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Find video protocols related to scientific articles indexed in Pubmed.
Correction: Rapidly improved determination of metabolites from biological data sets using the high-efficient TransOmics tool.
Mol Biosyst
PUBLISHED: 11-20-2014
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Correction for 'Rapidly improved determination of metabolites from biological data sets using the high-efficient TransOmics tool' by Aihua Zhang et al., Mol. BioSyst., 2014, 10, 2160-2165.
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Intramuscular diclofenac for the prevention of post-ERCP pancreatitis: a randomized trial.
Endoscopy
PUBLISHED: 11-19-2014
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Background and study aims: Rectal nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The aim of this study was to determine whether intramuscular diclofenac reduces the risk of PEP. Patients and methods: Patients who underwent ERCP were randomized to receive either 90?mg of diclofenac or placebo by intramuscular injection immediately after the procedure. PEP was defined as elevated serum amylase levels (at least three times the upper limit of normal 24 hours after the procedure) associated with new or worsened upper abdominal, epigastric, or back pain. Results: In total, 380 patients were randomized, and 343 were eligible for analysis. The two groups were similar regarding clinical and demographic factors, as well as patient- and procedure-related risk factors for PEP. PEP developed in 20/170 patients (11.8?%) in the placebo group and in 22/173 patients (12.7?%) in the diclofenac group (P?=?0.87). Multivariate regression analysis failed to illustrate that intramuscular diclofenac prevented PEP (odds ratio 0.79; 95?% confidence interval 0.39?-?1.25; P?=?0.51). Conclusion: Prophylactic intramuscular diclofenac had no beneficial preventive effect on PEP.Clinicaltrials.gov NCT01717599.
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Von Willebrand Factor is a cofactor in complement regulation.
Blood
PUBLISHED: 11-15-2014
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Several complement proteins interact with hemostatic factors. We discovered that von Willebrand Factor (VWF) acts as a cofactor for Factor I-mediated cleavage of complement C3b, thereby shutting down complement activation. The complement regulatory function of VWF multimers depends on their size. Smaller VWF multimers enhance cleavage of C3b but large and ultra-large VWF (ULVWF) multimers have no effect on C3b cleavage and permit default complement activation. We conclude that normal plasma VWF multimers prevent complement activation and steer the complement pathway toward generation of inactivated C3b (iC3b). ULVWF multimers, as are present in patients with thrombotic microangiopathy, lack an inhibitory effect on complement and permit complement activation.
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1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain.
ACS Med Chem Lett
PUBLISHED: 11-13-2014
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The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.
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Repurposing the antihelmintic mebendazole as a hedgehog inhibitor.
Mol. Cancer Ther.
PUBLISHED: 11-08-2014
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The hedgehog (Hh) signaling pathway is activated in many types of cancer and therefore presents an attractive target for new anticancer agents. Here we show that mebendazole (MBZ), a benzamidazole with a long history of safe use against nematode infestations and hydatid disease, potently inhibited Hh signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations. As an antiparasitic, MBZ avidly binds nematode tubulin and causes inhibition of intestinal microtubule synthesis. In human cells, MBZ suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation. The inhibition of Hh signaling by MBZ was unaffected by mutants in the gene that encodes the Hh pathway signaling protein SMO, which are selectively propagated in cell clones that survive treatment with the Hh inhibitor vismodegib. Combination of vismodegib and MBZ resulted in additive Hh signaling inhibition. Because MBZ can be safely administered to adults and children at high doses over extended time periods, we propose that MBZ could be rapidly repurposed and clinically tested as a prospective therapeutic agent for many tumors that are dependent on Hh signaling.
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Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin.
Hum. Mol. Genet.
PUBLISHED: 11-04-2014
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Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Here we report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types.
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Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Paolo Peterlongo, Jenny Chang-Claude, Kirsten B Moysich, Anja Rudolph, Rita K Schmutzler, Jacques Simard, Penny Soucy, Rosalind A Eeles, Douglas F Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A Rookus, Marjanka K Schmidt, Frederieke H van der Baan, Amanda B Spurdle, Logan C Walker, Felicity Lose, Ana-Teresa Maia, Marco Montagna, Laura Matricardi, Jan Lubiński, Anna Jakubowska, Encarna B Gomez-Garcia, Olufunmilayo I Olopade, Robert L Nussbaum, Katherine L Nathanson, Susan M Domchek, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Sandra Orsulic, Jenny Lester, Wendy K Chung, Alex Miron, Melissa C Southey, David E Goldgar, Saundra S Buys, Ramunas Janavicius, Cecelia M Dorfling, Elizabeth J van Rensburg, Yuan Chun Ding, Susan L Neuhausen, Thomas V O Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Lars Jønson, Ana Osorio, Cristina Martinez-Bouzas, Javier Benitez, Edye E Conway, Kathleen R Blazer, Jeffrey N Weitzel, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Monica Barile, Filomena Ficarazzi, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Giuseppe Giannini, Laura Papi, Aline Martayan, Maria Grazia Tibiletti, Paolo Radice, Athanassios Vratimos, Florentia Fostira, Judy E Garber, Alan Donaldson, Carole Brewer, Claire Foo, D Gareth R Evans, Debra Frost, Diana Eccles, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E Side, M John Kennedy, Mark T Rogers, Mary E Porteous, Patrick J Morrison, Radka Platte, Rosemarie Davidson, Shirley V Hodgson, Steve Ellis, Trevor Cole, Andrew K Godwin, Kathleen Claes, Tom Van Maerken, Alfons Meindl, Andrea Gehrig, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Shan Wang-Gohrke, Brigitte Bressac-de Paillerets, Bruno Buecher, Capucine Delnatte, Claude Houdayer, Dominique Stoppa-Lyonnet, Francesca Damiola, Isabelle Coupier, Laure Barjhoux, Laurence Venat-Bouvet, Lisa Golmard, Nadia Boutry-Kryza, Olga M Sinilnikova, Olivier Caron, Pascal Pujol, Sylvie Mazoyer, Muriel Belotti, Marion Piedmonte, Michael L Friedlander, Gustavo C Rodriguez, Larry J Copeland, Miguel de