Related Articles

Genetic variants, PM2.5 exposure level and global DNA methylation level: A multi-center population-based study in Chinese.

Toxicol Lett. 2017 Mar 05;269:77-82

Authors: Liu J, Xie K, Chen W, Zhu M, Shen W, Yuan J, Cheng Y, Geng L, Wang Y, Li Z, Zhang J, Jin G, Dai J, Ma H, Du J, Wang M, Zhang Z, Hu Z, Wu T, Shen H

Abstract
Global DNA methylation levels can be determined by environmental and genetic factors. There are emerging evidences that methylation status can be modified as exposed to environmental factors such as PM2.5, but the genetic determinants are still largely unknown. To explore whether genetic variants contribute to global DNA methylation levels with consideration of environmental exposures, we systematically evaluated the association between genetic variants and global DNA methylation levels in 301 subjects from three cities in southern, central and northern China with different PM2.5 exposure levels (Zhuhai, Wuhan and Tianjin, respectively). Personal 24-h PM2.5 exposure levels and global DNA methylation levels for each subject were evaluated. Using Illumina Human Exome BeadChip, 241,305 SNVs was genotyped and assessed for their association with global DNA methylation levels. We found that after adjusting for age, gender, PM2.5 exposure level, pack-years of smoking and BMI, 14 SNVs were consistently associated with global DNA methylation levels with pooled P≤1.00×10(-4) after meta-analysis of three cohorts, in which 8 SNVs together with age were independent factors modifying global DNA methylation levels. Joint analysis of these identified SNVs showed a significant allele-dosage association between the number of variants and global DNA methylation levels (P=1.82×10(-23)). In particular, we detected a significant multiplicative interaction between rs4344916 on chromosome 2p22.3 and PM2.5 exposure on global DNA methylation level (P=0.0095). Our findings indicate that genetic variants alone or in combination with PM2.5 play an important role in modifying individual global DNA methylation levels.

PMID: 28185982 [PubMed - indexed for MEDLINE]

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Highlight on DPYD gene polymorphisms and treatment by capecitabine (.).

Scand J Clin Lab Invest Suppl. 2016;245:S30-3

Authors: Milano G

Abstract
BACKGROUND: Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine.
METHODS: A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 and 2.1% G4, including one toxic death. DPYD exome, flanking intronic regions (20 bp), 3'UTR and part of 5'UTR (500 bp) were sequenced on MiSeq Illumina (Integragen, 97% coverage, HWE checked).
RESULTS: In total, 48 SNPs were identified: three in 3'UTR, 19 in coding regions (four synonymous including E412E; 15 missenses including D949V, V732I, R592W, I560S, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 19 in flanking intronic regions (including *2A) and seven in 5'UTR. In total, 11 SNPs have not been previously described, including three missense variations each heterozygous in three separate patients: R696H, F100L and A26T. The patient with a toxic death carried one D949V allele. The three consensual variants *2A, D949V and I560S were carried by seven patients (heterozygous). Analysis of consensual variants showed that they were associated with G3-4 toxicity (OR = 21.0, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously associated with DPD deficiency in vitro, i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, OR = 21.1) and was predictive of G4 toxicity (sensitivity 40%, OR = 19.0). Of note, adding the new F100L variant further improved predictivity of genotyping on G4 toxicity (sensitivity 60%, OR = 42.8).
CONCLUSIONS: Present data establish the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity.

PMID: 27454530 [PubMed - indexed for MEDLINE]

Notice NOT-HG-17-004 from the NIH Guide for Grants and Contracts

Notice NOT-TR-17-013 from the NIH Guide for Grants and Contracts

Notice NOT-TR-17-014 from the NIH Guide for Grants and Contracts

Notice NOT-AT-17-005 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-CA-17-023 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) is associated with the Beau Biden Cancer MoonshotSM Initiative that is intended to accelerate cancer research. The purpose of this FOA is to promote research on the advanced development and rigorous validation of new enabling technologies/tools/capabilities with a transformative potential for cancer research and clinical oncology.

