Drug repurposing for chronic myeloid leukemia: in silico and in vitro investigation of DrugBank database for allosteric Bcr-Abl inhibitors.

J Biomol Struct Dyn. 2016 Jun 29;:1-16

Authors: Singh VK, Chang HH, Kuo CC, Shiao HY, Hsieh HP, Coumar MS

Abstract
Chronic myeloid leukemia (CML) is caused by chromosomal rearrangement resulting in the expression of Bcr-Abl fusion protein with deregulated Abl tyrosine kinase activity. Approved drugs - imatinib, dasatinib, nilotinib, and ponatinib - target the ATP-binding site of Abl kinase. Even though these drugs are initially effective, long-term usefulness is limited by the development of resistance. To overcome this problem, targeting the allosteric site of Abl kinase, which is remote from the ATP-binding site is found to be a useful strategy. In this study, structure-based and ligand-based virtual screening methods were applied to narrow down possible drugs (from DrugBank database) that could target the allosteric site of Abl kinase. Detailed investigations of the selected drugs in the allosteric site of Abl kinase, using molecular dynamics and steered molecular dynamics simulation shows that gefitinib, an EGFR inhibitor approved for the treatment of lung cancer, could bind effectively to the allosteric site of Bcr-Abl. More interestingly, gefitinib was found to enhance the ability of imatinib to bind at the ATP-binding site of Bcr-Abl kinase. Based on the in silico findings, gefitinib was tested in combination with imatinib in K562 CML cell line using MTT cell proliferation assay and found to have a synergistic antiproliferative activity. Further detailed mechanistic study could help to unravel the full potential of imatinib - gefitinib combination for the treatment of CML.

PMID: 27353341 [PubMed - as supplied by publisher]

Pharmacogenomics for infectious diseases in sub-Saharan Africa: Successes and opportunities.

Appl Transl Genom. 2016 Jun;9:3-5

Authors: Chaudhry M, Alessandrini M, Pepper MS

PMID: 27354934 [PubMed]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons.

Nutr Metab Cardiovasc Dis. 2016 May 30;

Authors: Yadav K, Sharma M, Ferdinand KC

Abstract
AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition.
BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality. However, 70% of events occur even in the presence of statins. This residual risk may be approached with additional LDL-C reduction. Statin intolerance is a common clinical concern affecting adherence and the benefit with statins. There is also significant variation of individual lipid-lowering. Following rapid development, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have progressed from genetic observations, to mechanistic studies, to closer realization of the goal of CVD risk reduction. This review discusses the science behind PCSK9 inhibition, evidence of trials involving efficacy and safety, and reflections of its present and future role in clinical care, especially in high-risk patients with ASCVD, persons with suboptimal responses to statins and familial hyperlipidemia. Monoclonal antibodies have demonstrated LDL-C lowering of up to 57% as monotherapy and up to 73% when added to statins. Statins have limited efficacy in reduction of LDL-C due to an increased number of LDL-receptors. Elevated lipoprotein (a) levels may also be significantly lowered by PCSK9i. The journey from discovery to PSCK9 target validation took less than five years, and development and approval of therapeutic modalities for PCSK9 inhibitors happened over the next seven. This review highlights the drug development and pharmacogenomics leading to the recent approval of two agents, alirocumab and evolocumab, with a third bococizumab, and other novel approaches to the pathway pending.
DATA SYNTHESIS: We searched MEDLINE database via Pubmed for reviews, research publications and relevant trials available on PCSK9 inhibition.
CONCLUSION: Despite decades of medical advances, ASCVD remains one of the major causes of morbidity and mortality worldwide. Statin use has multiplied since the validation of LDL hypothesis, however, it is undeniable a more effective and well-tolerated agent is needed in significant number or patients. With the arrival of the era of unprecedented CV protection with PCSK9 inhibition, this exciting new therapy holds a pivotal promise as the future of lipid management. The data available already indicate safety, tolerability and superb efficacy of these agents, which are already changing contemporary cholesterol management. The rapid translation of innovative basic science research into drug development may lead to CV outcomes reduction and confirm that this pathway will become prominently utilized.

PMID: 27352986 [PubMed - as supplied by publisher]

Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.

Eur J Cancer. 2016 Mar;55:27-37

Authors: Cresti N, Lee J, Rourke E, Televantou D, Jamieson D, Verrill M, Boddy AV

Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease.

PMID: 26773371 [PubMed - indexed for MEDLINE]

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.