la Hoya, Pedro Perez Segura, Heli Nevanlinna, Kristiina Aittomäki, Theo A M van Os, Hanne E J Meijers-Heijboer, Annemarie H Van der Hout, Maaike P G Vreeswijk, Nicoline Hoogerbrugge, Margreet G E M Ausems, Helena C Van Doorn, J Margriet Collée, Edith Olah, Orland Díez, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Lídia Feliubadaló, Cezary Cybulski, Jacek Gronwald, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Grzegorz Sukiennicki, Adalgeir Arason, Jocelyne Chiquette, Manuel R Teixeira, Curtis Olswold, Fergus J Couch, Noralane M Lindor, Xianshu Wang, Csilla I Szabo, Kenneth Offit, Marina Corines, Lauren Jacobs, Mark Robson, Liying Zhang, Vijai Joseph, Andreas Berger, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng M Tea, Catherine M Phelan, Mark H Greene, Phuong L Mai, Gad Rennert, Anna Marie Mulligan, Gord Glendon, Sandrine Tchatchou, Irene L Andrulis, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Mads Thomassen, Uffe Birk Jensen, Yael Laitman, Johanna Rantala, Anna von Wachenfeldt, Hans Ehrencrona, Marie Stenmark Askmalm, Ake Borg, Karoline B Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Sue Healey, Andrew Lee, Paul D P Pharoah, Georgia Chenevix-Trench, Antonis C Antoniou, Eitan Friedman.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-23-2014
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Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
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A PTCH1 Homolog Transcriptionally Activated by p53 Suppresses Hedgehog Signaling.
J. Biol. Chem.
PUBLISHED: 10-08-2014
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The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation. PTCH53 was highly responsive to p53 in vitro, and was among a small number of genes that were consistently expressed at reduced levels in diverse TP53-mutant cell lines and human tumors. Increased expression of PTCH53 inhibited canonical Hh signaling by the G protein-coupled receptor SMO. PTCH53 thus delineates a novel, inducible pathway by which p53 can repress tumorigenic Hh signals.
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Genetic testing of children for diseases that have onset in adulthood: the limits of family interests.
Pediatrics
PUBLISHED: 10-03-2014
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Two recent policy statements, one from the American Academy of Pediatrics and one from the American College of Medical Genetics, reach very different conclusions about the question of whether children should be tested for adult-onset genetic conditions. The American Academy of Pediatrics policy begins with the presumption that genetic testing for children should be driven by the best interest of the child. It recognizes the importance of preserving the child's open future, recommending that genetic testing for adult-onset diseases be deferred. The American College of Medical Genetics, by contrast, recommended testing children for at least some adult conditions, although it should be noted they have recently modified this recommendation. They justified this recommendation by arguing that it, in fact, was in the best interests of the child and family to receive this information. In this article, we analyze these 2 different positions and suggest ways that the seeming conflicts between them might be reconciled.
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The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor.
J. Med. Chem.
PUBLISHED: 09-24-2014
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Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
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Genetics of pulmonary hypertension.
Curr. Opin. Cardiol.
PUBLISHED: 08-28-2014
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The identification of the genetic basis for heritable predisposition to pulmonary arterial hypertension (PAH) has altered the clinical and research landscape for PAH patients and their care providers. This review aims to describe the genetic discoveries and their impact on clinical medicine.
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Genetic testing preferences in families containing multiple individuals with epilepsy.
Epilepsia
PUBLISHED: 08-26-2014
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To examine genetic testing preferences in families containing multiple individuals with epilepsy.
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Opposing brain differences in 16p11.2 deletion and duplication carriers.
J. Neurosci.
PUBLISHED: 08-22-2014
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Deletions and duplications of the recurrent ~600 kb chromosomal BP4-BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development.
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A pilot study of S-1-based concurrent chemoradiotherapy in patients with biliary tract cancer.
Cancer Chemother. Pharmacol.
PUBLISHED: 08-17-2014
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S-1 chemotherapy is effective against advanced biliary tract cancer. The purpose was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer.
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Contrasting levels of clonal and within-population genetic diversity between the 2 ecologically different herbs Polygonatum stenophyllum and Polygonatum inflatum (Liliaceae).
J. Hered.
PUBLISHED: 08-16-2014
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Comparative studies on clonal and genetic structure between ecologically contrasting congeners may provide valuable insights into the mechanisms promoting the maintenance of genetic diversity in clonal plant species. Polygonatum stenophyllum has long rhizomes (ca. 30-40 cm long) and largely occurs on sandy soils in open river banks, whereas its congener Polygonatum inflatum has short ones (ca. 5-10 cm long) and occurs on humic soils under deciduous forests. Using 21 allozyme loci, we comparatively assessed levels of clonal and genetic diversity in the 2 clonal species. Seven populations of P. stenophyllum consisted of single clones, and levels of within-population clonal and genetic variation were considerably lower than those of P. inflatum. However, when samples were pooled, P. stenophyllum harbored higher genetic variation than P. inflatum, which is due to higher among-population genetic differentiation in the former species compared with the latter (FST=0.636 vs. FST=0.165). Our data suggest that populations of P. stenophyllum have been mainly founded by a single seed or rhizome (through river water) or by a few seeds, whereas populations of P. inflatum would have been established through multiple, repeated seedling recruitment. Moderate levels of genetic diversity in a population of P. stenophyllum located at the foot of the Baekdudaegan Mountains and in all the populations of P. inflatum are consistent with the previous hypothesis that these mountains served as a glacial refugium for many boreal species of the Korean Peninsula.
