Text Mining for Translational Bioinformatics.

Biomed Res Int. 2015;2015:368264

Authors: Dai HJ, Wei CH, Kao HY, Liu RL, Tsai RT, Lu Z

PMID: 26380272 [PubMed - indexed for MEDLINE]

TRRUST: a reference database of human transcriptional regulatory interactions.

Sci Rep. 2015;5:11432

Authors: Han H, Shim H, Shin D, Shim JE, Ko Y, Shin J, Kim H, Cho A, Kim E, Lee T, Kim H, Kim K, Yang S, Bae D, Yun A, Kim S, Kim CY, Cho HJ, Kang B, Shin S, Lee I

Abstract
The reconstruction of transcriptional regulatory networks (TRNs) is a long-standing challenge in human genetics. Numerous computational methods have been developed to infer regulatory interactions between human transcriptional factors (TFs) and target genes from high-throughput data, and their performance evaluation requires gold-standard interactions. Here we present a database of literature-curated human TF-target interactions, TRRUST (transcriptional regulatory relationships unravelled by sentence-based text-mining, http://www.grnpedia.org/trrust), which currently contains 8,015 interactions between 748 TF genes and 1,975 non-TF genes. A sentence-based text-mining approach was employed for efficient manual curation of regulatory interactions from approximately 20 million Medline abstracts. To the best of our knowledge, TRRUST is the largest publicly available database of literature-curated human TF-target interactions to date. TRRUST also has several useful features: i) information about the mode-of-regulation; ii) tests for target modularity of a query TF; iii) tests for TF cooperativity of a query target; iv) inferences about cooperating TFs of a query TF; and v) prioritizing associated pathways and diseases with a query TF. We observed high enrichment of TF-target pairs in TRRUST for top-scored interactions inferred from high-throughput data, which suggests that TRRUST provides a reliable benchmark for the computational reconstruction of human TRNs.

PMID: 26066708 [PubMed - indexed for MEDLINE]

Using Literature-Based Discovery to Explain Adverse Drug Effects.

J Med Syst. 2016 Aug;40(8):185

Authors: Hristovski D, Kastrin A, Dinevski D, Burgun A, Žiberna L, Rindflesch TC

Abstract
We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects.

PMID: 27318993 [PubMed - as supplied by publisher]

Identification and characterization of sulfated glycoproteins from small cell lung carcinoma cells assisted by management of molecular charges.

Glycoconj J. 2016 Jun 18;

Authors: Toyoda M, Kaji H, Sawaki H, Togayachi A, Angata T, Narimatsu H, Kameyama A

Abstract
Proteins carrying sulfated glycans (i.e., sulfated glycoproteins) are known to be associated with diseases, such as cancer, cystic fibrosis, and osteoarthritis. Sulfated glycoproteins, however, have not been isolated or characterized from complex biological samples due to lack of appropriate tools for their enrichment. Here, we describe a method to identify and characterize sulfated glycoproteins that are involved in chemical modifications to control the molecular charge of the peptides. In this method, acetohydrazidation of carboxyl groups was performed to accentuate the negative charge of the sulfate group, and Girard's T modification of aspartic acid was performed to assist in protein identification by MS tagging. Using this approach, we identified and characterized the sulfated glycoproteins: Golgi membrane protein 1, insulin-like growth factor binding protein-like 1, and amyloid beta precursor-like protein 1 from H2171 cells, a small cell lung carcinoma cell line. These sulfated glycoproteins carry a complex-type N-glycan with a core fucose and 4'-O-sulfated LacdiNAc as the major glycan.

PMID: 27318476 [PubMed - as supplied by publisher]

Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

J Genet Genomics. 2015 Dec 15;

Authors: Al-Harazi O, Al Insaif S, Al-Ajlan MA, Kaya N, Dzimiri N, Colak D

Abstract
A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field.

PMID: 27318646 [PubMed - as supplied by publisher]

Using Literature-Based Discovery to Explain Adverse Drug Effects.

J Med Syst. 2016 Aug;40(8):185

Authors: Hristovski D, Kastrin A, Dinevski D, Burgun A, Žiberna L, Rindflesch TC

Abstract
We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects.

PMID: 27318993 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/06/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.