BMC Cancer. 2015;15:718

Authors: Takahashi H, Kaniwa N, Saito Y, Sai K, Hamaguchi T, Shirao K, Shimada Y, Matsumura Y, Ohtsu A, Yoshino T, Doi T, Takahashi A, Odaka Y, Okuyama M, Sawada J, Sakamoto H, Yoshida T

Abstract
BACKGROUND: Variability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.
METHODS: We previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.
RESULTS: We identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10(-8) by Fisher's exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.
CONCLUSIONS: These results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.

PMID: 26475168 [PubMed - indexed for MEDLINE]

Pharmacogenomics and cardiology: improving treatment with existing drugs.

Pharmacogenomics. 2015;16(11):1223-6

Authors: Sorrentino MJ, O'Donnell PH

PMID: 26369612 [PubMed - indexed for MEDLINE]

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score.

Pharmacogenomics. 2015;16(11):1277-86

Authors: Henricks LM, Lunenburg CA, Meulendijks D, Gelderblom H, Cats A, Swen JJ, Schellens JH, Guchelaar HJ

Abstract
The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.

PMID: 26265346 [PubMed - indexed for MEDLINE]

Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes.

Pharmacogenomics J. 2015 Oct;15(5):443-51

Authors: Altar CA, Carhart JM, Allen JD, Hall-Flavin DK, Dechairo BM, Winner JG

Abstract
In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGx™) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support.

PMID: 25686762 [PubMed - indexed for MEDLINE]

Pyrosequencing Unveils Cystic Fibrosis Lung Microbiome Differences Associated with a Severe Lung Function Decline.

PLoS One. 2016;11(6):e0156807

Authors: Bacci G, Paganin P, Lopez L, Vanni C, Dalmastri C, Cantale C, Daddiego L, Perrotta G, Dolce D, Morelli P, Tuccio V, De Alessandri A, Fiscarelli EV, Taccetti G, Lucidi V, Bevivino A, Mengoni A

Abstract
Chronic airway infection is a hallmark feature of cystic fibrosis (CF) disease. In the present study, sputum samples from CF patients were collected and characterized by 16S rRNA gene-targeted approach, to assess how lung microbiota composition changes following a severe decline in lung function. In particular, we compared the airway microbiota of two groups of patients with CF, i.e. patients with a substantial decline in their lung function (SD) and patients with a stable lung function (S). The two groups showed a different bacterial composition, with SD patients reporting a more heterogeneous community than the S ones. Pseudomonas was the dominant genus in both S and SD patients followed by Staphylococcus and Prevotella. Other than the classical CF pathogens and the most commonly identified non-classical genera in CF, we found the presence of the unusual anaerobic genus Sneathia. Moreover, the oligotyping analysis revealed the presence of other minor genera described in CF, highlighting the polymicrobial nature of CF infection. Finally, the analysis of correlation and anti-correlation networks showed the presence of antagonism and ecological independence between members of Pseudomonas genus and the rest of CF airways microbiota, with S patients showing a more interconnected community in S patients than in SD ones. This population structure suggests a higher resilience of S microbiota with respect to SD, which in turn may hinder the potential adverse impact of aggressive pathogens (e.g. Pseudomonas). In conclusion, our findings shed a new light on CF airway microbiota ecology, improving current knowledge about its composition and polymicrobial interactions in patients with CF.

PMID: 27355625 [PubMed - as supplied by publisher]

Validity and Reliability Concerns Associated with Cardiopulmonary Exercise Testing Young People with Cystic Fibrosis.

Respiration. 2016 Jun 30;

Authors: Saynor ZL, Barker AR, Oades PJ, Tomlinson OW, Williams CA

PMID: 27355590 [PubMed - as supplied by publisher]

Specific phenotype and function of CD56-expressing innate immune cell subsets in human thymus.

J Leukoc Biol. 2016 Jun 28;

Authors: Gerstner S, Köhler W, Heidkamp G, Purbojo A, Uchida S, Ekici AB, Heger L, Luetke-Eversloh M, Schubert R, Bader P, Klingebiel T, Koehl U, Mackensen A, Romagnani C, Cesnjevar R, Dudziak D, Ullrich E

Abstract
Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56(+)CD3(-) cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56(+)CD3(-) cells. Thymic tissues lacked immunoregulatory CD56(high)CD16(dim) NK cells but showed two Eomes(+)CD56(dim) subsets on which common NK cell markers were significantly altered. CD56(dim)CD16(high) cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56(dim)CD16(dim) cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56(+)CD3(-) cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56(+) cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset.