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A case of phacolytic glaucoma with anterior lens capsule disruption identified by scanning electron microscopy.
BMC Ophthalmol
PUBLISHED: 08-14-2014
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Phacolytic glaucoma is induced by lens protein or macrophages that have leaked through a macroscopically intact anterior lens capsule. Here, we report a case of phacolytic glaucoma with anterior lens capsule disruptions visualized by scanning electron microscopy (SEM).
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Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.
Genet. Med.
PUBLISHED: 08-12-2014
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Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Purpose:Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3-4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.Methods:A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results:This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.Conclusion:A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.Genet Med advance online publication 06 November 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.128.
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Views of preimplantation genetic diagnosis among psychiatrists and neurologists.
J Reprod Med
PUBLISHED: 08-08-2014
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To examine key aspects of neurologists' and psychiatrists' views and approaches regarding prenatal genetic testing (GT) and preimplantation genetic diagnosis (PGD).
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Hemorrhagic Recurrence in Diffuse Astrocytoma without Malignant Transformation.
Brain Tumor Res Treat
PUBLISHED: 07-31-2014
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Although uncommon, hemorrhage can be a complication of low grade glioma with an unfavorable prognosis such as transformation to higher grade glioma. To our knowledge, hemorrhagic recurrence of World Health Organization Grade II, diffuse astrocytoma without malignant transformation has not been reported. Thus, we report a case of diffuse astrocytoma with hemorrhagic recurrence without malignant transformation. The patient had undergone craniotomy and tumor removal 7 years previously. Annual follow-up MRIs had shown evidence of slow tumor recurrence. With the sudden onset of seizure, the patient was diagnosed as hemorrhagic recurrence and underwent second tumor removal highly suspecting malignant change into higher grade glioma. Histopathology confirmed diffuse astrocytoma without malignant changes. As the patient's postoperative condition was excellent, we plan to withhold chemotherapy and radiation therapy for use as a later treatment option.
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Quantitative analysis of temperature dependent acoustic trapping characteristics by using concentric annular type dual element ultrasonic transducer.
Ultrasonics
PUBLISHED: 07-28-2014
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This paper presents the temperature dependence of lateral acoustic trapping capability by probing the speed of sound in individual lipid droplets at a given temperature of water and measuring its corresponding displacement, a value for quantitatively evaluating a spring-like behavior of the acoustic trap with certain strength. A 20/40MHz dual element LiNbO3 ultrasonic transducer is fabricated to simultaneously perform both transverse trapping and sound speed measurement for each droplet over a discrete temperature range from 20°C to 30°C. Time of flight method is employed for pulse tracking that determines the arrival time of an echo reflected back from either a trapped droplet or a mylar film. The estimated speeds of sound in water and droplets are 1484.8m/s and 1431.6m/s at 20°C, while 1506.0m/s and 1400.6m/s at 30°C, respectively. As the temperature rises, the sound speed in droplets decreases at an average rate of 3.1m/s/°C, and the speed in water increases at 2.1m/s/°C. The average displacement varies from 150.0?m to 179.0?m with an increasing rate of 2.9?m/°C, and its standard deviation is obtained between 1.0?m and 2.0?m over the same temperature range. Reduced sound speed as a function of rising temperature results in increased displacement, indicating that the trapping strength is adjustable by regulating ambient temperature in water as well as by changing transducer excitation parameters. Therefore, the results suggest that the temperature dependence of this trapping technique can be exploited for developing a remote manipulation tool of micron-sized particles in a thermally fluctuating environment. It is also shown that any deviated trapping strength caused by thermal disturbance near the trap can be restored to its desired level by compensating either temperature difference or trapping system condition.
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The efficacy of endoscopic palliation of obstructive jaundice in hepatocellular carcinoma.
Yonsei Med. J.
PUBLISHED: 07-23-2014
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Obstructive jaundice in patients with hepatocellular carcinoma (HCC) is uncommon (0.5-13%). Unlike other causes of obstructive jaundice, the role of endoscopic intervention in obstructive jaundice complicated by HCC has not been clearly defined. The aim of this study was to evaluate the clinical characteristics of obstructive jaundice caused by HCC and predictive factors for successful endoscopic intervention.
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A phage protein that inhibits the bacterial ATPase required for type IV pilus assembly.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-21-2014
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Type IV pili (TFPs) are required for bacterial twitching motility and for phage infection in the opportunistic human pathogen Pseudomonas aeruginosa. Here we describe a phage-encoded protein, D3112 protein gp05 (hereafter referred to as Tip, representing twitching inhibitory protein), whose expression is necessary and sufficient to mediate the inhibition of twitching motility. Tip interacts with and blocks the activity of bacterial-encoded PilB, the TFP assembly/extension ATPase, at an internal 40-aa region unique to PilB. Tip expression results in the loss of surface piliation. Based on these observations and the fact that many P. aeruginosa phages require TFPs for infection, Tip-mediated twitching inhibition may represent a generalized strategy for superinfection exclusion. Moreover, because TFPs are required for full virulence, PilB may be an attractive target for the development of novel antiinfectives.
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Brain Metastases of Papillary Thyroid Carcinoma with Horner's Syndrome.
