P2Y12-ADP receptor antagonists: Days of future and past.

World J Cardiol. 2016 May 26;8(5):327-32

Authors: Laine M, Paganelli F, Bonello L

Abstract
Antiplatelet therapy is the cornerstone of the therapeutic arsenal in coronary artery disease. Thanks to a better understanding in physiology, pharmacology and pharmacogenomics huge progress were made in the field of platelet reactivity inhibition thus allowing the expansion of percutaneous coronary intervention. Stent implantation requires the combination of two antiplatelet agents acting in a synergistic way. Asprin inhibit the cyclo-oxygenase pathway of platelet activation while clopidogrel is a P2Y12 adenosine diphosphate (ADP)-receptor antagonist. This dual antiplatelet therapy has dramatically improved the prognosis of stented patients. However, due to pharmacological limitations of clopidogrel (interindividual variability in its biological efficacy, slow onset of action, mild platelet reactivity inhibition) ischemic recurrences remained high following stent implantation especially in acute coronary syndrome patients. Thus, more potent P2Y12-ADP receptor inhibitors were developped including prasugrel, ticagrelor and more recently cangrelor to overcome these pitfalls. These new agents reduced the rate of thrombotic events in acute coronary syndrome patients at the cost of an increased bleeding risk. The abundance in antiplatelet agents allow us to tailor our strategy based on the thrombotic/bleeding profile of each patient. Recently, the ACCOAST trial cast a doubt on the benefit of pre treatment in non-ST segment elevation acute coronary syndrome. The aim of the present review is to summarize the results of the main studies dealing with antiplatelet therapy in stented/acute coronary syndromes patients.

PMID: 27231519 [PubMed]

Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling.

Elife. 2016 May 27;5

Authors: Raj A, Wang SH, Shim H, Harpak A, Li YI, Engelmann B, Stephens M, Gilad Y, Pritchard JK

Abstract
Accurate annotation of protein coding regions is essential for understanding how genetic information is translated into function. We describe riboHMM, a new method that uses ribosome footprint data to accurately infer translated sequences. Applying riboHMM to human lymphoblastoid cell lines, we identified 7,273 novel coding sequences, including 2,442 translated upstream open reading frames. We observed an enrichment of footprints at inferred initiation sites after drug-induced arrest of translation initiation, validating many of the novel coding sequences. The novel proteins exhibit significant selective constraint in the inferred reading frames, suggesting that many are functional. Moreover, ~40% of bicistronic transcripts showed negative correlation in the translation levels of their two coding sequences, suggesting a potential regulatory role for these novel regions. Despite known limitations of mass spectrometry to detect protein expressed at low level, we estimated a 14% validation rate. Our work significantly expands the set of known coding regions in humans.

PMID: 27232982 [PubMed - as supplied by publisher]

Crowdsourcing the nodulation gene network discovery environment.

BMC Bioinformatics. 2016;17(1):223

Authors: Li Y, Jackson SA

Abstract
BACKGROUND: The Legumes (Fabaceae) are an economically and ecologically important group of plant species with the conspicuous capacity for symbiotic nitrogen fixation in root nodules, specialized plant organs containing symbiotic microbes. With the aim of understanding the underlying molecular mechanisms leading to nodulation, many efforts are underway to identify nodulation-related genes and determine how these genes interact with each other. In order to accurately and efficiently reconstruct nodulation gene network, a crowdsourcing platform, CrowdNodNet, was created.
RESULTS: The platform implements the jQuery and vis.js JavaScript libraries, so that users are able to interactively visualize and edit the gene network, and easily access the information about the network, e.g. gene lists, gene interactions and gene functional annotations. In addition, all the gene information is written on MediaWiki pages, enabling users to edit and contribute to the network curation.
CONCLUSIONS: Utilizing the continuously updated, collaboratively written, and community-reviewed Wikipedia model, the platform could, in a short time, become a comprehensive knowledge base of nodulation-related pathways. The platform could also be used for other biological processes, and thus has great potential for integrating and advancing our understanding of the functional genomics and systems biology of any process for any species. The platform is available at http://crowd.bioops.info/ , and the source code can be openly accessed at https://github.com/bioops/crowdnodnet under MIT License.