J Med Genet. 2016 Jun 17;

Authors: Tlemsani C, Luscan A, Leulliot N, Bieth E, Afenjar A, Baujat G, Doco-Fenzy M, Goldenberg A, Lacombe D, Lambert L, Odent S, Pasche J, Sigaudy S, Buffet A, Violle-Poirsier C, Briand-Suleau A, Laurendeau I, Chin M, Saugier-Veber P, Vidaud D, Cormier-Daire V, Vidaud M, Pasmant E, Burglen L

Abstract
BACKGROUND: Heterozygous NSD1 mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark.
METHODS: We aimed at confirming the implication of DNMT3A and SETD2 mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no NSD1 mutation, from a French cohort.
RESULTS: Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia.
CONCLUSIONS: Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of SETD2 and DNMT3A in intellectual deficiency without overgrowth.

PMID: 27317772 [PubMed - as supplied by publisher]

Extensive surgery and lymphadenectomy do not improve survival in primary melanoma of the anorectum: results from analysis of a large database (SEER).

Colorectal Dis. 2016 Jun 18;

Authors: Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G

Abstract
AIM: Primary anorectal melanoma is a rare disease with a dismal prognosis due to early distant metastasis. The prognostic value of positive loco-regional lymph nodes and the impact of lymphadenectomy on overall survival is unclear. We have investigated this by analysis of data obtained from a national representative database, controlling for potential confounders.
METHODS: Data were retrieved from the SEER database. Multiple imputation analysis was performed to deal with missing data. Cox regression models were formulated using different prognostic factors including site of origin, gender, size, race, rate of lymph nodes metastasis (ratio between positive lymph nodes count and total lymph nodes harvested), extent of lymphadenectomy (none, level I etc), age, type of surgery, stage of disease and administration of radiotherapy.
RESULTS: Our population was comprised of 208 patients who underwent surgery between 1998 and 2012. Rate of lymph nodemetastasis (P = 0.027; HR = 1.873; CI 1.076 - 3.261) and race (P = 0.019; HR 2.291, CI 1.148 - 4.575) were found to be independent predictors of survival.
CONCLUSION: Based on the data retrieved from the SEER database, metastasis to loco-regional lymph nodes is an important prognostic factor, but lymphadenectomy does not improve survival. This article is protected by copyright. All rights reserved.

PMID: 27317493 [PubMed - as supplied by publisher]

Production of Retrovirus-Based Vectors in Mildly Acidic pH Conditions.

Methods Mol Biol. 2016;1448:41-8

Authors: Holic N, Fenard D

Abstract
Gene transfer vectors based on retroviridae are increasingly becoming a tool of choice for biomedical research and for the development of biotherapies in rare diseases or cancers. To meet the challenges of preclinical and clinical production, different steps of the production process of self-inactivating γ-retroviral (RVs) and lentiviral vectors (LVs) have been improved (e.g., transfection, media optimization, cell culture conditions). However, the increasing need for mass production of such vectors is still a challenge and could hamper their availability for therapeutic use. Recently, we observed that the use of a neutral pH during vector production is not optimal. The use of mildly acidic pH conditions (pH 6) can increase by two- to threefold the production of RVs and LVs pseudotyped with the vesicular stomatitis virus G (VSV-G) or gibbon ape leukemia virus (GALV) glycoproteins. Here, we describe the production protocol in mildly acidic pH conditions of GALVTR- and VSV-G-pseudotyped LVs using the transient transfection of HEK293T cells and the production protocol of GALV-pseudotyped RVs produced from a murine producer cell line. These protocols should help to achieve higher titers of vectors, thereby facilitating experimental research and therapeutic applications.

PMID: 27317171 [PubMed - in process]

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families.

Neurology. 2016 Jun 17;

Authors: Soehn AS, Rattay TW, Beck-Wödl S, Schäferhoff K, Monk D, Döbler-Neumann M, Hörtnagel K, Schlüter A, Ruiz M, Pujol A, Züchner S, Riess O, Schüle R, Bauer P, Schöls L

Abstract
OBJECTIVE: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.
METHOD: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes.
RESULTS: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling.
CONCLUSION: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.

PMID: 27316240 [PubMed - as supplied by publisher]

Iohexol plasma clearance, a simple and reliable method to measure renal function in conscious mice.