Brain Tumor Res Treat
PUBLISHED: 07-17-2014
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Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy and has relatively favorable prognosis. Blood-borne metastases of PTC are very rare among the thyroid malignancies. Moreover a case of blood-borne central nervous system metastasized PTC with only unilateral Horner's syndrome, and without any abnormalities in laboratory or physical examinations has not been described before. A 53-year-old female patient had been managed in ophthalmologic clinic due to vague symptoms of right monocular blurred vision with eye dryness for 3 months, but showed no signs of improvement. So it was performed a magnetic resonance imaging and magnetic resonance angiography to evaluate the possibilities of cerebral lesion. And a left frontal mass was incidentally found, and the tumor turned out to be a PTC that had metastasized to brain, regional lymph node, cervical, thoracic spine, and lung. We describe a PTC with extraordinary initial symptoms that metastasized to an unusual site. We recommend that if a papillary thyroid tumor with unusual symptoms or at an advanced stage is found, further investigation should be performed for distant metastasis.
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Clinical characteristics of long-term survivors of inoperable pancreatic cancer: an 8-year cohort analysis in Korea.
Pancreas
PUBLISHED: 07-04-2014
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Inoperable pancreatic ductal adenocarcinoma is known to have an extremely poor prognosis. Although rare, there are some patients who have unexpected long-term survival, but the reason is not yet clear.
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Complex genetics and the etiology of human congenital heart disease.
Cold Spring Harb Perspect Med
PUBLISHED: 07-03-2014
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Congenital heart disease (CHD) is the most common birth defect. Despite considerable advances in care, CHD remains a major contributor to newborn mortality and is associated with substantial morbidities and premature death. Genetic abnormalities appear to be the primary cause of CHD, but identifying precise defects has proven challenging, principally because CHD is a complex genetic trait. Mainly because of recent advances in genomic technology such as next-generation DNA sequencing, scientists have begun to identify the genetic variants underlying CHD. In this article, the roles of modifier genes, de novo mutations, copy number variants, common variants, and noncoding mutations in the pathogenesis of CHD are reviewed.
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Disseminated Hemangioblastoma of the Central Nervous System without Von Hippel-Lindau Disease.
Brain Tumor Res Treat
PUBLISHED: 06-19-2014
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Hemangioblastoma (HB) of the central nervous system may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Disseminated HB means malignant spread of the original primary HB without local recurrence at surgically resected site. It has been rarely reported previously, and rarer especially without VHL gene mutation. We report a case of disseminated HB without VHL disease. A 59-year-old man underwent a surgery for total removal of a cerebellar HB. From five years after the surgery, multiple dissemination of HB was identified intracranially and he subsequently underwent cyberknife radiosurgery. The lesions got smaller temporarily, but they soon grew larger. Nine years after the initial surgery for cerebellar HB, he showed severe back pain. His magnetic resonance image of spine revealed intradural extramedullary mass at T6-7 level. Complete surgical removal of the mass was performed and the pathological diagnosis was identical to the previous one. He had no evidence of VHL disease. And there was no recurrence of the tumor at the site of the original operation. The exact mechanism of dissemination is unknown, but the surgeon should be cautious of tumor cell spillage during surgery and prudently consider the decision to perform ventriculo-peritoneal shunt. In addition, continuous follow-up for recurrence or dissemination is necessary for patients even who underwent complete removal of cerebellar HB.
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Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.
Genet. Med.
PUBLISHED: 06-17-2014
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Purpose:Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Methods:Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.Results:In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.Conclusion:A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med advance online publication 09 October 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.134.
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Eating in the absence of hunger but not loss of control behaviors are associated with 16p11.2 deletions.
Obesity (Silver Spring)
PUBLISHED: 06-17-2014
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The ?600-kb BP4-BP5 16p11.2 deletion has been consistently associated with obesity. We studied two heritable disinhibited eating behaviors, eating in the absence of hunger (EAH) and loss of control (LOC), to better characterize the relationship between the deletion and obesity.
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Psychiatrists' views of the genetic bases of mental disorders and behavioral traits and their use of genetic tests.
J. Nerv. Ment. Dis.
PUBLISHED: 06-17-2014
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We examined how 372 psychiatrists view genetic aspects of mental disorders and behaviors and use genetic tests (GTs). Most thought that the genetic contribution was moderate/high for bipolar disorder, schizophrenia, depression, Alzheimer's, intelligence, creativity, anxiety, and suicidality. In the past 6 months, 14.1% ordered GTs, 18.3% discussed prenatal testing with patients, 36.0% initiated discussions about other GTs, 41.6% had patients ask about GTs, and 5.3% excluded GT results from patient records. Many thought that GTs; were available for schizophrenia (24.3%) and major depression (19.6%). Women were more likely to report that patients asked about GTs; and were less certain about the degree of genetic contribution to several disorders. Psychiatrists perceive strong genetic bases for numerous disorders and traits, and many have discussed and ordered tests for GTs, but have relatively limited knowledge about available tests. These data suggest possible sex differences in psychiatrists' beliefs about genetic contributions to disorders and have implications for future research, education, policy, and care.
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Models of consent to return of incidental findings in genomic research.
Hastings Cent Rep
PUBLISHED: 06-11-2014
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Genomic research-including whole genome sequencing and whole exome sequencing-has a growing presence in contemporary biomedical investigation. The capacity of sequencing techniques to generate results that go beyond the primary aims of the research-historically referred to as "incidental findings"-has generated considerable discussion as to how this information should be handled-that is, whether incidental results should be returned, and if so, which ones.Federal regulations governing most human subjects research in the United States require the disclosure of "the procedures to be followed" in the research as part of the informed consent process. It seems reasonable to assume-and indeed, many commentators have concluded-that genomic investigators will be expected to inform participants about, among other procedures, the prospect that incidental findings will become available and the mechanisms for dealing with them. Investigators, most of whom will not have dealt with these issues before, will face considerable challenges in framing meaningful disclosures for research participants.To help in this task, we undertook to identify the elements that should be included in the informed consent process related to incidental findings. We did this by surveying a large number of genomic researchers (n = 241) and by conducting in-depth interviews with a smaller number of researchers (n = 28) and genomic research participants (n = 20). Based on these findings, it seems clear to us that routine approaches to informed consent are not likely to be effective in genomic research in which the prospect of incidental findings exists. Ensuring that participants' decisions are informed and meaningful will require innovative approaches to dealing with the consent issue. We have identified four prototypical models of a consent process for return of incidental findings.