PMID: 27354408 [PubMed - as supplied by publisher]

Spatial Mapping of Pyocyanin in Pseudomonas Aeruginosa Bacterial Communities Using Surface Enhanced Raman Scattering.

Appl Spectrosc. 2016 Jun 28;

Authors: Polisetti S, Baig NF, Morales-Soto N, Shrout JD, Bohn PW

Abstract
Surface enhanced Raman spectroscopy (SERS) imaging was used in conjunction with principal component analysis (PCA) for the in situ spatiotemporal mapping of the virulence factor pyocyanin in communities of the pathogenic bacterium Pseudomonas aeruginosa. The combination of SERS imaging and PCA analysis provides a robust method for the characterization of heterogeneous biological systems while circumventing issues associated with interference from sample autofluorescence and low reproducibility of SERS signals. The production of pyocyanin is found to depend both on the growth carbon source and on the specific strain of P. aeruginosa studied. A cystic fibrosis lung isolate strain of P. aeruginosa synthesizes and secretes pyocyanin when grown with glucose and glutamate, while the laboratory strain exhibits detectable production of pyocyanin only when grown with glutamate as the source of carbon. Pyocyanin production in the laboratory strain grown with glucose was below the limit of detection of SERS. In addition, the combination of SERS imaging and PCA can elucidate subtle differences in the molecular composition of biofilms. PCA loading plots from the clinical isolate exhibit features corresponding to vibrational bands of carbohydrates, which represent the mucoid biofilm matrix specific to that isolate, features that are not seen in the PCA loading plots of the laboratory strain.

PMID: 27354400 [PubMed - as supplied by publisher]

Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction.

Circ Res. 2016 Jan 22;118(2):216-21

Authors: Haubner BJ, Schneider J, Schweigmann U, Schuetz T, Dichtl W, Velik-Salchner C, Stein JI, Penninger JM

Abstract
RATIONALE: Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translate findings in model organisms to future therapies in humans: what is the mechanism and can cardiac regeneration indeed occur in newborn humans?
OBJECTIVE: To assess whether human neonatal hearts can functionally recover after myocardial infarction.
METHODS AND RESULTS: Here, we report the case of a newborn child having a severe myocardial infarction due to coronary artery occlusion. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography. Remarkably, within weeks after the initial ischemic insult, we observed functional cardiac recovery, which translated into long-term normal heart function.
CONCLUSIONS: These data indicate that, similar to neonatal rodents, newborn humans might have the intrinsic capacity to repair myocardial damage and completely recover cardiac function.

PMID: 26659640 [PubMed - indexed for MEDLINE]

KymoRod: A method for automated kinematic analysis of rod-shaped plant organs.

Plant J. 2016 Jun 29;

Authors: Bastien R, Legland D, Martin M, Fregosi L, Peaucelle A, Douady S, Moulia B, Höfte H

Abstract
A major challenge in plant systems biology is the development of robust, predictive multiscale models for organ growth. In this context it is important to bridge the gap between the, rather well-documented, molecular scale and the organ scale by providing quantitative methods to study within-organ growth patterns. Here, we describe a simple method for the analysis of the evolution of growth patterns within rod-shaped organs, which does not require adding markers at the organ surface. The method allows for the simultaneous analysis of root and hypocotyl growth, provides spatio-temporal information on curvature, growth anisotropy and REGR and can cope with complex organ movements. We demonstrate the performance of the method by documenting previously unsuspected complex growth patterns within the growing hypocotyl of the model species Arabidopsis thaliana during normal growth, after treatment with a growth-inhibiting drug or in a mechano-sensing mutant. The method is freely available as an intuitive and user-friendly Matlab application called KymoRod. This article is protected by copyright. All rights reserved.

PMID: 27354251 [PubMed - as supplied by publisher]

A synopsis on Aging - theories, mechanisms and future prospects.

Ageing Res Rev. 2016 Jun 25;

Authors: da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T

Abstract
Answering the question as to why we age is tantamount to answering the question of what is life itself. There are countless theories as to why and how we age, but, until recently, the very definition of aging - senescence - was still uncertain. Here, we summarize the main views of the different models of senescence, with a special emphasis on the biochemical processes that accompany aging. Though inherently complex, aging is characterized by numerous changes that take place at different levels of the biological hierarchy. We therefore explore some of the most relevant changes that take place during aging and, finally, we overview the current status of emergent aging therapies and what the future holds for this field of research. From this multi-dimensional approach, it becomes clear that an integrative approach that couples aging research with systems biology, capable of providing novel insights into how and why we age, is necessary.

PMID: 27353257 [PubMed - as supplied by publisher]

Cell-to-cell infection by HIV contributes over half of virus infection.

