Genetic polymorphisms of pharmacogenomic VIP variants in the Mongol of Northwestern China.

BMC Genet. 2016;17(1):70

Authors: Jin T, Shi X, Wang L, Wang H, Feng T, Kang L

Abstract
BACKGROUND: Within a population, the differences of pharmacogenomic variant frequencies may produce diversities in drug efficacy, safety, and the risk associated with adverse drug reactions. With the development of pharmacogenomics, widespread genetic research on drug metabolism has been conducted on major populations, but less is known about minorities.
RESULTS: In this study, we recruited 100 unrelated, healthy Mongol adults from Xinjiang and genotyped 85 VIP variants from the PharmGKB database. We compared our data with eleven populations listed in 1000 genomes project and HapMap database. We used χ(2) tests to identify significantly different loci between these populations. We downloaded SNP allele frequencies from the ALlele FREquency Database to observe the global genetic variation distribution for these specific loci. And then we used Structure software to perform the genetic structure analysis of 12 populations.
CONCLUSIONS: Our results demonstrated that different polymorphic allele frequencies exist between different nationalities,and indicated Mongol is most similar to Chinese populations, followed by JPT. This information on the Mongol population complements the existing pharmacogenomic data and provides a theoretical basis for screening and therapy in the different ethnic groups within Xinjiang.

PMID: 27233804 [PubMed - as supplied by publisher]

FGFR2 risk SNPs confer breast cancer risk by augmenting estrogen responsiveness.

Carcinogenesis. 2016 May 28;

Authors: Campbell TM, Castro MA, de Santiago I, Fletcher MN, Halim S, Prathalingam R, Ponder BA, Meyer KB

Abstract
The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies (GWAS) for estrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by estrogen. In the presence of estrogen, the estrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased estrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesised that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared to wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased estrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with estrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

PMID: 27236187 [PubMed - as supplied by publisher]

Identification of associations between small molecule drugs and miRNAs based on functional similarity.

Oncotarget. 2016 May 24;

Authors: Wang J, Meng F, Dai E, Yang F, Wang S, Chen X, Yang L, Wang Y, Jiang W

Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in varieties of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapy for many human diseases, especially cancer. Here, we proposed a novel computational approach to identify associations between small molecules and miRNAs based on functional similarity of differentially expressed genes. At the significance level of p < 0.01, we constructed the small molecule and miRNA functional similarity network involving 111 small molecules and 20 miRNAs. Moreover, we also predicted associations between drugs and diseases through integrating our identified small molecule-miRNA associations with experimentally validated disease related miRNAs. As a result, we identified 2265 associations between FDA approved drugs and diseases, in which ~35% associations have been validated by comprehensive literature reviews. For breast cancer, we identified 19 potential drugs, in which 12 drugs were supported by previous studies. In addition, we performed survival analysis for the patients from TCGA and GEO database, which indicated that the associated miRNAs of 4 drugs might be good prognosis markers in breast cancer. Collectively, this study proposed a novel approach to predict small molecule and miRNA associations based on functional similarity, which may pave a new way for miRNA-targeted therapy and drug repositioning.

PMID: 27232942 [PubMed - as supplied by publisher]

What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Semin Respir Crit Care Med. 2016 Jun;37(3):358-367

Authors: Puglisi S, Torrisi SE, Giuliano R, Vindigni V, Vancheri C

Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF.

PMID: 27231860 [PubMed - as supplied by publisher]

Data integration to prioritize drugs using genomics and curated data.

BioData Min. 2016;9:21

Authors: Louhimo R, Laakso M, Belitskin D, Klefström J, Lehtonen R, Hautaniemi S

Abstract
BACKGROUND: Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature.
RESULTS: We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3.
CONCLUSIONS: Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.

PMID: 27231484 [PubMed]

GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype.

Am J Med Genet A. 2016 May 27;

Authors: Lee JS, Yoo Y, Lim BC, Kim KJ, Song J, Choi M, Chae JH

Abstract
There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile-onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett-like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures. One of them had microcephaly, while the other had small head circumference less than 10th centile. There were no abnormal laboratory findings with the exception of a high lactate level. MECP2/CDKL5/FOXG1 genetic tests with an array comparative genomic hybridization revealed no molecular defects. Through whole-exome sequencing of the proband, we found compound heterozygous ST3GAL5 variants (p.Gly201Arg and p.Cys195Ser), both of which were novel. The siblings were the same compound heterozygotes and their unaffected parents were heterozygous carriers of each variant. Liquid chromatography-mass spectrometry analysis confirmed a low level of GM3 and its downstream metabolites, indicating GM3 synthase deficiency. These cases expanded the clinical and genetic spectrum of the ultra-rare disease, GM3 synthase deficiency with ST3GAL5 variants. © 2016 Wiley Periodicals, Inc.