Pflugers Arch. 2016 Jun 17;

Authors: Luis-Lima S, Rodríguez-Rodríguez AE, Martín-Higueras C, Sierra-Ramos C, Carrara F, Arnau MR, de la Rosa DA, Salido E, Gaspari F, Porrini E

Abstract
In mice, renal function evaluated by serum creatinine has limitations. Gold standard methods using radioactive markers are cumbersome. We aimed to develop the iohexol plasma clearance as a simple assessment of renal function in conscious mice. We used two groups of mice: testing and validation, formed by 16 animals (8 male and 8 female) each. Iohexol was injected intravenously into the tail vein (6.47 mg), and tail tip blood samples were collected at 1, 3, 7, 10, 15, 35, 55, and 75 min. Iohexol plasma clearances were calculated in two ways: (1) two-compartment model (CL2) using all time points and (2) one-compartment model (CL1) using only the last four points. In the testing group, CL1 overestimated the true clearance (CL2). Therefore, CL1 was recalculated applying a correction factor calculated as the ratio between CL2/CL1. The latter was considered as the simplified method. CL2 averaged 223.3 ± 64.3 μl/min and CL1 252.4 ± 76.4 μl/min, which lead to a CF of 0.89. Comparable results for CL2, CL1, and simplified method were observed in the validation group. Additionally, we demonstrated the capacity of the simplified method to quantitatively assess different degrees of renal function in three mouse models: hyperoxaluric-CKD (87.4 ± 28.3 μl/min), heminephrectomized (135-0 ± 50.5 μl/min), and obese (399.6 ± 112.1 μl/min) mice. We have developed a simple and reliable method to evaluate renal function in conscious mice under diverse clinical conditions. Moreover, the test can be repeated in the same animal, which makes the method useful to examine renal function changes over time.

PMID: 27315812 [PubMed - as supplied by publisher]

Genetic heterogeneity in autism: From single gene to a pathway perspective.

Neurosci Biobehav Rev. 2016 Jun 15;

Authors: An JY, Claudianos C

Abstract
The extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD.

PMID: 27317861 [PubMed - as supplied by publisher]

Label-free Quantification of Proteins in Single Embryonic Cells with Neural Fate in the Cleavage-Stage Frog (Xenopus laevis) Embryo using CE-ESI-HRMS.

Mol Cell Proteomics. 2016 Jun 17;

Authors: Lombard-Banek C, Reddy S, Moody SA, Nemes P

Abstract
Quantification of protein expression in single cells promises to advance a systems-level understanding of normal development. Using a bottom-up proteomic workflow and multiplexing quantification by tandem mass tags, we recently demonstrated relative quantification between single embryonic cells (blastomeres) in the frog (Xenopus laevis) embryo. In this study, we minimize derivatization steps to enhance analytical sensitivity and use label-free quantification (LFQ) for single Xenopus cells. The technology builds on a custom-designed capillary electrophoresis microflow-electrospray ionization high-resolution mass spectrometry platform and LFQ by MaxLFQ (MaxQuant). By judiciously tailoring performance to peptide separation, ionization, and data-dependent acquisition, we demonstrate an ~75-amol (~11 nM) lower limit of detection and quantification for proteins in complex cell digests. The platform enabled the identification of 438 non-redundant protein groups by measuring 16 ng of protein digest, or <0.2% of the total protein contained in a blastomere in the 16-cell embryo. LFQ intensity was validated as a quantitative proxy for protein abundance. Correlation analysis was performed to compare protein quantities between the embryo and n = 3 different single D11 blastomeres, which are fated to develop into the nervous system. A total of 335 non-redundant protein groups were quantified in union between the single D11 cells spanning a 4 log-order concentration range. LFQ and correlation analysis detected expected proteomic differences between the whole embryo and blastomeres, and also found translational differences between individual D11 cells. LFQ on single cells raises exciting possibilities to study gene expression in other cells and models to help better understand cell processes on a systems biology level.

PMID: 27317400 [PubMed - as supplied by publisher]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/06/18

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/06/18

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer.

Int J Biol Sci. 2016;12(7):786-98

Authors: Jan CI, Tsai MH, Chiu CF, Huang YP, Liu CJ, Chang NW

Abstract
One anticancer strategy suggests targeting mitochondrial metabolism to trigger cell death through slowing down energy production from the Warburg effect. Fenofibrate is a clinical lipid-lowering agent and an effective anticancer drug. In the present study, we demonstrate that fenofibrate provided novel mechanisms for delaying oral tumor development via the reprogramming of metabolic processes. Fenofibrate induced cytotoxicity by decreasing oxygen consumption rate (OCR) that was accompanied with increasing extracellular acidification rate (ECAR) and reducing ATP content. Moreover, fenofibrate caused changes in the protein expressions of hexokinase II (HK II), pyruvate kinase, pyruvate dehydrogenase, and voltage-dependent anion channel (VDAC), which are associated with the Warburg effect. In addition, fenofibrate reprogrammed the metabolic pathway by interrupting the binding of HK II to VDAC. In an oral cancer mouse model, fenofibrate exhibited both preventive and therapeutic efficacy on oral tumorigenesis. Fenofibrate administration suppressed the incidence rate of tongue lesions, reduced the tumor sizes, decreased the tumor multiplicity, and decreased the immunoreactivities of VDAC and mTOR. The molecular mechanisms involved in fenofibrate's ability to delay tumor development included the down-regulation of mTOR activity via TSC1/2-dependent signaling through activation of AMPK and inactivation of Akt, or via a TSC1/2-independent pathway through direct suppression of raptor. Our findings provide a molecular rationale whereby fenofibrate exerts anticancer and additional beneficial effects for the treatment of oral cancer patients.

