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Unexploited Antineoplastic Effects of Commercially Available Anti-Diabetic Drugs.

Pharmaceuticals (Basel). 2016;9(2)

Authors: Papanagnou P, Stivarou T, Tsironi M

Abstract
The development of efficacious antitumor compounds with minimal toxicity is a hot research topic. Numerous cancer cell targeted agents are evaluated daily in laboratories for their antitumorigenicity at the pre-clinical level, but the process of their introduction into the market is costly and time-consuming. More importantly, even if these new antitumor agents manage to gain approval, clinicians have no former experience with them. Accruing evidence supports the idea that several medications already used to treat pathologies other than cancer display pleiotropic effects, exhibiting multi-level anti-cancer activity and chemosensitizing properties. This review aims to present the anticancer properties of marketed drugs (i.e., metformin and pioglitazone) used for the management of diabetes mellitus (DM) type II. Mode of action, pre-clinical in vitro and in vivo or clinical data as well as clinical applicability are discussed here. Given the precious multi-year clinical experience with these non-antineoplastic drugs their repurposing in oncology is a challenging alternative that would aid towards the development of therapeutic schemes with less toxicity than those of conventional chemotherapeutic agents. More importantly, harnessing the antitumor function of these agents would save precious time from bench to bedside to aid the fight in the arena of cancer.

PMID: 27164115 [PubMed - as supplied by publisher]

Punctuated evolution and transitional hybrid network in an ancestral cell cycle of fungi.

Elife. 2016;5

Authors: Medina EM, Turner JJ, Gordân R, Skotheim JM, Buchler NE

Abstract
Although cell cycle control is an ancient, conserved, and essential process, some core animal and fungal cell cycle regulators share no more sequence identity than non-homologous proteins. Here, we show that evolution along the fungal lineage was punctuated by the early acquisition and entrainment of the SBF transcription factor through horizontal gene transfer. Cell cycle evolution in the fungal ancestor then proceeded through a hybrid network containing both SBF and its ancestral animal counterpart E2F, which is still maintained in many basal fungi. We hypothesize that a virally-derived SBF may have initially hijacked cell cycle control by activating transcription via the cis-regulatory elements targeted by the ancestral cell cycle regulator E2F, much like extant viral oncogenes. Consistent with this hypothesis, we show that SBF can regulate promoters with E2F binding sites in budding yeast.

PMID: 27162172 [PubMed - in process]

Global de novo protein-protein interactome elucidates interactions of drought responsive proteins in horsegram (Macrotyloma uniflorum).

J Proteome Res. 2016 May 10;

Authors: Bhardwaj J, Gangwar I, Panzade GP, Shankar R, Yadav SK

Abstract
Inspired by the availability of de novo transcriptome of horsegram (Macrotyloma uniflorum) and recent developments in systems biology studies, first ever global protein-protein interactome (PPI) map was constructed for this highly drought tolerant legume. Large-scale studies of PPIs and the constructed database would provide rationale behind the interplay at cascading translational levels for drought stress adaptive mechanisms in horsegram. Using a bidirectional approach (interolog and domain-based), a high confidence interactome map and database for horsegram was constructed. Available transcriptomic information for shoot and root tissues of a sensitive genotype (M-191; genotype 1) and a drought tolerant (M-249; genotype 2) of horsegram was utilized to draw comparative PPI sub-networks under drought stress. High confidence 6804 interactions were predicted among 1812 proteins covering about one-fourth of the horsegram proteome. Highest number of interactions (33.86%) in horsegram interactome matched with Arabidopsis PPI data. Top five hub nodes mostly included ubiquitin and heat shock related proteins. Higher numbers of PPIs were found to be responsive in shoot tissue (416) and root tissue (2228) of genotype 2 compared to shoot tissue (136) and root tissue (579) of genotype 1. Characterization of PPIs using gene ontology analysis revealed that kinase and transferase activities involved in signal transduction, cellular processes, nucleocytoplasmic transport, protein ubiquitination and localization of molecules were most responsive to drought stress. Hence, these could be framed in stress adaptive mechanisms of horsegram. Being the first legume global PPI map, it would provide new insights in gene and protein regulatory networks for drought stress tolerance mechanisms in horsegram. Information compiled in form of database (MauPIR) will provide the much needed high confidence systems biology information for horsegram genes, proteins and involved processes. This information would ease the effort and increase the efficacy for similar studies on other legumes. Public access is available at http://14.139.59.221/MauPIR/.