PMID: 27232954 [PubMed - as supplied by publisher]

Research advances on medical genetics in China in 2015.

Yi Chuan. 2016 May 20;38(5):363-390

Authors: Yuanfeng L, Yubo H, Pengbo C, Jinfeng M, Haibei L, Geng Q, Feng Z, Guangfu J, Yong Y, Lingqian W, Jie P, Gangqiao Z

Abstract
Steady progress has been achieved in the medical genetics in China in 2015, as numerous original researches were published in the world's leading journals. Chinese scientists have made significant contributions to various fields of medical genetics, such as pathogenicity of rare diseases, predisposition of common diseases, somatic mutations of cancer, new technologies and methods, disease-related microRNAs (miRNAs), disease-related long non-coding RNAs (lncRNAs), disease-related competing endogenous RNAs (ceRNAs), disease-related RNA splicing and molecular evolution. In these fields, Chinese scientists have gradually formed the tendency, from common variants to rare variants, from single omic analyses to multipleomics integration analyses, from genetic discovery to functional confirmation, from basic research to clinical application. Meanwhile, the findings of Chinese scientists have been drawn great attentions of international peers. This review aims to provide an overall picture of the front in Chinese medical genetics, and highlights the important findings and their research strategy.

PMID: 27232486 [PubMed - as supplied by publisher]

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

Nat Commun. 2016;7:11601

Authors: Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, Hung CY, Simpson MA, Chong WK, Jacques TS, Woltjer RL, Eaton S, Gregory A, Sanford L, Kara E, Houlden H, Cuno SM, Prokisch H, Valletta L, Tiranti V, Younis R, Maher ER, Spencer J, Straatman-Iwanowska A, Gissen P, Selim LA, Pintos-Morell G, Coroleu-Lletget W, Mohammad SS, Yoganathan S, Dale RC, Thomas M, Rihel J, Bodamer OA, Enns CA, Hayflick SJ, Clayton PT, Mills PB, Kurian MA, Wilson SW

Abstract
Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

PMID: 27231142 [PubMed - in process]

Intradural synovial cyst of the atlantoaxial joint: a case report.

Acta Neurochir (Wien). 2016 May 27;

Authors: Hartmann S, Tschugg A, Kavakebi P, Thomé C

Abstract
BACKGROUND: Intradural synovial cysts of the cervical spine represent a rare disease entity, causing stenosis of the spinal canal and thereby leading to progressive myelopathy. In particular, at the cranio-cervical junction early intervention is necessary to prevent permanent neurological dysfunction. We present the case of a 74-year-old man who presented with moderate cervicogenic headache, gait disturbance and progressive left-sided weakness. Magnetic resonance imaging (MRI) of the cervical spine confirmed a left-sided cystic mass located anteriorly at the craniovertebral junction compressing the surrounding structures.
METHOD: Surgical decompression was performed by means of a minimal left-sided laminectomy of C1. Postoperatively, the patients symptoms slowly improved, albeit a persistent ataxic gait.
RESULTS: Intraoperatively, a large intradural cyst was removed via a minimal suboccipital craniectomy combined with laminectomy of C1. Histopathological evaluation revealed a synovial cyst without any features of neoplasia. Despite not using craniocervical instrumentation, no clinical or radiological signs of atlantoaxial instability were observed up to 2 years after surgery.
CONCLUSIONS: Cystic lesions located at the atlanto-axial joint are a rare cause of cervical myelopathy. Preoperative imaging of the cervical spine should include not only MRI and computerised tomography (CT) but also dynamic imaging. Dorsal decompression without instrumentation prevents progressive neurological decline and may allow cord function to recover. If there is additional preoperative instability, instrumentation and fusion may be necessary.

PMID: 27230912 [PubMed - as supplied by publisher]

Spatial analysis of gender variation in the prevalence of hypertension among the middle-aged and elderly population in Zhejiang Province, China.

