Hemophagocytic Lymphohistiocytosis and Progressive Disseminated Histoplasmosis.

Emerg Infect Dis. 2016 Jun;22(6):1119-1121

Authors: Ferguson-Paul K, Mangum S, Porter A, Leventaki V, Campbell P, Wolf J

PMID: 27191972 [PubMed - as supplied by publisher]

Treatment of genetic defects of thiamine transport and metabolism.

Expert Rev Neurother. 2016 May 18;

Authors: Ortigoza-Escobar JD, Molero-Luis M, Arias A, Martí-Sánchez L, Rodriguez-Pombo P, Artuch R, Pérez-Dueñas B

Abstract
INTRODUCTION: Thiamine is a key cofactor for energy metabolism in brain tissue. There are four major genetic defects (SLC19A2, SLC19A3, SLC25A19 and TPK1) involved in the metabolism and transport of thiamine through cellular and mitochondrial membranes. Neurological involvement predominates in three of them (SLC19A3, SCL25A19 and TPK1), whereas patients with SLC19A2 mutations mainly present extra-neurological features (e.g. diabetes mellitus, megaloblastic anaemia and sensory-neural hearing loss). These genetic defects may be amenable to therapeutic intervention with vitamins supplementation and hence, constitutes a main area of research. Areas Covered: We conducted a literature review of all reported cases with these genetic defects, and focused our paper on treatment efficacy and safety, adverse effects, dosing and treatment monitoring. Expert Commentary: Doses of thiamine vary according to the genetic defect: for SLC19A2, the usual dose is 25-200 mg/day (1-4 mg/kg per day), for SLC19A3, 10-40 mg/kg per day, and for TPK1, 30 mg/kg per day. Thiamine supplementation in SLC19A3-mutated patients restores CSF and intracellular thiamine levels, resulting in successful clinical benefits. In conclusion, evidence collected so far suggests that the administration of thiamine improves outcome in SLC19A-2, SLC19A3- and TPK1-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.

PMID: 27191787 [PubMed - as supplied by publisher]

Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Expert Rev Clin Immunol. 2016 May 18;

Authors: Pagnoux C, Groh M

Abstract
INTRODUCTION: The prevalence of eosinophilic granulomatosis with polyangiitis (EGPA; previously known as Churg-Strauss syndrome) is lower than that of other antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV's), and only a few randomized controlled trials have been conducted for this rare disease. However, recent international efforts have helped delineate the best treatment approach. Areas covered: At present, EGPA conventional therapy is by default similar to that of other AAVs. Limited, non-severe EGPA can initially be treated with glucocorticoids (GCs) alone. Patients with life-threatening manifestations and/or major organ involvement must receive a combination of GCs and an immunosuppressant, mainly cyclophosphamide. Remission can be achieved in >85% of patients with these first-line treatments, but vasculitis relapses occur in more than one-third of patients, and about 15% cannot stop GC treatment because of GC-dependent asthma and/or ENT manifestations. A few biologic agents, including rituximab or mepolizumab, are now under investigation after interesting preliminary results. Expert Commentary: Treatment for EGPA still has several unmet needs. Several biologic agents are now under investigation in randomized controlled trials, but a few others should be considered soon. Their benefit should be demonstrated for devising more EGPA-tailored therapeutic strategies (ideally GC-free).

PMID: 27191665 [PubMed - as supplied by publisher]

Rett syndrome: establishing a novel outcome measure for walking activity in an era of clinical trials for rare disorders.

Disabil Rehabil. 2015;37(21):1992-6

Authors: Downs J, Leonard H, Jacoby P, Brisco L, Baikie G, Hill K

Abstract
BACKGROUND: Rett syndrome is a pervasive neurological disorder with impaired gait as one criterion. This study investigated the capacity of three accelerometer-type devices to measure walking activity in Rett syndrome.
METHODS: Twenty-six participants (mean 18 years, SD 8) wore an Actigraph, ActivPAL and StepWatch Activity Monitor (SAM) during a video-taped session of activities. Agreement was determined between step-counts derived from each accelerometer and observation. Repeatability of SAM-derived step counts was determined using pairs of one-minute epochs during which the same participant was observed to walk with the same cadence.
RESULTS: The mean difference (limit of agreement) for the Actigraph, ActivPAL and SAM were -41 (SD 33), -16 (SD 21) and -1 (SD 16) steps/min, respectively. Agreement was influenced by a device/cadence interaction (p < 0.001) with greater under-recording at higher cadences. For SAM data, repeatability of step-count pairs was excellent (intraclass correlation coefficient 0.91, 95% CI 0.79-0.96). The standard error of measurement was 6 steps/min and we would be 95% confident that a change ≥17 steps/min would be greater than within-subject measurement error.
CONCLUSIONS: The capacity of the SAM to measure physical activity in Rett syndrome allows focus on participation-based activities in clinical practice and clinical trials. Implications for Rehabilitation Many girls and women with Rett syndrome are able to walk on their own or with assistance but with altered movement patterns. Validated measures of physical activity, such as step counts, have potential to monitor function during daily life. Compared with other forms of accelerometer-type devices, such as ActiGraph and ActivPAL, the StepWatch Activity Monitor (SAM) measured step counts with good accuracy and repeatability. The capacity of the SAM to measure physical activity in Rett syndrome allows focus on participation-based activities in clinical practice and clinical trials.