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The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations.
JIMD Rep
PUBLISHED: 05-20-2014
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The inborn errors of metabolism associated with 3-methylglutaconic aciduria are a diverse group of disorders characterized by the excretion of 3-methylglutaconic and 3-methylglutaric acids in the urine. Mutations in several genes have been identified in association with 3-methylglutaconic aciduria. We describe a patient of Saudi Arabian descent with 3-methylglutaconic aciduria, sensorineural hearing loss, encephalopathy, and Leigh-like pattern on MRI (MEGDEL syndrome), as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy. The patient had an earlier age of onset of optic atrophy than previously described in other MEGDEL syndrome patients. Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X), confirmed by Sanger sequencing. One of these mutations is novel (c.438delC). This case contributes to refining the MEGDEL phenotype.
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Preliminary study of neurocognitive dysfunction in adult moyamoya disease and improvement after superficial temporal artery-middle cerebral artery bypass.
J Korean Neurosurg Soc
PUBLISHED: 05-13-2014
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Moyamoya disease (MMD) is a chronic cerebrovascular occlusive disease of unknown etiology. In addition, the neurocognitive impairment of adults with MMD is infrequently reported and, to date, has not been well described. We attempted to determine both the neurocognitive profile of adult moyamoya disease and whether a superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis can improve the neurocognitive impairment in exhibiting hemodynamic disturbance without stroke.
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Aberrant white matter microstructure in children with 16p11.2 deletions.
J. Neurosci.
PUBLISHED: 05-03-2014
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Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV.
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CANOES: detecting rare copy number variants from whole exome sequencing data.
Nucleic Acids Res.
PUBLISHED: 04-25-2014
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We present CANOES, an algorithm for the detection of rare copy number variants from exome sequencing data. CANOES models read counts using a negative binomial distribution and estimates variance of the read counts using a regression-based approach based on selected reference samples in a given dataset. We test CANOES on a family-based exome sequencing dataset, and show that its sensitivity and specificity is comparable to that of XHMM. Moreover, the method is complementary to Gaussian approximation-based methods (e.g. XHMM or CoNIFER). When CANOES is used in combination with these methods, it will be possible to produce high accuracy calls, as demonstrated by a much reduced and more realistic de novo rate in results from trio data.
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Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes.
JAMA Neurol
PUBLISHED: 04-24-2014
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Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations.
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The usefulness of whole-exome sequencing in routine clinical practice.
Genet. Med.
PUBLISHED: 04-23-2014
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Purpose:Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and clinical usefulness in clinical care.Methods:Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care.Results:Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six.Conclusion:Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods.Genet Med advance online publication 29 May 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.58.
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Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study.
Epigenetics
PUBLISHED: 04-22-2014
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Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.
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Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice.
Cell Metab.
PUBLISHED: 04-18-2014
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Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l?/? mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l?/? mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
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Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.
Pediatr Diabetes
PUBLISHED: 04-07-2014
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Monogenic diabetes (MD) is rare and can often be confused with type 1 diabetes (T1D) in a pediatric cohort. We sought to determine clinical criteria that could optimally identify candidates for genetic testing of two common forms of MD that alter therapy: glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1?).
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Clinicopathologic characteristics associated with complications and long-term outcomes of endoscopic papillectomy for adenoma.
Yonsei Med. J.
PUBLISHED: 04-01-2014
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Endoscopic papillectomy (EP) is currently employed for the treatment of ampullary adenoma. This study aimed to evaluate the clinical, endoscopic, and histologic characteristics related to complications and long-term outcomes of EP.
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Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer.
Cancer Immunol. Immunother.
PUBLISHED: 03-20-2014
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Second-line chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer has shown disappointing survival outcomes due to rapid disease progression and performance deterioration. The aim of this phase II trial was to evaluate the efficacy and safety of adoptive immunotherapy using ex vivo-expanded, cytokine-induced killer (CIK) cells in gemcitabine-refractory advanced pancreatic cancer. Patients with advanced pancreatic cancer who showed disease progression during gemcitabine-based chemotherapy were enrolled in this study. For generation of CIK cells, peripheral blood samples were collected from each patient and cultured with anti-CD3 monoclonal antibody and IL-2. Patients received CIK cells intravenously 10 times, every week for 5 weeks and then every other week for 10 weeks. Twenty patients were enrolled between November 2009 and September 2010. The disease control rate was 25 % (4/16 patients). The median progression-free survival (PFS) was 11.0 weeks (95 % CI 8.8-13.2), and the median overall survival (OS) was 26.6 weeks (95 % CI 8.6-44.6). Grade 3 toxicities included general weakness in two patients and thrombocytopenia in one patient. Grade 4 hematologic or non-hematologic toxicity was not observed. Patients showed improvement in pancreatic pain, gastrointestinal distress, jaundice, body image alterations, altered bowel habits, health satisfaction, and sexuality when assessing quality of life (QoL). Adoptive immunotherapy using CIK cells showed comparable PFS and OS to survival data of previous trials that assessed conventional chemotherapies while maintaining tolerability and showing encouraging results in terms of patient QoL in gemcitabine-refractory advanced pancreatic cancer (clinicalTrials.gov number NCT00965718).