Funding Opportunity RFA-OD-17-004 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications to support Research Projects studying factors that influence key health behaviors at the individual level, using intensive longitudinal data collection and analytic methods. The network will also assess how study results can be leveraged to introduce innovations into longstanding behavioral theories to advance the field of theory-driven behavior change interventions.

Funding Opportunity RFA-OD-17-005 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to establish a Research Coordinating Center (RCC) to facilitate and support the Intensive Longitudinal Health Behaviors Initiative. The goal of this initiative is to support collaborative research projects studying factors that influence key health behaviors at the individual level, using intensive longitudinal data collection and analytic methods, as well as to further advance research through the broad dissemination of data with the research community, as appropriate. The network will also assess how study results can be leveraged to introduce innovations into longstanding behavioral theories to advance the field of theory-driven behavior change interventions. The RCC will coordinate common activities of the network including communications, meetings, governance, and the development of methods harmonization, data integration, and dissemination.

Notice NOT-AI-17-020 from the NIH Guide for Grants and Contracts

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Related Articles

Computational Drug Repositioning Using Continuous Self-Controlled Case Series.

KDD. 2016 Aug;2016:491-500

Authors: Kuang Z, Thomson J, Caldwell M, Peissig P, Stewart R, Page D

Abstract
Computational Drug Repositioning (CDR) is the task of discovering potential new indications for existing drugs by mining large-scale heterogeneous drug-related data sources. Leveraging the patient-level temporal ordering information between numeric physiological measurements and various drug prescriptions provided in Electronic Health Records (EHRs), we propose a Continuous Self-controlled Case Series (CSCCS) model for CDR. As an initial evaluation, we look for drugs that can control Fasting Blood Glucose (FBG) level in our experiments. Applying CSCCS to the Marshfield Clinic EHR, well-known drugs that are indicated for controlling blood glucose level are rediscovered. Furthermore, some drugs with recent literature support for the potential effect of blood glucose level control are also identified.

PMID: 28316874 [PubMed - in process]

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Integrative cancer pharmacogenomics to infer large-scale drug taxonomy.

Cancer Res. 2017 Mar 17;:

Authors: El-Hachem N, Gendoo DM, Soltan Ghoraie L, Safikhani Z, Smirnov P, Chung C, Deng K, Fang A, Birkwood E, Ho C, Isserlin R, Bader G, Goldenberg A, Haibe-Kains B

Abstract
Identification of drug targets and mechanism of action (MoA) for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Current MoA prediction largely relies on prior information including side effects, therapeutic indication, and chemo-informatics. Such information is not transferable or applicable for newly identified, previously uncharacterized small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary towards development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose here a new integrative computational pharmacogenomic approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that relies only on basic drug characteristics towards elucidating drug-drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation, and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. DNF taxonomy succeeded in identifying pertinent and novel drug-drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. The scalability of DNF facilitated identification of key drug relationships across different drug categories and poses as a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on compound MoA and potential insights for drug repurposing.

PMID: 28314784 [PubMed - as supplied by publisher]

Related Articles

Repositioning of anti-viral drugs as therapy for cervical cancer.

Pharmacol Rep. 2016 Oct;68(5):983-9

Authors: Sharma S, Baksi R, Agarwal M

Abstract
BACKGROUND: Increase in expression of eIF4E (Eukaryotic translation initiation factor 4E) protein is mediated by oncogenic proteins of Human Papilloma Virus (HPV). Increased expression of eIF4E plays an important role in HPV induced carcinogenesis. Ribavirin and Indinavir are known inhibitors of eIF4E activity.
METHODS: The effect of the drugs on HeLa cells was assessed by in vitro assays including cell viability using MTT and Neutral red assay, apoptotic potential using Caspase-3, Caspase-8 and Caspase-9 activity assays and MMP-2 and MMP-9 secretion by determination of Gelatinase activity. The in vivo effect of Ribavirin treatment on tumor volume was assessed in human xenograft in immunocompromised C57BL/6 mice.
RESULTS: In vitro analyses indicate that Ribavirin and Indinavir reduce viability of HeLa cells, induce apoptosis and decrease secretion of MMPs. Treatment with Ribavirin at a dose of 50mg/kg and 100mg/kg daily led to significant decrease in tumor volume in vivo.
CONCLUSION: The study thus provides evidence that Ribavirin and Indinavir can be explored as therapy against HPV-18 induced cervical cancer.