PMID: 25495774 [PubMed - indexed for MEDLINE]

Advancing our understanding of infant bronchiolitis through phenotyping and endotyping: Clinical and molecular approaches.

Expert Rev Respir Med. 2016 May 18;

Authors: Hasegawa K, Dumas O, Hartert TV, Camargo CA

Abstract
INTRODUCTION: Bronchiolitis is a major public health problem worldwide. However, no effective treatment strategies are available, other than supportive care. Areas Covered: Although bronchiolitis has been considered a single disease diagnosed based on clinical characteristics, emerging evidence supports both clinical and pathobiological heterogeneity. The characterization of this heterogeneity supports the concept that bronchiolitis consists of multiple phenotypes or consistent grouping of characteristics. Expert Commentary: Using unbiased statistical approaches, multidimentional clinical characteristics will derive bronchiolitis phenotypes. Furthermore, molecular and systems biology approaches will, by linking pathobiology to phenotype, identify endotypes. Large cohort studies of bronchiolitis with comprehensive clinical characterization and system-wide profiling of the "-omics" data (e.g., host genome, transcriptome, epigenome, viral genome, microbiome, metabolome) should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to bronchiolitis treatment.

PMID: 27192374 [PubMed - as supplied by publisher]

Practical aspects of NGS-based pathways analysis for personalized cancer science and medicine.

Oncotarget. 2016 May 14;

Authors: Kotelnikova EA, Pyatnitskiy M, Paleeva A, Kremenetskaya O, Vinogradov D

Abstract
Nowadays, the personalized approach to health care and cancer care in particular is becoming more and more popular and is taking an important place in the translational medicine paradigm. In some cases, detection of the patient-specific individual mutations that point to a targeted therapy has already become a routine practice for clinical oncologists. Wider panels of genetic markers are also on the market which cover a greater number of possible oncogenes including those with lower reliability of resulting medical conclusions. In light of the large availability of high-throughput technologies, it is very tempting to use complete patient-specific New Generation Sequencing (NGS) or other "omics" data for cancer treatment guidance. However, there are still no gold standard methods and protocols to evaluate them. Here we will discuss the clinical utility of each of the data types and describe a systems biology approach adapted for single patient measurements. We will try to summarize the current state of the field focusing on the clinically relevant case-studies and practical aspects of data processing.

PMID: 27191992 [PubMed - as supplied by publisher]

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"Systems Biology"[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

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'RE:fine drugs': an interactive dashboard to access drug repurposing opportunities.

Database (Oxford). 2016;2016

Authors: Moosavinasab S, Patterson J, Strouse R, Rastegar-Mojarad M, Regan K, Payne PR, Huang Y, Lin SM

Abstract
The process of discovering new drugs has been extremely costly and slow in the last decades despite enormous investment in pharmaceutical research. Drug repurposing enables researchers to speed up the process of discovering other conditions that existing drugs can effectively treat, with low cost and fast FDA approval. Here, we introduce 'RE:fine Drugs', a freely available interactive website for integrated search and discovery of drug repurposing candidates from GWAS and PheWAS repurposing datasets constructed using previously reported methods in Nature Biotechnology. 'RE:fine Drugs' demonstrates the possibilities to identify and prioritize novelty of candidates for drug repurposing based on the theory of transitive Drug-Gene-Disease triads. This public website provides a starting point for research, industry, clinical and regulatory communities to accelerate the investigation and validation of new therapeutic use of old drugs.Database URL: http://drug-repurposing.nationwidechildrens.org.

PMID: 27189611 [PubMed - as supplied by publisher]

Learning disease relationships from clinical drug trials.

