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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]

Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.

Thu, 08/17/2017 - 16:00
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Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.

Blood. 2017 Feb 09;129(6):783-790

Authors: Rühle F, Witten A, Barysenka A, Huge A, Arning A, Heller C, Krümpel A, Mesters R, Franke A, Lieb W, Riemenschneider M, Hiersche M, Limperger V, Nowak-Göttl U, Stoll M

Abstract
Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P < 10(-5)). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of P = 1.42 × 10(-6)/2.0 × 10(-6) and P = 6.11 × 10(-6)/1.8 × 10(-5), respectively. Rs2748331 was replicated (P = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined P = 7.88 × 10(-7)). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in SMAP1 and 3 in RIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: P = .08326, SMAP1; rs767118962: P = .08326, RIMS1; and rs41265501: P = .05778, RIMS1). In conjunction, our data provide compelling evidence for SMAP1, B3GAT2, and RIMS1 as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.

PMID: 28011674 [PubMed - indexed for MEDLINE]

ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice.

Tue, 08/15/2017 - 12:31

ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice.

Cancers (Basel). 2017 Aug 12;9(8):

Authors: Hofman P

Abstract
Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient's sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice.

PMID: 28805682 [PubMed]

ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients.

Tue, 08/15/2017 - 12:31

ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients.

Cancers (Basel). 2017 Aug 12;9(8):

Authors: Hofman P

Abstract
Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due to different resistance mechanisms including mutations in the tyrosine kinase domain of echinoderm microtubule-associated protein-like 4 (EML44)-ALK. The liquid biopsy concept has recently radically changed the clinical care of NSCLC patients, in particular for those harboring an epidermal growth factor receptor (EGFR) gene mutation. Therefore, liquid biopsy is an alternative or complementary method to tissue biopsy for the detection of some resistance mutations in EGFR arising during tyrosine kinase inhibitor treatment. Moreover, in some frail patients, or if the tumor lesion is not accessible to a tissue biopsy, a liquid biopsy can also detect some activating mutations in EGFR on initial assessment. Recent studies have evaluated the possibility of also using a liquid biopsy approach to detect an ALK rearrangement and/or the emergence during inhibitor treatment of some resistance mutations in ALK. These assessments can be performed by studying circulating tumor cells by fluorescent in situ hybridization and by immunocytochemistry and/or after the isolation of RNA from plasma samples, free or associated with platelets. Thus, the liquid biopsy may be a complementary or sometimes alternative method for the assessment of the ALK status in certain NSCLC patients, as well as a non-invasive approach for early detection of ALK mutations. In this review, we highlight the current data concerning the role of the liquid biopsy for the ALK status assessment for NSCLC patients, and we compare the different approaches for this evaluation from blood samples.

PMID: 28805673 [PubMed]

The climate impact on female acute pyelonephritis in Taiwan: A population-based study.

Tue, 08/15/2017 - 12:31

The climate impact on female acute pyelonephritis in Taiwan: A population-based study.

Taiwan J Obstet Gynecol. 2017 Aug;56(4):437-441

Authors: Liu JM, Chang YL, Hsu RJ, Su HY, Teng SW, Chang FW

Abstract
OBJECTIVE: Urinary tract infection (UTI) is the main reason of community-acquired infection which causes large losses in social economy. The individual as well as climate factors make changes on the incidence. Acute pyelonephritis (APN) is one of the most serious UTI in female. The object of our study is to analyze whether climate factors will have effect on the incidence of female APN in Taiwan.
MATERIALS AND METHODS: This study consisted of 14,568 female patients with APN from 2001 to 2013 in Taiwan and patients with repeated APN were excluded. The monthly climate data was collected from the Central Weather Bureau. The available monthly climate data included highest, lowest, and average level of temperatures, humidity, rainfall, total rain days, and sunshine hours.
RESULTS: The total incidence of female APN was 23.44 each 10,000 populations. The incidence of APN was positively correlated with temperature (r = 0.66), sunshine hours (r = 0.45), rainfall (r = 0.42), rain days (r = 0.29), and humidity (r = 0.23) per month. There is the strongest correlation between the average monthly temperature and the incidence of APN (β = 0.54). The correlation with the incidence of APN was also followed by rain days (β = 0.28) and humidity (β = 0.27).
CONCLUSION: There is a significant expression on the incidence of female APN affected by seasonality and climate parameters. The monthly average temperature has the strongest correlation with female APN. The results of this research may facilitate the potential preventive strategies on female APN.