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Human subjects protection: an event monitoring committee for research studies of girls from breast cancer families.
J Adolesc Health
PUBLISHED: 03-18-2014
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Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies.
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Sutureless intrascleral pocket technique of transscleral fixation of intraocular lens in previous vitrectomized eyes.
Korean J Ophthalmol
PUBLISHED: 03-14-2014
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In this case series, we assessed a new technique, the intrascleral pocket procedure of transscleral fixation (TF) of the intraocular lens (IOL) in post-vitrectomized eyes. We performed the transscleral fixation of IOL in four aphakic patients who underwent pars plana vitrectomy. Two points 180° apart were marked at the limbus. A 2-mm-sized intrascleral pocket was created by lamellar dissection using a crescent blade without conjunctival dissection. A 2.8-mm clear corneal incision (CCI) was made using a keratome. Prolene sutures were exteriorized through the CCI pocket and a three-piece foldable acrylic IOL was injected via CCI and the ends of the haptics were exteriorized through the CCI. The prolene sutures for each haptic in the intrascleral pocket bed were then tied and knots were buried under scleral flaps. No patient had complaints such as conjunctival irritation, and visual acuity was almost identical to preoperative best-corrected visual acuity at day 1 postoperatively. IOLs were well placed without tilting or subluxation. They had no wound dehiscence or endophthalmitis postoperatively. The intrascleral pocket procedure of TF without the need for conjunctival dissection is a successful method for sulcus fixation in post-vitrectomized eyes predisposed to developing glaucoma.
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Validation of group B borderline resectable pancreatic cancer: retrospective analysis.
Gut Liver
PUBLISHED: 02-24-2014
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Among borderline resectable pancreatic cancer (BRPC), group B BRPC patients have findings that are suggestive but not diagnostic of metastasis. In this study, we attempted to validate whether group B could truly be categorized as a borderline resectable group.
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The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains.
ACS Chem. Biol.
PUBLISHED: 02-19-2014
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A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.
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Adrenergic Receptor Genotype Influences Heart Failure Severity and ?-Blocker Response in Children with Dilated Cardiomyopathy.
Pediatr. Res.
PUBLISHED: 02-17-2014
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BackgroundAdrenergic receptor (ADR) genotypes are associated with heart failure (HF) and ?-blocker response in adults. We assessed the influence of ADR genotypes in children with dilated cardiomyopathy (DCM).Methods91 children with advanced DCM and 44 with stable DCM were genotyped for 3 ADR genotypes associated with HF risk in adults: ?2cdel322-325, ?1Arg389, and ?2Arg16. Data were analyzed by genotype and ?-blocker use. Mean age at enrollment was 8.5 years.ResultsOne-year event-free survival was 51% in advanced and 80% in stable DCM. High-risk genotypes were associated with higher left ventricular (LV) filling pressures, higher systemic and pulmonary vascular resistance, greater decline in LV ejection fraction (p<0.05), and a higher frequency of mechanical circulatory support while awaiting transplant (p=0.05). While ?-blockers did not reduce heart failure severity in the overall cohort, in the subset with multiple high-risk genotypes, those receiving ?-blockers showed better preservation of cardiac function and hemodynamics compared to those not receiving ?-blockers (interaction p<0.05).ConclusionOur study identifies genetic risk markers that may help in the identification of patients at risk for developing decompensated HF and who may benefit from early institution of ?-blocker therapy before progression to decompensated HF.Pediatric Research (2014); doi:10.1038/pr.2014.183.
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A prospective Korean multicenter study for infectious complications in patients undergoing prostate surgery: risk factors and efficacy of antibiotic prophylaxis.
J. Korean Med. Sci.
PUBLISHED: 02-06-2014
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This multicenter study was undertaken to determine the efficacy of antibiotic prophylaxis and identify the risk factors for infectious complications after prostate surgery in Korean patients. A total of 424 patients who underwent surgery of the prostate were reviewed. All patients underwent urinalysis and urine culture preoperatively and postoperatively. Efficacy of antibiotic prophylaxis and risk factors for infectious complications were investigated. Infectious complications were observed in 34.9% of all patients. Factors independently associated with infectious complications were diabetes mellitus (adjusted OR, 1.99; 95% CI, 1.09-3.65, P=0.025) and operation time (adjusted OR, 1.08; 95% CI, 1.03-1.13, P=0.004). Clinicians should be aware of the high risk of infectious complications in patients with diabetes and those who undergo a prolonged operation time. Neither the type nor duration of prophylactic antibiotics resulted in differences in infectious complications.
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Efficacy and Tolerability of Anticholinergics in Korean Children with Overactive Bladder: A Multicenter Retrospective Study.
J. Korean Med. Sci.
PUBLISHED: 02-04-2014
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We investigated the efficacy and tolerability of various anticholinergics in Korean children with non-neurogenic overactive bladder (OAB). A total of 326 children (males:females= 157:169) aged under 18 yr (mean age 7.3±2.6 yr) who were diagnosed with OAB from 2008 to 2011 were retrospectively reviewed. The mean duration of OAB symptoms before anticholinergic treatment was 16.9±19.0 months. The mean duration of medication was 5.6±7.3 months. Urgency urinary incontinence episodes per week decreased from 1.9±3.1 to 0.4±1.5 times (P<0.001). The median voiding frequency during daytime was decreased from 9.2±5.4 to 6.3±4.2 times (P<0.001). According to 3-day voiding diaries, the maximum and average bladder capacity were increased from 145.5±66.9 to 196.8±80.3 mL and from 80.8±39.6 to 121.8±56.5 mL, respectively (P<0.001). On uroflowmetry, maximum flow rate was increased from 17.6±8.4 to 20.5±8.2 mL/sec (P<0.001). Adverse effects were reported in 14 (4.3%) children and six children (1.8%) discontinued medication due to adverse effects. Our results indicate that anticholinergics are effective to improve OAB symptoms and tolerability was acceptable without severe complications in children.