J Am Med Inform Assoc. 2016 May 17;

Authors: Haslam B, Perez-Breva L

Abstract
OBJECTIVE: Our objective is to test the limits of the assumption that better learning from data in medicine requires more granular data. We hypothesize that clinical trial metadata contains latent scientific, clinical, and regulatory expert knowledge that can be accessed to draw conclusions about the underlying biology of diseases. We seek to demonstrate that this latent information can be uncovered from the whole body of clinical trials.
MATERIALS AND METHODS: We extract free-text metadata from 93 654 clinical drug trials and introduce a representation that allows us to compare different trials. We then construct a network of diseases using only the trial metadata. We view each trial as the summation of expert knowledge of biological mechanisms and medical evidence linking a disease to a drug believed to modulate the pathways of that disease. Our network representation allows us to visualize disease relationships based on this underlying information.
RESULTS: Our disease network shows surprising agreement with another disease network based on genetic data and on the Medical Subject Headings (MeSH) taxonomy, yet also contains unique disease similarities.
DISCUSSION AND CONCLUSION: The agreement of our results with other sources indicates that our premise regarding latent expert knowledge holds. The disease relationships unique to our network may be used to generate hypotheses for future biological and clinical research as well as drug repurposing and design. Our results provide an example of using experimental data on humans to generate biologically useful information and point to a set of new and promising strategies to link clinical outcomes data back to biological research.

PMID: 27189012 [PubMed - as supplied by publisher]

Enhancing the enrichment of pharmacophore-based target prediction for the polypharmacological profiles of drugs.

J Chem Inf Model. 2016 May 17;

Authors: Wang X, Pan C, Gong J, Liu X, Li H

Abstract
PharmMapper is a web server for drug targets identification by reversed pharmacophore matching the query compound against an annotated pharmacophore model database, which provides a computational polypharmacology prediction approach for drug repurposing and side effects risk evaluation. But due to the inherent non-discriminative feature of the simple fit scores used for prediction results ranking, the signal/noise ratio of the prediction results is high, posing a challenge for predictive reliability. In this paper, we improved the predictive accuracy of PharmMapper by generating a ligand-target pairwise fit scores matrix from profiling all the annotated pharmacophore models against corresponding ligands in the original complex structures that were used to extract these pharmacophore models. The matrix reflects the noise baseline of fit scores distribution of the background database, thus enables estimating the probability of finding a given target by random with the calculated ligand-pharmacophore fit score. Two retrospective tests were performed and confirmed the probability-based ranking score outperformed the simple fit score in terms of identification of both known drug targets and adverse drug reactions (ADRs) related off-targets.

PMID: 27187084 [PubMed - as supplied by publisher]

Using reverse docking for target identification and its applications for drug discovery.

Expert Opin Drug Discov. 2016 May 17;

Authors: Lee A, Lee K, Kim D

Abstract
Introduction In contrast to traditional molecular docking, inverse or reverse docking is used for identifying receptors for a given ligand among a large number of receptors. Reverse docking can be used to discover new targets for existing drugs and natural compounds, explain polypharmacology and the molecular mechanism of a substance, find alternative indications of drugs through drug repositioning, and detecting adverse drug reactions and drug toxicity. Areas covered In this review, the authors examine how reverse docking methods have evolved over the past fifteen years and how they have been used for target identification and related applications for drug discovery. They discuss various aspects of target databases, reverse docking tools and servers. Expert opinion There are several issues related to reverse docking methods such as target structure dataset construction, computational efficiency, how to include receptor flexibility, and most importantly, how to properly normalize the docking scores. In order for reverse docking to become a truly useful tool for the drug discovery, these issues need to be adequately resolved.

PMID: 27186904 [PubMed - as supplied by publisher]

Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability.

PLoS One. 2015;10(8):e0134915

Authors: Gresser AL, Gutzwiller LM, Gauck MK, Hartenstein V, Cook TA, Gebelein B

Abstract
Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability.

PMID: 26252385 [PubMed - indexed for MEDLINE]

Editorial.

Cell Mol Biol (Noisy-le-grand). 2016;62(5):1

Authors: Farooqi AA

Abstract
To optimize treatment, we need to understand biology of different diseases in much more detail with emphasis on morphological, proteomic, genetic and epigenetic grounds. Keeping in view the facts and stimulating developments in molecular pathology, it is worthwhile to present an up-date on this topic.It is becoming progressively more understandable that exciting fields of pharmacogenomics and pharmacogenetics have revolutionized field of medicine. Better understanding of underlying mechanisms of different diseases has provided us with better ways to treat illnesses. There cannot be a distinct definition of 'discipline' of pathology, mainly because investigation of human disease encompasses all the scientific disciplines of biomedical research. Sen et al reported that hyperbarıc oxygen (HBO) administration affected the endocrinological functions of fat tissue. Observation of significant increases in leptin, visfatin and IL-10 levels, leads to the consideration that in near future HBO administration may be applied as treatment for obesity, DM, eating disorders and obesity related diseases...