Elife. 2015;4

Authors: Iwami S, Takeuchi JS, Nakaoka S, Mammano F, Clavel F, Inaba H, Kobayashi T, Misawa N, Aihara K, Koyanagi Y, Sato K

Abstract
Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread.

PMID: 26441404 [PubMed - indexed for MEDLINE]

Disease specific modules and hub genes for intervention strategies: A co-expression network based approach for Plasmodium falciparum clinical isolates.

Infect Genet Evol. 2015 Oct;35:96-108

Authors: Subudhi AK, Boopathi PA, Pandey I, Kaur R, Middha S, Acharya J, Kochar SK, Kochar DK, Das A

Abstract
Systems biology approaches that are based on gene expression and bioinformatics analysis have been successful in predicting the functions of many genes in Plasmodium falciparum, a protozoan parasite responsible for most of the deaths due to malaria. However, approaches that can provide information about the biological processes that are active in this parasite in vivo during complicated malaria conditions have been scarcely deployed. Here we report the analysis of a weighted gene co-expression based network for P. falciparum, from non-cerebral clinical complications. Gene expression profiles of 20 P. falciparum clinical isolates were utilized to construct the same. A total of 20 highly interacting modules were identified post network creation. In 12 of these modules, at least 10% of the member genes, were found to be differentially regulated in parasites from patient isolates showing complications, when compared with those from patients with uncomplicated disease. Enrichment analysis helped identify biological processes like oxidation-reduction, electron transport chain, protein synthesis, ubiquitin dependent catabolic processes, RNA binding and purine nucleotide metabolic processes as associated with these modules. Additionally, for each module, highly connected hub genes were identified. Detailed functional analysis of many of these, which have known annotated functions underline their importance in parasite development and survival. This suggests, that other hub genes with unknown functions may also be playing crucial roles in parasite biology, and, are potential candidates for intervention strategies.

PMID: 26247716 [PubMed - indexed for MEDLINE]

Network analysis of gene expression in peripheral blood identifies mTOR and NF-κB pathways involved in antipsychotic-induced extrapyramidal symptoms.

Pharmacogenomics J. 2015 Oct;15(5):452-60

Authors: Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A

Abstract
To identify the candidate genes for pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we propose a systems biology analytical approach, based on protein-protein interaction network construction and functional annotation analysis, of changes in gene expression (Human Genome U219 Array Plate) induced by treatment with risperidone or paliperidone in peripheral blood. 12 AP-naïve patients with first-episode psychosis participated in the present study. Our analysis revealed that, in response to AP treatment, constructed networks were enriched for different biological processes in patients without EPS (ubiquitination, protein folding and adenosine triphosphate (ATP) metabolism) compared with those presenting EPS (insulin receptor signaling, lipid modification, regulation of autophagy and immune response). Moreover, the observed differences also involved specific pathways, such as anaphase promoting complex /cdc20, prefoldin/CCT/triC and ATP synthesis in no-EPS patients, and mammalian target of rapamycin and NF-κB kinases in patients with EPS. Our results showing different patterns of gene expression in EPS patients, offer new and valuable markers for pharmacogenetic studies.

PMID: 25623440 [PubMed - indexed for MEDLINE]

Protein-protein interaction identification using a hybrid model.

Artif Intell Med. 2015 Jul;64(3):185-93

Authors: Niu Y, Wang Y

Abstract
BACKGROUND: Most existing systems that identify protein-protein interaction (PPI) in literature make decisions solely on evidence within a single sentence and ignore the rich context of PPI descriptions in large corpora. Moreover, they often suffer from the heavy burden of manual annotation.
METHODS: To address these problems, a new relational-similarity (RS)-based approach exploiting context in large-scale text is proposed. A basic RS model is first established to make initial predictions. Then word similarity matrices that are sensitive to the PPI identification task are constructed using a corpus-based approach. Finally, a hybrid model is developed to integrate the word similarity model with the basic RS model.
RESULTS: The experimental results show that the basic RS model achieves F-scores much higher than a baseline of random guessing on interactions (from 50.6% to 75.0%) and non-interactions (from 49.4% to 74.2%). The hybrid model further improves F-score by about 2% on interactions and 3% on non-interactions.
CONCLUSION: The experimental evaluations conducted with PPIs in well-known databases showed the effectiveness of our approach that explores context information in PPI identification. This investigation confirmed that within the framework of relational similarity, the word similarity model relieves the data sparseness problem in similarity calculation.

PMID: 26054427 [PubMed - indexed for MEDLINE]

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