BMC Public Health. 2016;16(1):447

Authors: Xu L, Lai D, Fang Y

Abstract
BACKGROUND: Previous studies have shown that there may be gender disparities in the prevalence of hypertension; however, these studies do not address the spatial information contained in the sample which may limit the analytical results. Our study extends the existing Shared Component Model (SCM) and compares its utility with a logistic regression model to evaluate the significance of spatial information for identifying risk factors for hypertension and other non-rare diseases.
METHODS: A total of 1267 residents aged 45 years of age and over were included in our study, of which 48.1 % were males. The overall prevalence of hypertension was 33.2 %, with females experiencing a higher prevalence than males (35.5 % vs. 30.6 %). The research variables included body mass index (BMI), Waist -to-Height Ratio (WHtR), smoking status, alcohol consumption etc. The extended SCM is employed to investigate regional gender variations in the risk of hypertension and assess the gender variation in the middle-aged and elderly populations of Zhejiang Province in eastern China and then its performance is compared with that of a traditional multiple logistic regression model.
RESULTS: Our SCM analysis determined that the spatial pattern of hypertension risk for the middle-aged and elderly populations of Zhejiang Province in eastern China is quite different for males and females. Furthermore, Waist -to-Height Ratio (WHtR) continues to be a simple and effective predictor of hypertension risk for males at the regional level.
CONCLUSIONS: We believe that the extended SCM spatial model is a useful tool for identifying risk factors at the regional level.

PMID: 27230660 [PubMed - in process]

Feasibility and Success Rate of a Fetal MRI and MR Spectroscopy Research Protocol Performed at Term Using a 3.0-Tesla Scanner.

Fetal Diagn Ther. 2016 May 27;

Authors: Sanz Cortes M, Bargallo N, Arranz A, Simoes R, Figueras F, Gratacos E

Abstract
OBJECTIVES: To report the feasibility and main factors affecting the success of a fetal magnetic resonance imaging (MRI) and MR spectroscopy (MRS) research protocol performed at term using a 3-tesla scanner.
METHODS: Pregnant patients at term underwent an MRI. Specific measures were taken to prevent maternal discomfort and distress, such as detailed counseling and maternal repositioning if needed. MRS data were acquired from the frontal lobe and basal ganglia, and processed applying quality control criteria.
RESULTS: The mean gestational age at MRI was 37.4 ± 0.9 weeks. From a total of 245 patients that showed up for the MRI, 11 referred claustrophobia which prevented the test from starting, and 30 patients started the test but decided to discontinue due to discomfort. Thus, the examination was complete in 204 patients. MRS data could be obtained in 170 cases from the frontal lobe and 165 cases from the basal ganglia, of which 52.4 and 68.6%, respectively, complied with our defined quality criteria. The mean scanning time was 34:16 ± 9:30 min:s after excluding those cases presenting initial intolerance to the test. Minor abnormalities were described in 11 MRI reports.
CONCLUSIONS: The fetal MRI/MRS protocol was feasible and generally well tolerated at term on a 3-tesla scanner, but a significant number of cases were lost to analysis. The rate of patients that eventually provided usable research information was 95.5% for anatomical examination and 52.4-68.6% for MRS. This information should be taken into account in the design of fetal brain MRI studies.

PMID: 27230519 [PubMed - as supplied by publisher]

Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada.

Eur Respir J. 2016 May 26;

Authors: Hopkins RB, Burke N, Fell C, Dion G, Kolb M

Abstract
Idiopathic pulmonary fibrosis (IPF) is a rare disease, with estimates of prevalence varying considerably across countries due to paucity in data collection. The aim of this study was to investigate the prevalence and incidence of IPF in Canada using administrative data requiring minimal extrapolation.We used mandatory national administrative data from 2007-2011 to identify IPF cases of all ages with an International Classification of Diseases (Version 10, Canadian) diagnosis code of J84.1. We used a broad definition that excluded cases with subsequent diagnosis of other interstitial lung diseases, and a narrow definition that required further diagnostic testing prior to IPF diagnosis. We explored survival and quality of life.For all ages, the broad prevalence of IPF was 41.8 per 100 000 (14 259 cases) and was higher for men. The incidence rate was 18.7 per 100 000 (6390 cases) and was higher for men. The narrow prevalence was 20.0 per 100 000 (6822 cases) and incidence was 9.0 per 100 000 (3057 cases). The 4-year risk of death was 41.0% and the quality of life with IPF after 2 years was lower than for Global Initiative for Chronic Obstructive Lung Disease stage IV chronic obstructive pulmonary disease.Using comprehensive national data, the prevalence of IPF in Canada was higher than other national estimates, suggesting that either IPF may be more common in Canada or that data capture may have been previously limited.

