Funding Opportunity RFA-DK-17-010 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to continue development and expansion of the NIDDK Information Network (dkNET) under the direction of the dkNET Coordinating Unit (dkNET-CU). dkNET supports NIDDK research by providing a user-friendly web portal that seamlessly connects the NIDDK research community to an expanding universe of biomedical resources and data. The dkNET-CU will be responsible for providing the scientific direction, vision, and administrative management needed to advance dkNET goals.

Funding Opportunity RFA-MH-18-410 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) seeks to support efforts focused on linking pertinent data from healthcare system records (e.g., suicide attempt events) to mortality data so that a more accurate understanding of the risk factors for, and the burden of, suicide among those seen in structured healthcare settings can be discerned. Specifically, data are needed on the type, severity, and timing of suicide predictors in the U.S. In addition to improving our national knowledge of the burden of suicide, these data offer the hope of yielding essential benchmarks for both public and private care providers/insurers, who increasingly will be seeking improvements to reduce the frequency of suicide events in their systems. Projects supported by this FOA will help address gaps identified in the 2014 Prioritized Research Agenda for Suicide Prevention.

Funding Opportunity PA-17-299 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications that propose to conduct secondary analyses of publicly available NICHD-funded data sets or stored biospecimens. The goal of this program is to facilitate innovative yet cost-effective research utilizing data and biospecimens collected with NICHD resources.

Funding Opportunity RFA-CA-17-030 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to advance our understanding of the role of the tumor niche or microenvironment in the risks, development, progression, diagnosis, and treatment of cancer observed in individuals with an underlying HIV infection or Acquired Immune Deficiency Syndrome (AIDS).

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

Notice NOT-NS-17-032 from the NIH Guide for Grants and Contracts

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

Related Articles

AlzhCPI: A knowledge base for predicting chemical-protein interactions towards Alzheimer's disease.

PLoS One. 2017;12(5):e0178347

Authors: Fang J, Wang L, Li Y, Lian W, Pang X, Wang H, Yuan D, Wang Q, Liu AL, Du GH

Abstract
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD. Another 104 binary classifiers were further constructed to predict the CPI for 26 preclinical AD targets based on the naive Bayesian (NB) and recursive partitioning (RP) algorithms. The internal 5-fold cross-validation and external test set validation were applied to evaluate the performance of the training sets and test set, respectively. The area under the receiver operating characteristic curve (ROC) for the test sets ranged from 0.629 to 1.0, with an average of 0.903. In addition, we developed a web server named AlzhCPI to integrate the comprehensive information of approximately 204 binary classifiers, which has potential applications in network pharmacology and drug repositioning. AlzhCPI is available online at http://rcidm.org/AlzhCPI/index.html. To illustrate the applicability of AlzhCPI, the developed system was employed for the systems pharmacology-based investigation of shichangpu against AD to enhance the understanding of the mechanisms of action of shichangpu from a holistic perspective.

PMID: 28542505 [PubMed - in process]

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Drug target prediction by multi-view low rank embedding.

IEEE/ACM Trans Comput Biol Bioinform. 2017 May 18;:

Authors: Li L, Cai M

Abstract
Drug repositioning has been a key problem in drug development, and heterogeneous data sources are used to predict drug-target interactions by different approaches. However, most of studies focus on a single representation of drugs or proteins. It has been shown that integrating multi-view representations of drugs and proteins can strengthen the prediction ability. For example, a drug can be represented by its chemical structure, or by its chemical response in different cells. A protein can be represented by its sequence, or by its gene expression values in different cells. The docking of drugs and proteins based on their structure can be considered as one view (structural view), and the chemical performance of them based on gene expression and drug response can be considered as another view (chemical view). In this work, we first propose a single-view approach of SLRE based on low rank embedding for an arbitrary view, and then extend it to a multi-view approach of MLRE, which could integrate both views. Our experiments show that our methods perform significantly better than baseline methods including single-view methods and multi-view methods. We finally report predicted drug target interactions for 30 FDA-approved drugs.

PMID: 28541222 [PubMed - as supplied by publisher]

Related Articles

Network mirroring for drug repositioning.