PMID: 27230384 [PubMed - in process]

Unraveling the environmental and genetic interactions in atherosclerosis: Central role of the gut microbiota.

Atherosclerosis. 2015 Aug;241(2):387-99

Authors: Org E, Mehrabian M, Lusis AJ

Abstract
Recent studies have convincingly linked gut microbiota to traits relevant to atherosclerosis, such as insulin resistance, dyslipidemia and inflammation, and have revealed novel disease pathways involving microbe-derived metabolites. These results have important implications for understanding how environmental and genetic factors act together to influence cardiovascular disease (CVD) risk. Thus, dietary constituents are not only absorbed and metabolized by the host but they also perturb the gut microbiota, which in turn influence host metabolism and inflammation. It also appears that host genetics helps to shape the gut microbiota community. Here, we discuss challenges in understanding these interactions and the role they play in CVD.

PMID: 26071662 [PubMed - indexed for MEDLINE]

Deciphering principles of morphogenesis from temporal and spatial patterns on the integument.

Dev Dyn. 2015 Aug;244(8):905-20

Authors: Li A, Lai YC, Figueroa S, Yang T, Widelitz RB, Kobielak K, Nie Q, Chuong CM

Abstract
BACKGROUND: How tissue patterns form in development and regeneration is a fundamental issue remaining to be fully understood. The integument often forms repetitive units in space (periodic patterning) and time (cyclic renewal), such as feathers and hairs. Integument patterns are visible and experimentally manipulatable, helping us reveal pattern formative processes. Variability is seen in regional phenotypic specificities and temporal cycling at different physiological stages.
RESULTS: Here we show some cellular/molecular bases revealed by analyzing integument patterns. (1) Localized cellular activity (proliferation, rearrangement, apoptosis, differentiation) transforms prototypic organ primordia into specific shapes. Combinatorial positioning of different localized activity zones generates diverse and complex organ forms. (2) Competitive equilibrium between activators and inhibitors regulates stem cells through cyclic quiescence and activation.
CONCLUSIONS: Dynamic interactions between stem cells and their adjacent niche regulate regenerative behavior, modulated by multi-layers of macro-environmental factors (dermis, body hormone status, and external environment). Genomics studies may reveal how positional information of localized cellular activity is stored. In vivo skin imaging and lineage tracing unveils new insights into stem cell plasticity. Principles of self-assembly obtained from the integumentary organ model can be applied to help restore damaged patterns during regenerative wound healing and for tissue engineering to rebuild tissues. Developmental Dynamics 244:905-920, 2015. © 2015 Wiley Periodicals, Inc.

PMID: 25858668 [PubMed - indexed for MEDLINE]

Eosinophil progenitor levels are increased in patients with active pediatric eosinophilic esophagitis.

J Allergy Clin Immunol. 2016 May 4;

Authors: Morris DW, Stucke EM, Martin LJ, Abonia JP, Mukkada VA, Putnam PE, Rothenberg ME, Fulkerson PC

PMID: 27199214 [PubMed - as supplied by publisher]

[Bouveret syndrome: a case report and literature review].

Rozhl Chir. 2016;95(4):164-7

Authors: Kocián P, Bocková M, Schwarz J

Abstract
UNLABELLED: Bouveret syndrome is a gastric outlet obstruction caused by impaction of a gallstone that passes through a cholecystoduodenal or cholecystogastric fistula. It is a rare disease, most common in elderly women with multiple comorbidities and high surgical risk. The diagnosis can be made either radiologically or endoscopically. Endoscopic extraction is the preferred therapeutic option. Surgical intervention is indicated when endoscopic methods fail. We describe a case of Bouveret syndrome in a 79 years old woman. The report is followed by a review of literature on the diagnostics and treatment of this rare syndrome.
KEY WORDS: gallstones bilioenteric fistula gallstone ileus duodenal obstruction Bouveret syndrome.