PMID: 27161830 [PubMed - as supplied by publisher]

Proteome-wide alterations on adipose tissue from obese patients as age-, diabetes- and gender-specific hallmarks.

Sci Rep. 2016;6:25756

Authors: Gómez-Serrano M, Camafeita E, García-Santos E, López JA, Rubio MA, Sánchez-Pernaute A, Torres A, Vázquez J, Peral B

Abstract
Obesity is a main global health issue and an outstanding cause of morbidity and mortality predisposing to type 2 diabetes (T2DM) and cardiovascular diseases. Huge research efforts focused on gene expression, cellular signalling and metabolism in obesity have improved our understanding of these disorders; nevertheless, to bridge the gap between the regulation of gene expression and changes in signalling/metabolism, protein levels must be assessed. We have extensively analysed visceral adipose tissue from age-, T2DM- and gender-matched obese patients using high-throughput proteomics and systems biology methods to identify new biomarkers for the onset of T2DM in obesity, as well as to gain insight into the influence of aging and gender in these disorders. About 250 proteins showed significant abundance differences in the age, T2DM and gender comparisons. In diabetic patients, remarkable gender-specific hallmarks were discovered regarding redox status, immune response and adipose tissue accumulation. Both aging and T2DM processes were associated with mitochondrial remodelling, albeit through well-differentiated proteome changes. Systems biology analysis highlighted mitochondrial proteins that could play a key role in the age-dependent pathophysiology of T2DM. Our findings could serve as a framework for future research in Translational Medicine directed at improving the quality of life of obese patients.

PMID: 27160966 [PubMed - in process]

Understanding the Metabolic Consequences of Human Arylsulfatase A Deficiency through a Computational Systems Biology Study.

Cent Nerv Syst Agents Med Chem. 2016 May 10;

Authors: Echeverri Olga Y, Salazar Diego A, Rodriguez-Lopez A, Janneth G, Almeciga-Diaz Carlos J, Barrera Luis A

Abstract
The nervous system is responsible for the communication between the organism and its environment. This task is possible by the presence of the myelin sheath, which is a double membrane formed by about 75% lipids and 25% proteins. The sulfatide represents one of the main lipids of the myelin band; its degradation is catabolized by the enzyme Arylsulfatase A (ARSA), to generated galactosylceramide. Mutations affecting ARSA function lead to the neurodegenerative disease Metachromatic Leukodystrophy. This disease is characterized by accumulation of sulfatide within the band of myelin affecting its functionality. The biochemical consequences of ARSA deficiency are not well understood yet. In this paper, we used an in-silico systems-biology approach to model the biochemical consequences of ARSA deficiency within a general human metabolic network (Recon2) and a glia cellular model. We expected that ARSA deficiency mainly affected the glycosphingolipid pathways. However, the results suggest that mitochondrial metabolism and amino acid transport were the main reactions affected within both cellular models. In the glia cell model, it was highlighted the high number of affected reactions of neurotransmitters metabolism, while only a reduced effect was observed in reactions involved in glycosphingolipids metabolism. We hypothesize that ARSA deficiency might lead to metabolic consequences that not only compromise the myelin band or the glycosphingolipids metabolism but also the overall metabolic function of the nervous system. Furthermore, these results offer the bases for the design of in-vitro and in-vivo experiments that allow generating new knowledge of MLD pathophysiology and other neurodegenerative diseases.

PMID: 27160716 [PubMed - as supplied by publisher]

Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.

Elife. 2015;4

Authors: Korkut A, Wang W, Demir E, Aksoy BA, Jing X, Molinelli EJ, Babur Ö, Bemis DL, Onur Sumer S, Solit DB, Pratilas CA, Sander C

Abstract
Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.

PMID: 26284497 [PubMed - indexed for MEDLINE]

Prioritizing Chemicals for Risk Assessment Using Chemoinformatics: Examples from the IARC Monographs on Pesticides.