PMID: 28805597 [PubMed - in process]

Stallion Sperm Cryopreservation Using Various Permeating Agents: Interplay Between Concentration and Cooling Rate.

Tue, 08/15/2017 - 12:31

Stallion Sperm Cryopreservation Using Various Permeating Agents: Interplay Between Concentration and Cooling Rate.

Biopreserv Biobank. 2017 Aug 14;:

Authors: Oldenhof H, Bigalk J, Hettel C, Oliveira Barros L, Sydykov B, Bajcsy ÁC, Sieme H, Wolkers WF

Abstract
In this study, modeling and experimental approaches were used to investigate the interplay between cooling rate and protectant concentration for cryopreservation of stallion sperm. Glycerol (GLY), ethylene glycol (EG), dimethylformamide (DMF), propylene glycol (PG), and dimethyl sulfoxide (DMSO) were tested as cryoprotective agents (CPAs), using concentrations up to 1500 mM and cooling rates ranging from 5°C to 55°C min(-1). Modeling of the extent of sperm dehydration during freezing was done using previously determined values of the sperm membrane permeability to water to predict optimal cooling rates for cryopreservation. Sperm cryosurvival was experimentally determined through flow cytometric assessments on membrane intactness and using computer-assisted analysis of motility. Sperm could withstand exposure to 1500 mM concentrations prefreeze for all CPAs tested. The overall highest cryosurvival rates were obtained with DMF, followed by GLY and EG, whereas the use of PG and DMSO resulted in poor cryosurvival rates. Cryosurvival with DMF increased with increasing concentration, reaching a plateau at 500 mM, whereas for GLY and EG, an optimum concentration between 250 and 500 mM resulted in maximal survival. An optimal cooling rate was only observed at low CPA concentrations, whereas at higher concentrations, cryosurvival rates were not affected by the cooling rate. In the case of DMF, survival remained relatively high in the investigated range of concentrations and cooling rates, whereas with GLY and EG, a much narrower combination of CPA concentration and cooling rate resulted in optimal cryosurvival. Sperm cryopreserved with DMF showed altered motility characteristics indicating hyperactivation, which was not observed with GLY and EG. Optimal cooling rates that were predicted from calculated dehydration curves did not match experimentally determined optimal cooling rates.

PMID: 28805449 [PubMed - as supplied by publisher]

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

Tue, 08/15/2017 - 12:31
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Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

Prostate. 2017 Aug 14;:

Authors: Dong B, Fan L, Wang Y, Chi C, Ma X, Wang R, Cai W, Shao X, Pan J, Zhu Y, Shangguan X, Xin Z, Hu J, Xie S, Kang X, Zhou L, Xue W

Abstract
BACKGROUND: To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
METHODS: We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED.
RESULTS: Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED.
CONCLUSIONS: We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients.

PMID: 28804908 [PubMed - as supplied by publisher]

Biobanking in the subcontinent: exploring concerns.

Tue, 08/15/2017 - 12:31
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Biobanking in the subcontinent: exploring concerns.

Indian J Med Ethics. 2017 Jul 11;:1-7

Authors: Jafarey AM, Shekhani SS, Shirazi B

Abstract
Biobanking is an important tool for biomedical research. However, it raises a variety of ethical issues, which are compounded in the developing world. This paper is based on data from three sources on the ethical issues associated with biobanking, including a mixed method pilot study conducted with students in Karachi, Pakistan, a workshop in Karachi, and another workshop held in Bengaluru, India. Findings from these sources reveal a unanimous lack of clarity about what constitutes a biobank. While informed consent was deemed necessary for storage of materials, participants were unsure of how this could be achieved for samples stored indefinitely for future research. Although study participants showed limited understanding of genetic research, concerns were raised in the Karachi workshop. A majority of survey participants found it acceptable to transfer biospecimens across borders, but possibility of misuse was highlighted in both workshops. This paper reveals ambiguities with respect to ethical challenges of biobanking, indicating the need for further discourse.