PMID: 27226271 [PubMed - in process]

Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol.

Syst Rev. 2016;5(1):89

Authors: Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L, Stewart DJ

Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies.
METHODS: We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines.
DISCUSSION: This systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies.
SYSTEMATIC REVIEW REGISTRATION: CAMARADES ( http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm ).

PMID: 27225668 [PubMed - in process]

Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net).

Orphanet J Rare Dis. 2016;11(1):69

Authors: Coler-Reilly AL, Yagishita N, Suzuki H, Sato T, Araya N, Inoue E, Takata A, Yamano Y

Abstract
BACKGROUND: At least one million people are infected with human T-lymphotropic virus type 1 (HTLV-1) in Japan, a small percentage of whom develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T-cell leukemia/lymphoma (ATLL). Patients with HAM/TSP suffer from progressively worsening myelopathic symptoms, such as motor disability and bladder dysfunction, and may become wheelchair-bound or even bedridden.
METHODS: To learn more about this rare, debilitating disease, we established the national registration system "HAM-net" in March 2012. We continuously obtain detailed data from enrolled patients using the registration forms and an annual telephone interview. In this retrospective study, we describe the demographics and clinical histories of 383 registered patients from all over Japan.
RESULTS: Patients were diagnosed at a median of 53 years old, long after disease onset at 45. Most (55.3 %) were originally from the southernmost regions, Kyushu and Okinawa. The main initial symptoms were difficulty walking (81.9 %), urinary dysfunction (38.5 %), and lower limb sensory disturbances (13.9 %). Many patients reported frequent leg numbness and leg pain, and the vast majority required medical intervention for urinary symptoms and constipation. A median of 8 years elapsed from the onset of motor symptoms to Osame Motor Disability Score (OMDS) 5 (requiring unilateral support), 12.5 years to OMDS 6 (requiring bilateral support), and 18 years to OMDS 9 (unable to walk). Health Assessment Questionnaire - Disability Index (HAQ-DI) tasks related to mobility, as opposed to hand motions, were very difficult for HAM/TSP patients and well-correlated with OMDS. Scores on the MOS 36-Item Short-Form Health Survey (SF-36) indicated that physical functioning was severely impaired in HAM/TSP patients. Patients with a history of blood transfusion (19.1 %) were older and suffered from more severe disability as indicated by their high HAQ-DI scores. Patients with a family history of HAM/TSP (8.4 %) were younger and had relatively mild symptoms given their long disease durations; many (15.6 %) also had a relative with ATLL.
CONCLUSIONS: The HAM-net national registration system has been an effective tool for gathering personal and clinical data from HAM/TSP patients scattered throughout Japan. We expect to conduct many retrospective and prospective epidemiological studies using HAM-net in the future.

PMID: 27225443 [PubMed - in process]

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers.

Orphanet J Rare Dis. 2016;11(1):70

Authors: Morel T, Aymé S, Cassiman D, Simoens S, Morgan M, Vandebroek M

Abstract
BACKGROUND: Rare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.
METHODS: A mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents.
RESULTS: Final study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk.
CONCLUSIONS: This is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations.

PMID: 27225337 [PubMed - in process]

Crowd Sourcing.

J Med Pract Manage. 2016 Jan-Feb;31(4):238-9

Authors: Baum N

Abstract
The Internet has contributed new words and slang to our daily vernacular. A few terms, such as tweeting, texting, sexting, blogging, and googling, have become common in most vocabularies and in many languages, and are now included in the dictionary. A new buzzword making the rounds in industry is crowd sourcing, which involves outsourcing an activity, task, or problem by sending it to people or groups outside a business or a practice. Crowd sourcing allows doctors and practices to tap the wisdom of many instead of relying only on the few members of their close-knit group. This article defines "crowd sourcing," offers examples, and explains how to get started with this approach that can increase your ability to finish a task or solve problems that you don't have the time or expertise to accomplish.