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BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.
Cancer
PUBLISHED: 01-22-2014
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Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing.
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The effect of 0.02% mitomycin C injection into the hair follicle with radiofrequency ablation in trichiasis patients.
Korean J Ophthalmol
PUBLISHED: 01-21-2014
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To investigate the inhibitory effect of 0.02% mitomycin C on eyelash regrowth when injected to the eyelash hair follicle immediately after radiofrequency ablation.
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Gemcitabine-induced hemolytic uremic syndrome in pancreatic cancer: a case report and review of the literature.
Gut Liver
PUBLISHED: 01-13-2014
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Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS may be caused by several different conditions, including infection, malignancy, and chemotherapeutic agents, such as mitomycin, cisplatin, and most recently, gemcitabine. The outcome of gemcitabine-induced HUS is poor, and the disease has a high mortality rate. This study reports a case of gemcitabine-induced HUS in a patient with pancreatic cancer in Korea.
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Superinfection exclusion reveals heteroimmunity between Pseudomonas aeruginosa temperate phages.
J. Microbiol.
PUBLISHED: 01-07-2014
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Temperate siphophages (MP29, MP42, and MP48) were isolated from the culture supernatant of clinical Pseudomonas aeruginosa isolates. The complete nucleotide sequences and annotation of the phage genomes revealed the overall synteny to the known temperate P. aeruginosa phages such as MP22, D3112, and DMS3. Genome-level sequence analysis showed the conservation of both ends of the linear genome and the divergence at the previously identified dissimilarity regions (R1 to R9). Protein sequence alignment of the c repressor (ORF1) of each phage enabled us to divide the six phages into two groups: D3112 group (D3112, MP29, MP42, and MP48) and MP22 group (MP22 and DMS3). Superinfection exclusion was observed between the phages belonging to the same group, which was mediated by the specific interaction between the c repressor and the cognate operator. Based on these, we suggest that the temperate siphophages prevalent in the clinical strains of P. aeruginosa represent at least two distinct heteroimmunity groups.
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Duodenal adenocarcinoma following a neuroendocrine tumor in the duodenum.
Korean J. Intern. Med.
PUBLISHED: 01-02-2014
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Primary duodenal adenocarcinoma is a rare malignant neoplasm accounting for 0.3% of all gastrointestinal tract carcinomas. We herein present one case of duodenal adenocarcinoma after duodenal neuroendocrine carcinoma. Poorly differentiated duodenal neuroendocrine carcinoma with liver metastasis (TxNxM1) was confirmed, and eight cycles of palliative chemotherapy (5-fluorouracil/etoposide/cisplatin) were administered. The patient was then in a clinically complete response status. About 1 year later, newly developed adenocarcinoma was detected at the same site. It was completely surgically resected, and the patient was cured.
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Complex Changes in von Willebrand Factor-Associated Parameters Are Acquired during Uncomplicated Pregnancy.
PLoS ONE
PUBLISHED: 01-01-2014
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The coagulation protein von Willebrand Factor (VWF) is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood.
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A Poorly Differentiated Malignant Neoplasm Lacking Lung Markers Harbors an EML4-ALK Rearrangement and Responds to Crizotinib.
Case Rep Oncol
PUBLISHED: 01-01-2014
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Suspected metastatic site lesions that are poorly differentiated present a diagnostic challenge when morphologic and immunohistochemical profiling cannot establish the primary tumor site. Here we present a patient diagnosed with both a malignant neoplasm in the lung and a right upper extremity (RUE) neoplasm of unclear histogenetic origin. Immunohistochemical staining performed on the latter specimen was inconclusive in determining the site of origin. Although the lung biopsy sample was insufficient for molecular testing, hybrid capture-based comprehensive genomic profiling (FoundationOne) identified an EML4-ALK rearrangement in the RUE lesion. Crizotinib treatment resulted in a major response in both the RUE and the lung lesions. This report illustrates the utility of comprehensive genomic profiling employed at the initial presentation of an unknown primary malignant neoplasm, which resulted in the front-line use of targeted therapy and a significant and sustained antitumor response.
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Gastrojejunostomy by pure natural orifice transluminal endoscopic surgery using a newly designed anastomosing metal stent in a porcine model.
Surg Endosc
PUBLISHED: 01-01-2014
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The accepted palliative treatment for malignant gastric outlet obstruction (GOO) is surgical bypass or placement of self-expandable metal stents. We developed a safe and simple natural orifice transluminal endoscopic surgery (NOTES) technique for gastrojejunostomy using a fully covered, anastomosing metal stent in a porcine model.
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A loss-of-function mutation in PTCH1 suggests a role for autocrine hedgehog signaling in colorectal tumorigenesis.
Oncotarget
PUBLISHED: 12-26-2013
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Hedgehog (Hh) signaling is largely suppressed in the normal differentiated tissues of the adult but activated in many cancers. The Hh pathway can either be activated by the expression of Hh ligands, or by mutations that cause constitutive, ligand-independent signaling. Colorectal cancer cells frequently express Hh ligands that are believed to exert paracrine effects on the stromal component of the tumor. Evidence for a more direct role of Hh signaling on the growth and evolution of colorectal cancer cell clones has been lacking. Here, we report a loss-of-function mutation of PTCH1, a tumor suppressor in the Hh pathway, in a colorectal cancer that exhibits transcriptional upregulation of the downstream Hh gene GLI1. This finding demonstrates that autocrine Hh signaling can provide a selective advantage to evolving tumors that arise in the colorectal epithelia, and suggests a definable group of colorectal cancer patients that could derive enhanced benefit from Hh pathway inhibitors.