Environ Health Perspect. 2016 May 10;

Authors: Guha N, Guyton KZ, Loomis D, Barupal DK

Abstract
BACKGROUND: Identifying cancer hazards is the first step towards cancer prevention. The IARC Monographs Programme, which has evaluated nearly 1000 agents for carcinogenic potential since 1971, typically selects agents for hazard identification on the basis of public nominations, expert advice, published data on carcinogenicity, and public health importance.
OBJECTIVES: Here we present a novel and complementary strategy for identifying agents for hazard evaluation using chemoinformatics, database integration and automated text mining.
DISCUSSION: To inform selection among a broad range of pesticides nominated for evaluation, we identified and screened nearly 6000 relevant chemical structures, thereafter systematically compiled information on 980 pesticides, creating chemical similarity network maps that allowed cluster visualization by chemical similarity, pesticide class, and publicly available information concerning cancer epidemiology, cancer bioassays, and carcinogenic mechanisms. For the IARC Monograph meetings that took place in March and June 2015, this approach supported high priority evaluation of glyphosate, malathion, parathion, tetrachlorvinphos, diazinon, DDT, lindane, and 2,4-D.
CONCLUSIONS: This systematic approach, accounting for chemical similarity and overlaying multiple data sources, can be used by risk assessors as well as researchers to systematize, inform and increase efficiency in selecting and prioritizing agents for hazard identification, risk assessment, regulation or further investigation. This approach could be extended to an array of outcomes and agents, including occupational carcinogens, drugs, and foods.

PMID: 27164621 [PubMed - as supplied by publisher]

Convex biclustering.

Biometrics. 2016 May 10;

Authors: Chi EC, Allen GI, Baraniuk RG

Abstract
In the biclustering problem, we seek to simultaneously group observations and features. While biclustering has applications in a wide array of domains, ranging from text mining to collaborative filtering, the problem of identifying structure in high-dimensional genomic data motivates this work. In this context, biclustering enables us to identify subsets of genes that are co-expressed only within a subset of experimental conditions. We present a convex formulation of the biclustering problem that possesses a unique global minimizer and an iterative algorithm, COBRA, that is guaranteed to identify it. Our approach generates an entire solution path of possible biclusters as a single tuning parameter is varied. We also show how to reduce the problem of selecting this tuning parameter to solving a trivial modification of the convex biclustering problem. The key contributions of our work are its simplicity, interpretability, and algorithmic guarantees-features that arguably are lacking in the current alternative algorithms. We demonstrate the advantages of our approach, which includes stably and reproducibly identifying biclusterings, on simulated and real microarray data.

PMID: 27163413 [PubMed - as supplied by publisher]

BioCreative V CDR task corpus: a resource for chemical disease relation extraction.

Database (Oxford). 2016;2016

Authors: Li J, Sun Y, Johnson RJ, Sciaky D, Wei CH, Leaman R, Davis AP, Mattingly CJ, Wiegers TC, Lu Z

Abstract
Community-run, formal evaluations and manually annotated text corpora are critically important for advancing biomedical text-mining research. Recently in BioCreative V, a new challenge was organized for the tasks of disease named entity recognition (DNER) and chemical-induced disease (CID) relation extraction. Given the nature of both tasks, a test collection is required to contain both disease/chemical annotations and relation annotations in the same set of articles. Despite previous efforts in biomedical corpus construction, none was found to be sufficient for the task. Thus, we developed our own corpus called BC5CDR during the challenge by inviting a team of Medical Subject Headings (MeSH) indexers for disease/chemical entity annotation and Comparative Toxicogenomics Database (CTD) curators for CID relation annotation. To ensure high annotation quality and productivity, detailed annotation guidelines and automatic annotation tools were provided. The resulting BC5CDR corpus consists of 1500 PubMed articles with 4409 annotated chemicals, 5818 diseases and 3116 chemical-disease interactions. Each entity annotation includes both the mention text spans and normalized concept identifiers, using MeSH as the controlled vocabulary. To ensure accuracy, the entities were first captured independently by two annotators followed by a consensus annotation: The average inter-annotator agreement (IAA) scores were 87.49% and 96.05% for the disease and chemicals, respectively, in the test set according to the Jaccard similarity coefficient. Our corpus was successfully used for the BioCreative V challenge tasks and should serve as a valuable resource for the text-mining research community.Database URL: http://www.biocreative.org/tasks/biocreative-v/track-3-cdr/.

PMID: 27161011 [PubMed - in process]

Clinical Management of Head and Neck Cancer Cases: Role of Pharmacogenetics of CYP2 and GSTs.