PMID: 27039640 [PubMed - indexed for MEDLINE]

New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Ann Neurol. 2015 Dec;78(6):871-86

Authors: Pilliod J, Moutton S, Lavie J, Maurat E, Hubert C, Bellance N, Anheim M, Forlani S, Mochel F, N'Guyen K, Thauvin-Robinet C, Verny C, Milea D, Lesca G, Koenig M, Rodriguez D, Houcinat N, Van-Gils J, Durand CM, Guichet A, Barth M, Bonneau D, Convers P, Maillart E, Guyant-Marechal L, Hannequin D, Fromager G, Afenjar A, Chantot-Bastaraud S, Valence S, Charles P, Berquin P, Rooryck C, Bouron J, Brice A, Lacombe D, Rossignol R, Stevanin G, Benard G, Burglen L, Durr A, Goizet C, Coupry I

Abstract
OBJECTIVE: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment.
METHODS: A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene.
RESULTS: We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested.
INTERPRETATION: Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria.

PMID: 26288984 [PubMed - indexed for MEDLINE]

Routine nail clipping leads to the diagnosis of amelanotic nail unit melanoma in a young construction worker.

J Cutan Pathol. 2015 Aug;42(8):505-9

Authors: Boni A, Chu EY, Rubin AI

PMID: 26272255 [PubMed - indexed for MEDLINE]

Noteworthy Professional News.

Adv Neonatal Care. 2015 Aug;15(4):235-6

Authors:

PMID: 26225589 [PubMed - indexed for MEDLINE]

Prenatal diagnosis of orbital melanotic neuroectodermal tumor in infancy.

Ultrasound Obstet Gynecol. 2015 Aug;46(2):249-50

Authors: Koob M, Fayard C, Pariente D, Adamsbaum C, Franchi-Abella S

PMID: 25594399 [PubMed - indexed for MEDLINE]

Fluorescence-based bioassays for the detection and evaluation of food materials.

Sensors (Basel). 2015;15(10):25831-67

Authors: Nishi K, Isobe S, Zhu Y, Kiyama R

Abstract
We summarize here the recent progress in fluorescence-based bioassays for the detection and evaluation of food materials by focusing on fluorescent dyes used in bioassays and applications of these assays for food safety, quality and efficacy. Fluorescent dyes have been used in various bioassays, such as biosensing, cell assay, energy transfer-based assay, probing, protein/immunological assay and microarray/biochip assay. Among the arrays used in microarray/biochip assay, fluorescence-based microarrays/biochips, such as antibody/protein microarrays, bead/suspension arrays, capillary/sensor arrays, DNA microarrays/polymerase chain reaction (PCR)-based arrays, glycan/lectin arrays, immunoassay/enzyme-linked immunosorbent assay (ELISA)-based arrays, microfluidic chips and tissue arrays, have been developed and used for the assessment of allergy/poisoning/toxicity, contamination and efficacy/mechanism, and quality control/safety. DNA microarray assays have been used widely for food safety and quality as well as searches for active components. DNA microarray-based gene expression profiling may be useful for such purposes due to its advantages in the evaluation of pathway-based intracellular signaling in response to food materials.

PMID: 26473869 [PubMed - indexed for MEDLINE]

Principles of Systems Biology-No. 5.

Cell Syst. 2016 May 25;2(5):290-292

Authors:

Abstract
If systems biology is about understanding how links between components yield emergent phenomena, this month's Cell Systems Call (Cell Systems 1, 307) contains a veritable bounty of examples, showcasing the breadth of the field from systems oceanography to molecular evolution to the influence of cellular niche microenvironments on stem cell development.

PMID: 27228344 [PubMed - as supplied by publisher]

TissueMiner: a multiscale analysis toolkit to quantify how cellular processes create tissue dynamics.