BMC Med Inform Decis Mak. 2017 May 18;17(Suppl 1):55

Authors: Park S, Lee DG, Shin H

Abstract
BACKGROUND: Although drug discoveries can provide meaningful insights and significant enhancements in pharmaceutical field, the longevity and cost that it takes can be extensive where the success rate is low. In order to circumvent the problem, there has been increased interest in 'Drug Repositioning' where one searches for already approved drugs that have high potential of efficacy when applied to other diseases. To increase the success rate for drug repositioning, one considers stepwise screening and experiments based on biological reactions. Given the amount of drugs and diseases, however, the one-by-one procedure may be time consuming and expensive.
METHODS: In this study, we propose a machine learning based approach for efficiently selecting candidate diseases and drugs. We assume that if two diseases are similar, then a drug for one disease can be effective against the other disease too. For the procedure, we first construct two disease networks; one with disease-protein association and the other with disease-drug information. If two networks are dissimilar, in a sense that the edge distribution of a disease node differ, it indicates high potential for repositioning new candidate drugs for that disease. The Kullback-Leibler divergence is employed to measure difference of connections in two constructed disease networks. Lastly, we perform repositioning of drugs to the top 20% ranked diseases.
RESULTS: The results showed that F-measure of the proposed method was 0.75, outperforming 0.5 of greedy searching for the entire diseases. For the utility of the proposed method, it was applied to dementia and verified 75% accuracy for repositioned drugs assuming that there are not any known drugs to be used for dementia.
CONCLUSION: This research has novelty in that it discovers drugs with high potential of repositioning based on disease networks with the quantitative measure. Through the study, it is expected to produce profound insights for possibility of undiscovered drug repositioning.

PMID: 28539121 [PubMed - in process]

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Chromone as a privileged scaffold in drug discovery - recent advances.

J Med Chem. 2017 May 24;:

Authors: Reis J, Gaspar A, Milhazes N, Borges FM

Abstract
The use of privileged structures in drug discovery has proven to be an effective strategy allowing the generation of innovative hits/leads and successful optimization processes. Chromone is actually recognized as a privileged structure and a valid template for the design of novel compounds with potential pharmacological interest, particularly in the field of neurodegenerative, inflammatory and infectious diseases as well as diabetes and cancer. Within this framework, this review provides the reader with a literature update following the preceding article entitled Chromone: a valid scaffold in Medicinal Chemistry. The review is mainly focused on the biological interest of chromones, including those isolated from natural sources. Moreover, as drug repurposing is becoming an attractive drug discovery approach, the opening repurposing studies on chromone-based drugs are also reported.

PMID: 28537720 [PubMed - as supplied by publisher]

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[Anesthetic management of two patients with alkaptonuric ochronosis for total knee arthroplasty].

Rev Bras Anestesiol. 2017 May 20;:

Authors: Kozanhan B

Abstract
The current case report describes two cases of alkaptonuric ochronosis for anesthetic management. Alkaptonuria is a rare genetic orphan disease of tyrosine metabolism characterized by an accumulation of homogentisic acid in cartilage and connective tissues. Patients present most commonly for orthopedic joint surgery due to progressive arthropathy that can be misdiagnosed many a times. However respiratory, airway, cardiovascular and genitourinary systems complications can occur with age progressing. Restricted range of motion of cervical spine may lead to difficulty with airway management. In addition, degenerative changes and stiffness of lumbar spine due to ochronosis would make neuraxial blockade challenging. Although this inherited condition is extremely rare, anesthesiologists should be aware of its existence and prepare for management of potential challenging problems. This report highlights special care and precautions that need to be taken during anesthetic management.

PMID: 28535941 [PubMed - as supplied by publisher]

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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Am J Hum Genet. 2017 01 05;100(1):75-90

Authors: Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, Carmichael J, Chitre M, Henderson RH, Hurst J, MacLaren RE, Murphy E, Paterson J, Rosser E, Thompson DA, Wakeling E, Ouwehand WH, Michaelides M, Moore AT, NIHR-BioResource Rare Diseases Consortium, Webster AR, Raymond FL

Abstract
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

PMID: 28041643 [PubMed - indexed for MEDLINE]

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The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States.