PMID: 27379616 [PubMed - indexed for MEDLINE]

Related Articles

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

Am J Hum Genet. 2017 Mar 11;:

Authors: Ta-Shma A, Khan TN, Vivante A, Willer JR, Matak P, Jalas C, Pode-Shakked B, Salem Y, Anikster Y, Hildebrandt F, Katsanis N, Elpeleg O, Davis EE

Abstract
Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

PMID: 28318500 [PubMed - as supplied by publisher]

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Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.

Am J Hum Genet. 2017 Mar 08;:

Authors: Xue S, Maluenda J, Marguet F, Shboul M, Quevarec L, Bonnard C, Ng AY, Tohari S, Tan TT, Kong MK, Monaghan KG, Cho MT, Siskind CE, Sampson JB, Rocha CT, Alkazaleh F, Gonzales M, Rigonnot L, Whalen S, Gut M, Gut I, Bucourt M, Venkatesh B, Laquerrière A, Reversade B, Melki J

Abstract
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

PMID: 28318499 [PubMed - as supplied by publisher]

Related Articles

Reasons for Declining Preconception Expanded Carrier Screening Using Genome Sequencing.

J Genet Couns. 2017 Mar 17;:

Authors: Gilmore MJ, Schneider J, Davis JV, Kauffman TL, Leo MC, Bergen K, Reiss JA, Himes P, Morris E, Young C, McMullen C, Wilfond BS, Goddard KA

Abstract
Genomic carrier screening can identify more disease-associated variants than existing carrier screening methodologies, but its utility from patients' perspective is not yet established. A randomized controlled trial for preconception genomic carrier screening provided an opportunity to understand patients' decisions about whether to accept or decline testing. We administered a survey to potential genomic carrier screening recipients who declined participation (N = 240) to evaluate their reasons for doing so. Two thirds of women declined participation. We identified major themes describing reasons these individuals declined to participate; the most common were time limitation, lack of interest, not wanting to know the information, and potential cause of worry or anxiety. Most women eligible for genomic carrier screening indicated that their reasons for opting out were due to logistical issues rather than opposing the rationale for testing. As expanded carrier screening and genomic sequencing become a more routine part of clinical care, it is anticipated there will be variable uptake from individuals for this testing. Thus, the advancement of clinical carrier screening from single genes, to expanded screening panels, to an exome- or genome-wide platform, will require approaches that respect individual choice to receive genetic testing for reproductive risk assessment.

PMID: 28315134 [PubMed - as supplied by publisher]

Related Articles

[Cost-effectiveness analysis of octreotide long acting release and lanreotide slow release for the treatment of postoperative patients with active acromegaly in China].

Zhonghua Yi Xue Za Zhi. 2017 Mar 14;97(10):765-769

Authors: Xuan JW, Zhang ZY, Wang YF, Mao ZG, Lu YJ, Wang RZ

Abstract
Objective: To evaluate the cost-effectiveness of octreotide long acting release (LAR) vs lanreotide slow release (SR) for the treatment of postoperative acromegalic patients with elevated levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in China. Methods: A decision tree model was constructed and the treatment impact was projected for one year in Chinese setting. The clinical efficacy measure used was the percentage of patients achieving normalization (control) of either IGF-1 or GH levels. Efficacy of octreotide LAR and lanreotide SR, incidence of comorbidities, impact of acromegaly on health-related quality of life, and drug-related side effects data were obtained from literature. The cost of medication was collected through a chart review from five hospitals in five cities of China. Clinical experts from these hospitals were requested to complete a questionnaire to document the utilization of medical resources, costs of comorbidities, side effects as well as cost of administration. One-way sensitivity analysis was performed to evaluate the robustness of the results. Results: Compared to lanreotied SR group, the percentage of patients achieving normalization of IGF-1 and GH levels of octreotide LAR group were 10% and 9% higher, respectively. When either IGF-1 or GH control were used as the efficacy measure, patients in the octreotide LAR group exhibit less comorbidities and need less continued treatment with a second operation and radiotherapy than those in lanreotide SR group. When IGF-1 was used as efficacy measure, octreotide LAR not only achieved better efficacy but resulted in overall cost-saving, with a total cost savings of ￥ 3 792 per patient for one year, which demonstrated that octreotide LAR was a dominant cost-saving strategy. When GH control was used as the efficacy measure, octreotide LAR achieved a better overall clinical efficacy with a slightly higher total costs (￥ 4 121 higher per patient per year). Sensitivity analysis didn't change the conclusion that octreotide LAR remains dominant over lanreotide SR, indicating the robustness of this model. Conclusion: Octreotide LAR achieved better overall biochemical control compared with lanreotide SR which result in less comorbidity rate, second operation and radiotherapy as well as related costs.