PMID: 27188861 [PubMed - as supplied by publisher]

Hepatotoxicity of targeted therapy for cancer.

Expert Opin Drug Metab Toxicol. 2016 May 17;

Authors: Lee KW, Chan SL

Abstract
Molecular targeted agents (MTA) have become the mainstay of treatment for many cancers in the past decade. Hepatotoxicity of varying forms and severity is common with the use of MTA and risk factors have been identified. Hepatotoxicity can result from direct hepatocellular, cholestatic or steatotic injury, through immunogenic pathways or reactivation of viral hepatitis. Selecting an appropriate starting dose for special populations, arranging viral hepatitis screening prior to initiation of relevant MTA and knowing the standards for liver function test (LFT) monitoring are crucial to preventing morbidity and mortality from drug-induced liver injury (DILI) and minimising discontinuation of MTA. This is a comprehensive review on how to interpret LFTs in the light of MTA use, mechanisms of DILI, identification of high risk groups, and measures for preventing and managing hepatotoxicity.
INTRODUCTION: Understanding the mechanism of DILI with MTA, and how to avoid and manage these toxicities is essential for minimising inferior cancer treatment outcomes. An organised and comprehensive overview of MTA-associated hepatotoxicity is lacking; this review aims to fill the gap. Areas covered: A literature review was performed based on published case reports and relevant studies or articles pertaining to the topics on PubMed. Food and Drug Administration drug information documents and search on the US National Library of Medicine LiverTox database was performed for all relevant MTA. Expert opinion: MTA-associated hepatotoxicity is common but rarely fatal. The pattern of hepatotoxicity is predominantly idiosyncratic. Pharmacogenomics show potential in predicting patients at risk of poorly metabolising or developing immunoallergic responses to MTA, but prospective data is scant. Preventing reactivation of viral hepatitis using anti-viral drugs, and avoidance of drug combinations at high risk of negative interactions are the most readily preventable measures for DILI.

PMID: 27187715 [PubMed - as supplied by publisher]

Clinical Zheng-hou Pharmacology: the Missing Link between Pharmacogenomics and Personalized Medicine?

Curr Vasc Pharmacol. 2015;13(4):423-32

Authors: Yu YN, Liu J, Zhang L, Wang Z, Duan DD, Wang YY

Abstract
In Chinese medicine, Zheng-hou, instead of disease, is used to define complex medical problems in clinical practice. In the postgenomics era, it becomes particularly compelling to review the application of Zheng-hou in characterizing complex clinical problems independent of disease or syndrome. While disease or syndrome describes a pathological phenotype or phenotypes, Zheng-hou spells the pathological phenome. Clinical Zheng-hou pharmacology (CZP) is an emerging clinical discipline that aims to leverage breakthroughs in the genome-wide solutions for complex medical problems through a combination of the current "omics" technology and the knowledge of Chinese medicine. The concept of CZP suggests that systematic and standard studies of multiple phenotypes will be important because of the collaborative cross between diversified external and internal factors at different levels both in vitro and in vivo. In this paper, we discuss the novel phenomic approaches to the understanding of Zheng-hou and the link of pharmacogenomics to personalized medicine through CZP, or pharmacophenomics. CZP enables ever-finer mapping of Zheng-hou and detection of dynamic variations in most current omics platforms. Although major challenges still remain in identifying and effectively investigating the diversity of Zheng-hou, CZP is expected to pave new paths to the systemic understanding of medical problems. While still at early stages in the clinical phenome domain, there remains great promise that CZP can help us realize the application of personalized medicine and contribute to rational holistic diagnosis and treatment.

PMID: 25360846 [PubMed - indexed for MEDLINE]

Autoantigen Microarray for High-throughput Autoantibody Profiling in Systemic Lupus Erythematosus.