J Hum Genet. 2017 Feb;62(2):243-252

Authors: Reddy HM, Cho KA, Lek M, Estrella E, Valkanas E, Jones MD, Mitsuhashi S, Darras BT, Amato AA, Lidov HG, Brownstein CA, Margulies DM, Yu TW, Salih MA, Kunkel LM, MacArthur DG, Kang PB

Abstract
The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1 and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.

PMID: 27708273 [PubMed - indexed for MEDLINE]

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Epidemiological investigations on the potential transmissibility of a rare disease: the case of atypical scrapie in Great Britain.

Epidemiol Infect. 2016 Jul;144(10):2107-16

Authors: Ortiz-Peláez A, Arnold ME, Vidal-Diez A

Abstract
Multiple cases of atypical scrapie in the same holding and co-existence with classical scrapie have been reported in Great Britain. A two-stage simulation tool was developed by combining a sampling algorithm and a hierarchical Bayesian model to simulate the number of positive cases of atypical scrapie from: (i) random sampling and (ii) using the actual sampled population in Great Britain, being the output probability of detection of flocks with one and more cases. Cluster analysis was conducted to assess the level of geographical over- and under-sampling over the years. The probability of detecting at least two cases of atypical scrapie in the same holding is much lower in simulated random data than in simulated actual data for all scenarios. Sampling bias in the selection of sheep for testing led to multiple sampling from fewer but larger holdings, Scotland, and areas of Wales were under-sampled and the South-West and East of England oversampled. The pattern of atypical scrapie cases observed is unlikely to be explained by a multi-case event epidemiologically linked. The co-existence of classical and atypical scrapie is a rare event with 19 holdings detected in GB and does not suggest an epidemiological link between the two types of disease.

PMID: 26976340 [PubMed - indexed for MEDLINE]

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Semantic Technologies and Bio-Ontologies.

Methods Mol Biol. 2017;1617:83-91

Authors: Gutierrez F

Abstract
As information available through data repositories constantly grows, the need for automated mechanisms for linking, querying, and sharing data has become a relevant factor both in research and industry. This situation is more evident in research fields such as the life sciences, where new experiments by different research groups are constantly generating new information regarding a wide variety of related study objects. However, current methods for representing information and knowledge are not suited for machine processing. The Semantic Technologies are a set of standards and protocols that intend to provide methods for representing and handling data that encourages reusability of information and is machine-readable. In this chapter, we will provide a brief introduction to Semantic Technologies, and how these protocols and standards have been incorporated into the life sciences to facilitate dissemination and access to information.

PMID: 28540678 [PubMed - in process]

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Genetic determination of body fat distribution and the attributive influence on metabolism.

Obesity (Silver Spring). 2017 May 25;:

Authors: Fehlert E, Wagner R, Ketterer C, Böhm A, Machann J, Fritsche L, Machicao F, Schick F, Staiger H, Stefan N, Häring HU, Fritsche A, Heni M

Abstract
OBJECTIVE: Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with estimates of body fat distribution. Using predefined risk allele scores, the correlation of these scores with precisely quantified body fat distribution assessed by magnetic resonance (MR) imaging techniques and with metabolic traits was investigated.
METHODS: Data from 4,944 MR scans from 915 subjects of European ancestry were analyzed. Body fat distribution was determined by MR imaging and liver fat content by (1) H-MR spectroscopy. All subjects underwent a five-point 75-g oral glucose tolerance test. A total of 65 SNPs with reported genome-wide significant associations regarding estimates of body fat distribution were genotyped. Four genetic risk scores were created by summation of risk alleles.
RESULTS: A higher allelic load of waist-to-hip ratio SNPs was associated with lower insulin sensitivity, higher postchallenge glucose levels, and more visceral and less subcutaneous fat mass.
CONCLUSIONS: GWAS-derived polymorphisms estimating body fat distribution are associated with distinct patterns of body fat distribution exactly measured by MR. Only the risk score associated with the waist-to-hip ratio in GWAS showed an unhealthy pattern of metabolism and body fat distribution. This score might be useful for predicting diseases associated with genetically determined, unhealthy obesity.

PMID: 28544651 [PubMed - as supplied by publisher]

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The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anemia in chronic hepatitis C Egyptian patients.