PMID: 27230442 [PubMed - as supplied by publisher]

Achieving optimal cancer outcomes in East Africa through multidisciplinary partnership: a case study of the Kenyan National Retinoblastoma Strategy group.

Global Health. 2016;12(1):23

Authors: Hill JA, Kimani K, White A, Barasa F, Livingstone M, Gallie BL, Dimaras H, Daisy’s Eye Cancer Fund & The Kenyan National Retinoblastoma Strategy Group

Abstract
BACKGROUND: Strategic, interdisciplinary partnerships are essential to addressing the complex drivers of health inequities that result in survival disparities worldwide. Take for example the aggressive early childhood eye cancer retinoblastoma, where survival reaches 97 % in resource-rich countries, but is as low 30 % in some resource-limited nations, where 92 % of the burden lies. This suggests a need for a multifaceted approach to achieve a tangible and sustainable increase in survival.
METHODS: We assembled the history the Kenyan National Retinoblastoma Strategy (KNRbS), using information documented in NGO reports, grant applications, news articles, meeting agendas and summaries. We evaluated the KNRbS using the principles found in the guide for transboundary research partnerships developed by the Swiss Commission for Research Partnerships with Developing Countries.
RESULTS: A nationally co-ordinated approach drawing input and expertise from multiple disciplines and sectors presented opportunities to optimise cure of children with retinoblastoma. Annual meetings were key to achieving the over 40 major outputs of the group's efforts, related to Awareness, Medical Care, Family Support and Resource Mobilization. Three features were found to be critical to the KNRbS success: multidisciplinarity, consistency and flexibility.
CONCLUSION: The KNRbS has achieved a number of key outputs with limited financial investment. As a partnership, the KNRbS meets most of the criteria identified for success. Challenges remain in securing the long-term sustainability of its achievements. Elements of the Kenyan National Retinoblastoma Strategy may be useful to other developing countries struggling with limited survival of retinoblastoma and other cancers or rare diseases.

PMID: 27229322 [PubMed - in process]

Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries.

Orphanet J Rare Dis. 2015;10:80

Authors: Bosch AM, Burlina A, Cunningham A, Bettiol E, Moreau-Stucker F, Koledova E, Benmedjahed K, Regnault A

Abstract
BACKGROUND: The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL.
METHODS: A multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient's health status by the investigator and treatment with tetrahydrobiopterin (BH4).
RESULTS: Data from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake.
CONCLUSION: Patients with PKU showed good HRQoL in the study, both with the generic and PKU-specific measures. Negative impacts of PKU on a patient's life, including the emotional impact of PKU and its management, was delineated by the PKU-QOLs across all age groups.

PMID: 26084935 [PubMed - indexed for MEDLINE]

UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels.

Pharmacogenomics. 2016 May 27;

Authors: Chatzistefanidis D, Lazaros L, Giaka K, Nakou I, Tzoufi M, Georgiou I, Kyritsis A, Markoula S

Abstract
AIM: The role of UGT1A6 and UGT2B7 polymorphisms and the impact of total drug plasma concentration in valproic acid (VPA) pharmacogenomics.
PATIENTS & METHODS: A total of 134 Greek patients were recruited (76 adults). Patients were genotyped for UGT1A6 19T>G, 541A>G and 552A>C and UGT2B7 802T>C polymorphisms. Patients' demographic and clinical data were registered. Natural logarithm of concentration-to-dose ratio (CDR) was also calculated as the final outcome.
RESULTS: No significant genotype-related differences in VPA metabolism were noted among various subgroups. An increased lnCDR ratio was noted in children patients compared with adults suggesting increased metabolic capability in younger ages.
CONCLUSION: UGT1A6 and UGT2B7 genotypes were not related to significant changes in VPA metabolism, even after controlling for total drug concentration levels. Younger ages were associated with increased VPA clearance rate.

PMID: 27232006 [PubMed - as supplied by publisher]

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]