONCLUSIONS: Among Chinese women, increases in pregnancy, and a history and recurrence of miscarriage, induced abortion, and stillbirth are each associated with a higher risk of CVD.

PMID: 28784170 [PubMed - in process]

Determination of Dielectric Properties of Cryoprotective Agent Solutions with a Resonant Cavity for the Electromagnetic Rewarming in Cryopreservation.

Tue, 08/08/2017 - 14:30
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Determination of Dielectric Properties of Cryoprotective Agent Solutions with a Resonant Cavity for the Electromagnetic Rewarming in Cryopreservation.

Biopreserv Biobank. 2017 Aug 07;:

Authors: Pan J, Shu Z, Ren S, Gao D

Abstract
In the rewarming process during cryopreservation, preventing ice recrystallization and thermal stress is important, especially for large tissues and organs. Uniform and rapid heating is essential in ameliorating the problem and maintaining the viability of cryopreserved biological samples. Currently, the most promising method is heating by application of electromagnetic (EM) waves, the effectiveness of which is dependent on the dielectric properties (DP) of the cryopreserved materials. In this work, the cavity perturbation method was adopted to measure the DP of cryoprotectant solutions. Based on the values of DP, the cryoprotectant solutions most amenable to EM heating can be identified. A system composed of a rectangular resonant cavity, a network analyzer, and a fiber optic temperature meter was implemented for the measurement. The DP of three cryoprotectant solutions during cooling to -80°C were measured and presented. The data can be used to optimize the rewarming process with the numerical method. The results show that a cryoprotectant solution consisting of 41% (w/v) dimethyl sulfoxide and 6% (w/v) polyvinylpyrrolidone has the highest dielectric loss for EM rewarming among the tested solutions. In addition, the developed DP measurement system could not only improve the EM heating in cryopreservation but also benefit hyperthermia or other therapies associated with EM waves.

PMID: 28783479 [PubMed - as supplied by publisher]

Cumulative occupational mechanical exposures during working life and risk of sickness absence and disability pension: prospective cohort study.

Tue, 08/08/2017 - 14:30
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Cumulative occupational mechanical exposures during working life and risk of sickness absence and disability pension: prospective cohort study.

Scand J Work Environ Health. 2017 Aug 07;:

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

Abstract
Objectives The aim of this study was to determine the prospective association of cumulative mechanical exposure during working life with health-related labor market outcomes. Methods This prospective cohort study combines data from 5076 older workers (age 49-63 years) from the Copenhagen Aging and Midlife Biobank with a job exposure matrix and a national register containing information on social transfer payment. By coding individual job histories from the Danish version of ISCO-codes (International Standard Classification of Occupations), we calculated cumulative occupational mechanical exposures from a JEM for ton-years (lifting 1000 kg each day in one year), lifting-years (lifting loads weighing ≥20 kg >10 times each day in one year), kneeling-years (kneeling for one hour each day in one year) and vibration-years (whole-body vibration for one hour each day in one year). Cox-regression analyses estimated the relative risk of register-based long-term sickness absence (LTSA) and disability pension with cumulative occupational mechanical exposures throughout working life. Analyses were censored for competing events and adjusted for multiple confounders. Results During the follow-up period, 970 persons (19.3%) had ≥1 episode of LTSA and 85 persons (1.7%) were granted a disability pension. Number of ton-, lifting- and kneeling-years showed an exposure-response association with increased risk of LTSA (P<0.0001). In addition, both long term [≥20 years; hazard ratio (HR) 1.76 95% CI 1.39-2.22] and short term (<10 years; HR 1.20 95% CI 1.02-1.41) exposure to kneeling work increased the risk of LTSA. Lifting-years, but not the other mechanical exposures, were associated with risk of disability pension (HR 1.75 95% CI 1.01-3.04). Conclusions Cumulative occupational mechanical exposures during working life - such as lifting and kneeling work - increased the risk of LTSA. Importantly, being exposed to lifting increased the risk of disability pension.

PMID: 28783203 [PubMed - as supplied by publisher]

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Tue, 08/08/2017 - 14:30
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DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Nat Med. 2017 Mar;23(3):386-395

Authors: Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Álava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C, Tomazou EM

Abstract
Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

PMID: 28134926 [PubMed - indexed for MEDLINE]

Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

Tue, 08/08/2017 - 14:30
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Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

Breast Cancer Res. 2016 Dec 08;18(1):124

Authors: Wen W, Shu XO, Guo X, Cai Q, Long J, Bolla MK, Michailidou K, Dennis J, Wang Q, Gao YT, Zheng Y, Dunning AM, García-Closas M, Brennan P, Chen ST, Choi JY, Hartman M, Ito H, Lophatananon A, Matsuo K, Miao H, Muir K, Sangrajrang S, Shen CY, Teo SH, Tseng CC, Wu AH, Yip CH, Simard J, Pharoah PD, Hall P, Kang D, Xiang Y, Easton DF, Zheng W

Abstract
BACKGROUND: Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry.
METHODS: We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk.
RESULTS: We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively.
CONCLUSION: Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

PMID: 27931260 [PubMed - indexed for MEDLINE]

Improving the Performance of Somatic Mutation Identification by Recovering Circulating Tumor DNA Mutations.

Tue, 08/08/2017 - 14:30
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Improving the Performance of Somatic Mutation Identification by Recovering Circulating Tumor DNA Mutations.

Cancer Res. 2016 Oct 15;76(20):5954-5961

Authors: Fu Y, Jovelet C, Filleron T, Pedrero M, Motté N, Boursin Y, Luo Y, Massard C, Campone M, Levy C, Diéras V, Bachelot T, Garrabey J, Soria JC, Lacroix L, André F, Lefebvre C

Abstract
DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53 We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell-free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954-61. ©2016 AACR.

PMID: 27535334 [PubMed - indexed for MEDLINE]