PMID: 28316158 [PubMed - in process]

Related Articles

Association of itraconazole and potassium iodide in the treatment of feline sporotrichosis: a prospective study.

Med Mycol. 2016 Oct 01;54(7):684-90

Authors: Reis ÉG, Schubach TM, Pereira SA, Silva JN, Carvalho BW, Quintana MS, Gremião ID

Abstract
Feline sporotrichosis is an endemic disease in Rio de Janeiro, Brazil, where zoonotic transmission of Sporothrix spp. has been reported since 1998. Itraconazole (ITZ) remains the first choice for treating this disease in cats. However, there have been reports of therapeutic failure and a long-term endeavor. Potassium iodide (KI), considered in the past as a drug with variable effectiveness in cats with sporotrichosis, arises as an important option in the treatment of cats from the endemic area of Rio de Janeiro. In order to evaluate the effectiveness of the association of ITZ and KI in naive cats with sporotrichosis, a prospective cohort study was conducted on 30 cats receiving ITZ 100 mg/day and KI 2.5 mg-20 mg/kg/day. Clinical and laboratory adverse effects were assessed once a month according to the standard care protocol. The cure rate was 96.15% within a median of 14 weeks of treatment. Adverse effects were observed in 50% of cats and were managed with a temporary drug suspension and/or a hepatoprotective therapy. The association of ITZ and KI emerges as an effective option for the treatment of feline sporotrichosis.

PMID: 27207412 [PubMed - indexed for MEDLINE]

Related Articles

[Adverse drug reactions in children: 10 years of pharmacovigilance].

Arch Pediatr. 2016 May;23(5):468-76

Authors: Damien S, Patural H, Trombert-Paviot B, Beyens MN

Abstract
BACKGROUND: Knowledge of drug tolerance and safety in children is limited. The study of spontaneous notifications of adverse events (AEs) can be an important source of information.
OBJECTIVE: Describe the characteristics of drug adverse effects (DAEs) in children 0-17 years of age reported to the pharmacovigilance center of Saint-Étienne in 2004-2013.
METHODS: This retrospective descriptive study was conducted based on DAE notifications, classified according to age, sex, severity of organ affected (using classification by the System organ class [SOC]) and by suspected drug (Anatomical therapeutic chemical [ATC] drugs).
RESULTS: A total of 371 notifications were analyzed. The male:female ratio was 1. Serious cases accounted for 36%, of which 73% resulted in hospitalization or prolongation of hospitalization. The most frequent DAEs were cutaneous (21.1%), infection (13.5%) and general (11.5%). The most frequently involved therapeutic classes were anti-infectives for systemic use (38.7%), mainly vaccines and antibiotics, as well as antineoplastic and immunomodulatory therapy (19.2%) and drugs acting on the nervous system (12.5%).
CONCLUSIONS: The analysis of notifications of adverse drug reactions is an important source of information and is underutilized in pediatrics. The data from this study confirm those of European databases with spontaneous reporting. The majority of anti-infectives including antibiotics raises the question of the proper use of this class in this population. Larger studies focused on the drugs at risk would improve the knowledge and safe use of medicines in children.

PMID: 27062190 [PubMed - indexed for MEDLINE]