PMID: 28803222 [PubMed - as supplied by publisher]

The AREST CF experience in biobanking - More than just tissues, tubes and time.

Tue, 08/15/2017 - 12:31
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The AREST CF experience in biobanking - More than just tissues, tubes and time.

J Cyst Fibros. 2017 Aug 09;:

Authors: Garratt LW, Kicic A, Robertson C, Ranganathan S, Sly PD, Stick SM, AREST CF

Abstract
Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank.

PMID: 28803050 [PubMed - as supplied by publisher]

Online self-test identifies women at high familial breast cancer risk in population-based breast cancer screening without inducing anxiety or distress.

Tue, 08/15/2017 - 12:31
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Online self-test identifies women at high familial breast cancer risk in population-based breast cancer screening without inducing anxiety or distress.

Eur J Cancer. 2017 Jun;78:45-52

Authors: van Erkelens A, Sie AS, Manders P, Visser A, Duijm LE, Mann RM, Ten Voorde M, Kroeze H, Prins JB, Hoogerbrugge N

Abstract
INTRODUCTION: Identifying high familial breast cancer (FBC) risk improves detection of yet unknown BRCA1/2-mutation carriers, for whom BC risk is both highly likely and potentially preventable. We assessed whether a new online self-test could identify women at high FBC risk in population-based BC screening without inducing anxiety or distress.
METHODS: After their visit for screening mammography, women were invited by email to take an online self-test for identifying highly increased FBC risk-based on Dutch guidelines. Exclusion criteria were previously diagnosed as increased FBC risk or a personal history of BC. Anxiety (State-Trait Anxiety Inventory Dutch Version), distress (Hospital Anxiety Depression Scale) and BC risk perception were assessed using questionnaires, which were completed immediately before and after taking the online self-test and 2 weeks later.
RESULTS: Of the 562 women invited by email, 406 (72%) completed the online self-test while 304 also completed questionnaires (response rate 54%). After exclusion criteria, 287 (51%) were included for data analysis. Median age was 56 years (range 50-74). A high or moderate FBC risk was identified in 12 (4%) and three (1%) women, respectively. After completion of the online self-test, anxiety and BC risk perception were decreased while distress scores remained unchanged. Levels were below clinical relevance. Most women (85%) would recommend the self-test; few (3%) would not.
CONCLUSION: The online self-test identified previously unknown women at high FBC risk (4%), who may carry a BRCA1/2-mutation, without inducing anxiety or distress. We therefore recommend offering this self-test to women who attend population-based screening mammography for the first time.

PMID: 28412588 [PubMed - indexed for MEDLINE]

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.

Tue, 08/15/2017 - 12:31
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Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.

Leukemia. 2016 Dec;30(12):2312-2321

Authors: Bashford-Rogers RJ, Nicolaou KA, Bartram J, Goulden NJ, Loizou L, Koumas L, Chi J, Hubank M, Kellam P, Costeas PA, Vassiliou GS

Abstract
The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.

PMID: 27211266 [PubMed - indexed for MEDLINE]

Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

Sat, 08/12/2017 - 15:04
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Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

Cancer Epidemiol. 2017 Aug 07;50(Pt A):39-45

Authors: Cheng Y, Yu C, Huang M, Du F, Song C, Ma Z, Zhai X, Yang Y, Liu J, Bei JX, Jia W, Jin G, Li S, Zhou W, Liu J, Dai J, Hu Z

Abstract
BACKGROUND: Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk.
METHODS: Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk.
RESULTS: We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups.
CONCLUSIONS: Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association.

PMID: 28797893 [PubMed - as supplied by publisher]