Oncol Res Treat. 2016;39(4):221-6

Authors: Ruwali M, Dhawan A, Pant MC, Rahman Q, Khurana SM, Parmar D

Abstract
Head and neck squamous cell carcinoma (HNSCC) describes a wide range of malignant tumors which originate in the upper aerodigestive tract and have a multifactorial origin involving both genetic and lifestyle risk factors. The clinical management of head and neck cancer involves surgery, radiotherapy, and chemotherapy. With the advances in treatment strategies for HNSCC, newer targeted therapies are adding to the progress already achieved in the multimodality management of patients although the problems of differences in drug response and adverse drug reactions are still grave concerns. Cancer pharmacogenomics has fast emerged as a new and promising field for the early identification of genetic markers that can predict drug response or toxicity. This could greatly help in identifying genetic markers useful for the selection of optimal drugs, dose, and treatment duration on an individual basis resulting in improved drug efficacy and decreased toxicity. This review focuses on the various treatment modalities available for the clinical management of HNSCC followed by a description of the contribution of genetic variations to chemotherapeutic toxicity and response. Furthermore, studies addressing the association of genetic variants of drug-metabolizing enzymes with treatment response in head and neck cancer are also discussed.

PMID: 27160276 [PubMed - in process]

Recent advances in large-scale protein interactome mapping.

F1000Res. 2016;5

Authors: Mehta V, Trinkle-Mulcahy L

Abstract
Protein-protein interactions (PPIs) underlie most, if not all, cellular functions. The comprehensive mapping of these complex networks of stable and transient associations thus remains a key goal, both for systems biology-based initiatives (where it can be combined with other 'omics' data to gain a better understanding of functional pathways and networks) and for focused biological studies. Despite the significant challenges of such an undertaking, major strides have been made over the past few years. They include improvements in the computation prediction of PPIs and the literature curation of low-throughput studies of specific protein complexes, but also an increase in the deposition of high-quality data from non-biased high-throughput experimental PPI mapping strategies into publicly available databases.

PMID: 27158474 [PubMed]

Dental and dentofacial problems in a female child with Toriello-Carey -syndrome: changes in 3 years.

Spec Care Dentist. 2016 May 9;

Authors: Tirali RE, İlhan B, Şar Ç, Çehreli SB

Abstract
Toriello-Carey syndrome is a rare disease whose clinical manifestations are midline facial defects, laryngeal and pharyngeal hypoplasia, cardiac defect, and corpus callosum hypoplasia. Literature states that clinical manifestations are more evident in males. This is the second report in the literature which describes the dental and dentofacial -features in an 8-year-old female patient with Toriello-Carey syndrome.

PMID: 27159668 [PubMed - as supplied by publisher]

Paraneoplastic stiff person syndrome: Inpatient rehabilitation outcomes of a rare disease from two cancer rehabilitation programmes.

J Rehabil Med. 2016 May 3;

Authors: Robinson Smith S, Fu JB

Abstract
Paraneoplastic stiff person syndrome is a rare, but debilitating, manifestation of cancer, characterized by painful extremities, truncal and facial spasms. The resultant functional impairment may necessitate comprehensive rehabilitation and symptom management. This case series describes the acute inpatient rehabilitation courses of 2 patients at different tertiary care referral cancer rehabilitation programmes, including work-up and diagnosis, medical management of symptoms, and functional outcomes. Both patients had a reduction in symptom burden and an improvement in motor function as a result of multidisciplinary acute inpatient rehabilitation.

PMID: 27157044 [PubMed - as supplied by publisher]

Chronic recurrent multifocal osteomyelitis: a rare skeletal disorder.

BMJ Case Rep. 2015;2015

Authors: Aygun D, Barut K, Camcioglu Y, Kasapcopur O

Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare non-infectious inflammatory bone disease of unknown aetiology. CRMO mainly affects the metaphyses of long bones and spine in children and young adolescents. It presents with recurrent episodes of bone pain and fever, resembling bacterial osteomyelitis, but cultures of lesions are sterile and it is unresponsive to antibiotic therapy. We report a case of a 3-year-old boy diagnosed with CRMO, who was initially treated for bacterial osteomyelitis, and received prolonged antibiotic therapy for chronic pain, and swelling of mandible and ulna. CRMO should be kept in mind in the differential diagnosis of chronic bone pain and osteomyelitis unresponsive to antibiotic treatment.

PMID: 26307646 [PubMed - indexed for MEDLINE]

Report on the EUROMAC McArdle Exercise Testing Workshop, Madrid, Spain, 11-12 July 2014.

Neuromuscul Disord. 2015 Sep;25(9):739-45

Authors: Quinlivan R, Lucia A, Scalco RS, Santalla A, Pattni J, Godfrey R, Marti R, Workshop Participants

PMID: 26159598 [PubMed - indexed for MEDLINE]

Breast: Sezary Syndrome: A Unique Presentation.