PMID: 27313493 [PubMed - in process]

Using Social Media Data to Identify Potential Candidates for Drug Repurposing: A Feasibility Study.

JMIR Res Protoc. 2016;5(2):e121

Authors: Rastegar-Mojarad M, Liu H, Nambisan P

Abstract
BACKGROUND: Drug repurposing (defined as discovering new indications for existing drugs) could play a significant role in drug development, especially considering the declining success rates of developing novel drugs. Typically, new indications for existing medications are identified by accident. However, new technologies and a large number of available resources enable the development of systematic approaches to identify and validate drug-repurposing candidates. Patients today report their experiences with medications on social media and reveal side effects as well as beneficial effects of those medications.
OBJECTIVE: Our aim was to assess the feasibility of using patient reviews from social media to identify potential candidates for drug repurposing.
METHODS: We retrieved patient reviews of 180 medications from an online forum, WebMD. Using dictionary-based and machine learning approaches, we identified disease names in the reviews. Several publicly available resources were used to exclude comments containing known indications and adverse drug effects. After manually reviewing some of the remaining comments, we implemented a rule-based system to identify beneficial effects.
RESULTS: The dictionary-based system and machine learning system identified 2178 and 6171 disease names respectively in 64,616 patient comments. We provided a list of 10 common patterns that patients used to report any beneficial effects or uses of medication. After manually reviewing the comments tagged by our rule-based system, we identified five potential drug repurposing candidates.
CONCLUSIONS: To our knowledge, this is the first study to consider using social media data to identify drug-repurposing candidates. We found that even a rule-based system, with a limited number of rules, could identify beneficial effect mentions in patient comments. Our preliminary study shows that social media has the potential to be used in drug repurposing.

PMID: 27311964 [PubMed]

Tulane virus recognizes sialic acids as cellular receptors.

Sci Rep. 2015;5:11784

Authors: Tan M, Wei C, Huang P, Fan Q, Quigley C, Xia M, Fang H, Zhang X, Zhong W, Klassen JS, Jiang X

Abstract
The recent discovery that human noroviruses (huNoVs) recognize sialic acids (SAs) in addition to histo-blood group antigens (HBGAs) pointed to a new direction in studying virus-host interactions during calicivirus infection. HuNoVs remain difficult to study due to the lack of an effective cell culture model. In this study, we demonstrated that Tulane virus (TV), a cultivable primate calicivirus, also recognizes SAs in addition to the previously known TV-HBGA interactions. Evidence supporting this discovery includes that TV virions bound synthetic sialoglycoconjugates (SGCs) and that treatment of TV permissive LLC-MK2 cells with either neuraminidases or SA-binding lectins inhibited TV infectivity. In addition, we found that Maackia amurensis leukoagglutinin (MAL), a lectin that recognizes the α-2,3 linked SAs, bound LLC-MK2 cells, as well as TV, by which MAL promoted TV infectivity in cell culture. Our findings further highlight TV as a valuable surrogate for huNoVs, particularly in studying virus-host interactions that may involve two host carbohydrate receptors or co-receptors for infection.

PMID: 26146020 [PubMed - indexed for MEDLINE]

stringgaussnet: from differentially expressed genes to semantic and Gaussian networks generation.

Bioinformatics. 2015 Dec 1;31(23):3865-7

Authors: Chaplais E, Garchon HJ

Abstract
MOTIVATION: Knowledge-based and co-expression networks are two kinds of gene networks that can be currently implemented by sophisticated but distinct tools. We developed stringgaussnet, an R package that integrates both approaches, starting from a list of differentially expressed genes.
CONTACT: henri-jean.garchon@inserm.fr.
AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://cran.r-project.org/web/packages/stringgaussnet.

PMID: 26231430 [PubMed - indexed for MEDLINE]