Genomics Proteomics Bioinformatics. 2015 Aug;13(4):210-8

Authors: Zhu H, Luo H, Yan M, Zuo X, Li QZ

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to a broad range of self-antigens. Profiling the autoantibody repertoire using array-based technology has emerged as a powerful tool for the identification of biomarkers in SLE and other autoimmune diseases. Proteomic microarray has the capacity to hold large number of self-antigens on a solid surface and serve as a high-throughput screening method for the determination of autoantibody specificities. The autoantigen arrays carrying a wide variety of self-antigens, such as cell nuclear components (nucleic acids and associated proteins), cytoplasmic proteins, phospholipid proteins, cell matrix proteins, mucosal/secreted proteins, glomeruli, and other tissue-specific proteins, have been used for screening of autoantibody specificities associated with different manifestations of SLE. Arrays containing synthetic peptides and molecular modified proteins are also being utilized for identification of autoantibodies targeting to special antigenic epitopes. Different isotypes of autoantibodies, including IgG, IgM, IgA, and IgE, as well as other Ig subtypes, can be detected simultaneously with multi-color labeled secondary antibodies. Serum and plasma are the most common biologic materials for autoantibody detection, but other body fluids such as cerebrospinal fluid, synovial fluid, and saliva can also be a source of autoantibody detection. Proteomic microarray as a multiplexed high-throughput screening platform is playing an increasingly-important role in autoantibody diagnostics. In this article, we highlight the use of autoantigen microarrays for autoantibody exploration in SLE.

PMID: 26415621 [PubMed - indexed for MEDLINE]

Molecular cytopathology for thyroid nodules: A review of methodology and test performance.

Cancer Cytopathol. 2016 Jan;124(1):14-27

Authors: Nishino M

Abstract
Advances in the molecular characterization of thyroid cancers have fueled the development of genetic and gene expression-based tests for thyroid fine-needle aspirations. Collectively, these tests are designed to improve the diagnostic certainty of thyroid cytology. This review summarizes the early published experience with the commercially available versions of these tests: the Afirma Gene Expression Classifier, ThyGenX (formerly miRInform)/ThyraMIR, and ThyroSeq. Key differences in testing approaches and issues regarding test performance and interpretation are also discussed.

PMID: 26348024 [PubMed - indexed for MEDLINE]

RNA-Seq: Improving Our Understanding of Retinal Biology and Disease.

Cold Spring Harb Perspect Med. 2015;5(9):a017152

Authors: Farkas MH, Au ED, Sousa ME, Pierce EA

Abstract
Over the past several years, rapid technological advances have allowed for a dramatic increase in our knowledge and understanding of the transcriptional landscape, because of the ability to study gene expression in greater depth and with more detail than previously possible. To this end, RNA-Seq has quickly become one of the most widely used methods for studying transcriptomes of tissues and individual cells. Unlike previously favored analysis methods, RNA-Seq is extremely high-throughput, and is not dependent on an annotated transcriptome, laying the foundation for novel genetic discovery. Additionally, RNA-Seq derived transcriptomes provide a basis for widening the scope of research to identify potential targets in the treatment of retinal disease.

PMID: 25722474 [PubMed - indexed for MEDLINE]

Argo: enabling the development of bespoke workflows and services for disease annotation.

Database (Oxford). 2016;2016

Authors: Batista-Navarro R, Carter J, Ananiadou S

Abstract
Argo (http://argo.nactem.ac.uk) is a generic text mining workbench that can cater to a variety of use cases, including the semi-automatic annotation of literature. It enables its technical users to build their own customised text mining solutions by providing a wide array of interoperable and configurable elementary components that can be seamlessly integrated into processing workflows. With Argo's graphical annotation interface, domain experts can then make use of the workflows' automatically generated output to curate information of interest.With the continuously rising need to understand the aetiology of diseases as well as the demand for their informed diagnosis and personalised treatment, the curation of disease-relevant information from medical and clinical documents has become an indispensable scientific activity. In the Fifth BioCreative Challenge Evaluation Workshop (BioCreative V), there was substantial interest in the mining of literature for disease-relevant information. Apart from a panel discussion focussed on disease annotations, the chemical-disease relations (CDR) track was also organised to foster the sharing and advancement of disease annotation tools and resources.This article presents the application of Argo's capabilities to the literature-based annotation of diseases. As part of our participation in BioCreative V's User Interactive Track (IAT), we demonstrated and evaluated Argo's suitability to the semi-automatic curation of chronic obstructive pulmonary disease (COPD) phenotypes. Furthermore, the workbench facilitated the development of some of the CDR track's top-performing web services for normalising disease mentions against the Medical Subject Headings (MeSH) database. In this work, we highlight Argo's support for developing various types of bespoke workflows ranging from ones which enabled us to easily incorporate information from various databases, to those which train and apply machine learning-based concept recognition models, through to user-interactive ones which allow human curators to manually provide their corrections to automatically generated annotations. Our participation in the BioCreative V challenges shows Argo's potential as an enabling technology for curating disease and phenotypic information from literature.Database URL: http://argo.nactem.ac.uk.

PMID: 27189607 [PubMed - as supplied by publisher]