Breast J. 2015 Jul-Aug;21(4):423-7

Authors: Bedayat A, Mirzabeigi M, Yu H, Hultman R, MacMaster S

Abstract
Sezary syndrome is a subtype of cutaneous T cell lymphoma which usually presents as generalized skin disease with erytheroderma. Distal organ involvement is rare and is usually a late finding in the course of the disease. Breast involvement is extremely rare. Herein, we present a case report of a patient whose initial presentation involved an intramammary lymph node prior to the onset of more characteristic skin disease. Sezary syndrome was confirmed by cythopathologic findings.

PMID: 25939954 [PubMed - indexed for MEDLINE]

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy.

Cell Death Differ. 2015 Nov;22(11):1742-53

Authors: Morató L, Ruiz M, Boada J, Calingasan NY, Galino J, Guilera C, Jové M, Naudí A, Ferrer I, Pamplona R, Serrano M, Portero-Otín M, Beal MF, Fourcade S, Pujol A

Abstract
Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired.

PMID: 25822341 [PubMed - indexed for MEDLINE]

Use of Pharmacogenomics and Biomarkers in the Development of New Drugs for Alzheimer Disease in Japan.

Clin Ther. 2015 Aug;37(8):1627-31

Authors: Otsubo Y

Abstract
PURPOSE: Pharmacogenomics (PGx) and biomarkers have been utilized for improving the benefit/risk ratios of drugs and the efficiency of drug development. In the development of drugs for Alzheimer disease (AD), a number of clinical trials have failed to demonstrate clinical efficacy. To overcome this circumstance, the importance of using PGx/biomarkers for enhancing recruitment into clinical trials and for evaluating the efficacy of treatments has been increasingly recognized. In this article, the current status and examples of the use of PGx/biomarkers in Japan for drug development are explained.
METHODS: Guidelines, notifications, and administrative notices related to PGx/biomarkers were downloaded from the Web sites of the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration, and the European Medicines Agency. Data from clinical studies of AD drugs were obtained from the review reports of the PMDA. To analyze the current status of the use of PGx/biomarkers in Japan, "Issues to Consider in the Clinical Evaluation and Development of Drugs for Alzheimer's Disease (Interim Summary)" was also downloaded from PMDA Web site.
FINDINGS: There are 2 major measures of utilizing PGx/biomarkers for drug development: (1) biomarker qualification and (2) companion diagnostics. Recently, the PMDA issued a number of guidelines and notifications for their practical use. Although examples of qualified PGx/biomarkers and approved companion diagnostics are limited at present, it is expected that the use of PGx/biomarkers for the development of drugs against AD would increase.
IMPLICATIONS: For promoting the use of PGx/biomarkers in the development of drugs against AD, PGx/biomarkers should be qualified as early as possible. To that end, accumulating data on PGx/biomarkers from nonclinical or clinical trials and the concurrent development of reliable diagnostics in the early stage of the development process are indispensable. It is important to strengthen collaboration among the academia, industries, and regulatory agencies, followed by the establishment of an effective guideline in the area of AD.

PMID: 25963998 [PubMed - indexed for MEDLINE]

The Contribution of Transcriptomics to Biomarker Development in Systemic Vasculitis and SLE.

Curr Pharm Des. 2015;21(17):2225-35

Authors: Flint SM, McKinney EF, Lyons PA, Smith KG

Abstract
A small but increasing number of gene expression based biomarkers are becoming available for routine clinical use, principally in oncology and transplantation. These underscore the potential of gene expression arrays and RNA sequencing for biomarker development, but this potential has not yet been fully realized and most candidates do not progress beyond the initial report. The first part of this review examines the process of gene expression- based biomarker development, highlighting how systematic biases and confounding can significantly skew study outcomes. Adequate validation in an independent cohort remains the single best means of protecting against these concerns. The second part considers gene-expression based biomarkers in Systemic Lupus Erythematosus (SLE) and systemic vasculitis. The type 1 interferon inducible gene signature remains by far the most studied in autoimmune rheumatic disease. While initially presented as an objective, blood-based biomarker of active SLE, subsequent research has shown that it is not specific to SLE and that its association with disease activity is considerably more nuanced than first thought. Nonetheless, it is currently under evaluation in ongoing trials of anti-interferon therapy. Other candidate markers of note include a prognostic CD8+ T-cell gene signature validated in SLE and ANCA-associated vasculitis, and a disease activity biomarker for SLE derived from modules of tightly correlated genes.

PMID: 25771200 [PubMed - indexed for MEDLINE]