Elife. 2016 May 26;5

Authors: Etournay R, Merkel M, Popovi M, Brandl H, Dye NA, Aigouy B, Salbreux G, Eaton S, Jülicher F

Abstract
Segmentation and tracking of cells in long-term time-lapse experiments has emerged as a powerful method to understand how tissue shape changes emerge from the complex choreography of constituent cells. However, methods to store and interrogate the large datasets produced by these experiments are not widely available. Furthermore, recently developed methods for relating tissue shape changes to cell dynamics have not yet been widely applied by biologists because of their technical complexity. We therefore developed a database format that stores cellular connectivity and geometry information of deforming epithelial tissues, and computational tools to interrogate it and perform multi-scale analysis of morphogenesis. We provide tutorials for this computational framework, called TissueMiner, and demonstrate its capabilities by comparing cell and tissue dynamics in vein and inter-vein subregions of the Drosophila pupal wing. These analyses reveal an unexpected role for convergent extension in shaping wing veins.

PMID: 27228153 [PubMed - as supplied by publisher]

Recent Progress on Systems and Synthetic Biology Approaches to Engineer Fungi As Microbial Cell Factories.

Curr Genomics. 2016 Apr;17(2):85-98

Authors: Amores GR, Guazzaroni ME, Arruda LM, Silva-Rocha R

Abstract
Filamentous fungi are remarkable organisms naturally specialized in deconstructing plant biomass and this feature has a tremendous potential for biofuel production from renewable sources. The past decades have been marked by a remarkable progress in the genetic engineering of fungi to generate industry-compatible strains needed for some biotech applications. In this sense, progress in this field has been marked by the utilization of high-throughput techniques to gain deep understanding of the molecular machinery controlling the physiology of these organisms, starting thus the Systems Biology era of fungi. Additionally, genetic engineering has been extensively applied to modify wellcharacterized promoters in order to construct new expression systems with enhanced performance under the conditions of interest. In this review, we discuss some aspects related to significant progress in the understating and engineering of fungi for biotechnological applications, with special focus on the construction of synthetic promoters and circuits in organisms relevant for industry. Different engineering approaches are shown, and their potential and limitations for the construction of complex synthetic circuits in these organisms are examined. Finally, we discuss the impact of engineered promoter architecture in the single-cell behavior of the system, an often-neglected relationship with a tremendous impact in the final performance of the process of interest. We expect to provide here some new directions to drive future research directed to the construction of high-performance, engineered fungal strains working as microbial cell factories.

PMID: 27226765 [PubMed]

Complement membrane attack and tumourigenesis: a systems biology approach.

J Biol Chem. 2016 May 19;

Authors: Towner LD, Wheat RA, Hughes TR, Morgan BP

Abstract
Tumour development driven by inflammation is now an established phenomenon but the role that complement plays remains uncertain. Recent evidence has suggested that various components of the complement (C) cascade may influence tumour development in disparate ways; however, little attention has been paid to that of the membrane attack complex (MAC). This is despite abundant evidence documenting the effects of this complex on cell behaviour, including cell activation, protection from/induction of apoptosis, release of inflammatory cytokines, growth factors and ECM components and regulators and the triggering of the NLRP3 inflammasome. Here we present a novel approach to this issue by using global gene expression studies in conjunction with a systems biology analysis. Using network analysis of MAC responsive expression changes we demonstrated a cluster of co-regulated genes known to have their impact in the extracellular space and on the supporting stroma and with well-characterized tumour promoting roles. Network analysis highlighted the central role for EGFR activation in mediating the observed responses to MAC exposure. Overall, the study sheds light on the mechanisms by which sublytic MAC causes tumour cell responses and exposes a gene expression signature that implicates MAC as a driver of tumour progression. These findings have implications for understanding of the roles of C and the MAC in tumour development and progression which in turn will inform future therapeutic strategies in cancer.

PMID: 27226542 [PubMed - as supplied by publisher]