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Cancer Genetic Counselor Information Needs for Risk Communication: A Qualitative Evaluation of Interview Transcripts.
J Pers Med
PUBLISHED: 12-21-2013
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Personalized medicine is a model of healthcare that is predictive, personalized, preventive and participatory ("P4 Medicine"). Genetic counselors are an ideal group to study when designing tools to support cancer P4 Medicine activities more broadly. The goal for this work was to gain a better understanding of the information cancer genetic counselors seek from their patients to facilitate effective information exchange for discussing risk. This was an analysis of a qualitative data set from interviews of eight cancer genetic counselors, recruited from three institutions. Genetic counselors at each site were interviewed using a semi-structured, open-ended questionnaire. A selective coding approach was used to determine major themes associated with genetic counseling information needs for communicating risk. We generated a model for understanding categories of genetic counseling information needs to support risk communication activities. Common activities for risk communication included risk assessment and tailoring communication. Categories of information needs included: (a) clinical patient characteristics, (b) social and cognitive patient characteristics and (c) patient motivation and goals for the genetic counseling session. A logical next step is for this model to inform the design of software systems for pre-visit patient planning and delivering just-in-time educational information to facilitate cancer risk communication activities.
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Genetics and genomics of pulmonary arterial hypertension.
J. Am. Coll. Cardiol.
PUBLISHED: 10-15-2013
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Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.
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Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.
J. Med. Chem.
PUBLISHED: 09-25-2013
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The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
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Squamous cell carcinoma of the suprapubic cystostomy tract with bladder involvement.
Korean J Urol
PUBLISHED: 09-10-2013
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Herein we report a case of a squamous cell carcinoma of a well-healed suprapubic cystostomy tract scar involving the bladder mucosa in a 56-year-old man. He presented with a spontaneous suprapubic urinary leak from a suprapubic cystostomy tract scar. He had a history of urethral stricture and failed urethroplasty. Preoperative cystoscopy suggested a bladder mass. Transurethral biopsy of the bladder mass revealed a squamous cell carcinoma confined to the suprapubic cystostomy tract involving the bladder mucosa. The patient died 6 months after the start of radiation therapy after lung metastasis and pneumonia.
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Effect of copy number variants on outcomes for infants with single ventricle heart defects.
Circ Cardiovasc Genet
PUBLISHED: 09-10-2013
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Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes.
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Defining a comprehensive verotype using electronic health records for personalized medicine.
J Am Med Inform Assoc
PUBLISHED: 09-03-2013
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The burgeoning adoption of electronic health records (EHR) introduces a golden opportunity for studying individual manifestations of myriad diseases, which is called EHR phenotyping. In this paper, we break down this concept by: relating it to phenotype definitions from Johannsen; comparing it to cohort identification and disease subtyping; introducing a new concept called verotype (Latin: vere?=?true, actually) to represent the true population of similar patients for treatment purposes through the integration of genotype, phenotype, and disease subtype (eg, specific glucose value pattern in patients with diabetes) information; analyzing the value of the verotype concept for personalized medicine; and outlining the potential for using network-based approaches to reverse engineer clinical disease subtypes.
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Common virulence factors for Pseudomonas tolaasii pathogenesis in Agaricus and Arabidopsis.
Res. Microbiol.
PUBLISHED: 08-18-2013
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Brown blotch of cultivatable mushrooms is a disease caused by the small peptide toxin (tolaasin) secreted by Pseudomonas tolaasii. Here we found that the wild type tolassin-producing P. tolaasii stain 6264 was capable of infection in Arabidopsis thaliana cotyledons, causing chlorotic symptoms and growth arrest as a result of bacterial proliferation. Seven virulence-attenuated mutants of P. tolaasii were isolated from the Agaricus bisporous screen using 2,512 mariner-based transposon insertion mutants, and all of them displayed reduced virulence and bacterial proliferation in Arabidopsis infection as well. The transposon was inserted within the genes for tolassin biosynthesis and amino acid biosynthesis, and within an intergenic region between the genes of unknown function. The finding that some virulence factors are commonly required for both Agaricus and Arabidopsis infections suggests that Arabidopsis could be exploited to study the host-pathogen interaction involving P. tolaasii.
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Genetic loss of SH2B3 in acute lymphoblastic leukemia.
Blood
PUBLISHED: 08-01-2013
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The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.
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Demonstrating Enhanced Throughput of RapidFire Mass Spectrometry through Multiplexing Using the JmjD2d Demethylase as a Model System.
J Biomol Screen
PUBLISHED: 07-29-2013
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Using mass spectrometry to detect enzymatic activity offers several advantages over fluorescence-based methods. Automation of sample handling and analysis using platforms such as the RapidFire (Agilent Technologies, Lexington, MA) has made these assays amenable to medium-throughput screening (of the order of 100,000 wells). However, true high-throughput screens (HTS) of large compound collections (>1 million) are still considered too time-consuming to be feasible. Here we propose a simple multiplexing strategy that can be used to increase the throughput of RapidFire, making it viable for HTS. The method relies on the ability to analyze pooled samples from several reactions simultaneously and to deconvolute their origin using "mass-tagged" substrates. Using the JmjD2d H3K9me3 demethylase as a model system, we demonstrate the practicality of this method to achieve a 4-fold increase in throughput. This was achieved without any loss of assay quality. This multiplex strategy could easily be scaled to give even greater reductions in analysis time.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.