Clin Exp Pharmacol Physiol. 2017 May 24;:

Authors: El Desoky ES, Abdelhafez AT, Cusato J, Kamel SI, Hussein AMR, De Nicolo A, Di Perri G, D'Avolio A

Abstract
Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anemia among Egyptians with chronic hepatitis C (CHC). Genotyping of 3 ITPA gene variants and 2 variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline hemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration. This article is protected by copyright. All rights reserved.

PMID: 28543275 [PubMed - as supplied by publisher]

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Evaluation of connectivity map-discovered celastrol as a radiosensitizing agent in a murine lung carcinoma model: Feasibility study of diffusion-weighted magnetic resonance imaging.

PLoS One. 2017;12(5):e0178204

Authors: Jun HY, Kim TH, Choi JW, Lee YH, Lee KK, Yoon KH

Abstract
This study was designed to identify potential radiosensitizing (RS) agents for combined radio- and chemotherapy in a murine model of human lung carcinoma, and to evaluate the in vivo effect of the RS agents using diffusion-weighted magnetic resonance imaging (DW-MRI). Radioresistance-associated genes in A549 and H460 cells were isolated on the basis of their gene expression profiles. Celastrol was selected as a candidate RS by using connectivity mapping, and its efficacy in lung cancer radiotherapy was tested. Mice inoculated with A549 carcinoma cells were treated with single ionizing radiation (SIR), single celastrol (SC), or celastrol-combined ionizing radiation (CCIR). Changes in radiosensitization over time were assessed using DW-MRI before and at 3, 6, and 12 days after therapy initiation. The tumors were stained with hematoxylin and eosin at 6 and 12 days after therapy. The percentage change in the apparent diffusion coefficient (ADC) value in the CCIR group was significantly higher than that in the SC and SIR group on the 12th day (Mann-Whitney U-test, p = 0.05; Kruskal-Wallis test, p < 0.05). A significant correlation (Spearman's rho correlation coefficient of 0.713, p = 0.001) was observed between the mean percentage tumor necrotic area and the mean ADC values after therapy initiation. These results suggest that the novel radiosensitizing agent celastrol has therapeutic effects when combined with ionizing radiation (IR), thereby maximizing the therapeutic effect of radiation in non-small cell lung carcinoma. In addition, DW-MRI is a useful noninvasive tool to monitor the effects of RS agents by assessing cellularity changes and sequential therapeutic responses.

PMID: 28542649 [PubMed - in process]

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Genotype-specific methylation of HPV in cervical intraepithelial neoplasia.

J Gynecol Oncol. 2017 Jul;28(4):e56

Authors: Hsu YW, Huang RL, Su PH, Chen YC, Wang HC, Liao CC, Lai HC

Abstract
OBJECTIVE: Hypermethylation of human papillomavirus (HPV) and host genes has been reported in cervical cancer. However, the degree of methylation of different HPV types relative to the severity of the cervical lesions remains controversial. Studies of the degree of methylation associated with the host gene and the HPV genome to the severity of cervical lesions are rare. We examined the association of methylation status between host genes and late gene 1 (L1) regions of HPV16, 18, 52, and 58 in cervical brushings.
METHODS: Cervical brushings from 147 HPV-infected patients were obtained. The samples comprised normal (n=28), cervical intraepithelial neoplasia (CIN) 1 (n=45), CIN2 (n=13), and CIN3/carcinoma in situ (n=61). The methylation status of HPV and host genes was measured using bisulfite pyrosequencing and quantitative methylation-specific polymerase chain reaction (PCR).
RESULTS: The degree of methylation of L1 in HPV16, 18, and 52 was associated with the severity of the cervical lesion. In HPV52, C-phosphate-G (CpG) sites 6368m, 6405m, and 6443m showed significantly higher methylation in lesions ≥CIN3 (p=0.005, 0.003, and 0.026, respectively). Methylation of most HPV types except HPV52 (r<-0.1) was positively correlated with the degree of methylation of host genes including PAX1 and SOX1 (0.4≤r≤0.7). Combining HPV methylation with PAX1 methylation improved the clustering for ≥CIN2.
CONCLUSION: Our study showed that the degree of L1 methylation of HPV16, 18, and 52 but not 58 is associated with the severity of cervical lesions. The association between HPV methylation and host gene methylation suggests different responses of host cellular epigenetic machinery to different HPV genotypes.

PMID: 28541643 [PubMed - in process]