Science.gov

Sample records for aggressive disease phenotype

  1. Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas.

    PubMed

    Zaidi, Hasan A; Cote, David J; Dunn, Ian F; Laws, Edward R

    2016-12-01

    Despite formal pathological criteria, not all atypical pituitary adenomas display clinically aggressive behavior. We set out to determine which factors predict a clinically aggressive phenotype among a cohort of atypical pituitary adenomas. Medical records were retrospectively reviewed from April 2008 to July 2015. Of 569 pituitary adenomas, 47 (8.3%) patients were surgically treated for atypical adenomas as defined by the WHO criteria. Clinically aggressive adenomas were defined as occurring in those patients who necessitated additional therapeutic intervention after the index (first) surgery, including additional surgery, medical therapy, or radiosurgery. Forty-seven patients with histopathological and immunohistochemical confirmation of atypical adenomas were identified and of these, 23 were noted to have a clinically aggressive course. Among the remaining 24 patients, the disease remained quiescent after the index surgery. On univariate analysis, clinically aggressive lesions were more likely to have a larger axial diameter on MRI (2.9±1.9cm vs. 1.9±0.7cm, p=0.02), greater incidence of cavernous sinus invasion (65.2% vs. 20.8%, p<0.01), and greater incidence of clival extension (60.9% vs. 0, p<0.01) on preoperative imaging. The two groups were equivalent with regard to immunohistochemical staining for ACTH, HGH, LH, FSH, PRL, and TSH. Clinically aggressive lesions, however, trended towards a greater average MIB-1 proliferative index (7.5%±4.9 vs. 6.0%±3.6, p=0.03). On multivariate analysis, the MIB-1 proliferative index trended towards statistical significance (p=0.06) as an independent predictor of clinical aggressiveness. Atypical pituitary adenomas are defined by a rigid set of immunohistochemical markers, but not all necessarily demonstrate an aggressive clinical phenotype.

  2. Predictors of Aggressive Inflammatory Bowel Disease

    PubMed Central

    Yarur, Andres J.; Strobel, Sebastian G.; Deshpande, Amar R.

    2011-01-01

    Inflammatory bowel disease comprises a group of conditions characterized by idiopathic inflammation of the gastrointestinal tract. The natural course of disease can range from an indolent course with prolonged periods of remission to aggressive, incapacitating disease. Predicting which patients are more susceptible to developing severe disease is important, especially when choosing therapeutic agents and treatment strategies. This paper reviews current evidence on the main demographic, clinical, endoscopic, histologic, serologic, and genetic markers that predict aggressive inflammatory bowel disease. In ulcerative colitis, we considered disease to be aggressive when patients had a high relapse rate, need for admission and/or surgery, development of colon cancer, or extraintestinal manifestations. We defined aggressive Crohn's disease as having a high relapse rate, development of penetrating disease, need for repeat surgery, or multiple admissions for flares. In Crohn's disease, involvement of the upper gastrointestinal tract and ileum, penetrating disease, early age at diagnosis, smoking, extensive ulceration of the mucosa, high titers of serum antibodies, and mutations of the NOD2 gene are markers of aggressive disease. In ulcerative colitis, patients with more extensive involvement of the colon (pancolitis) have more symptomatology and are at higher risk for needing a colectomy and developing colon cancer. Also, plasmocytic infiltration of the colonic mucosa and crypt atrophy predict treatment failure. As with diagnosis, no single method can predict disease aggressiveness. Multiple serologic and genetic tests are being developed to refine the accuracy of prediction. Endoscopic findings can also predict the future course of disease. At present, clinical manifestations are the most useful way to make therapeutic decisions. PMID:22298958

  3. Phenotyping of aggressive behavior in golden retriever dogs with a questionnaire.

    PubMed

    van den Berg, L; Schilder, M B H; de Vries, H; Leegwater, P A J; van Oost, B A

    2006-11-01

    Reliable and valid phenotyping is crucial for our study of genetic factors underlying aggression in Golden Retriever dogs. A mail questionnaire based on the Canine Behavioral Assessment and Research Questionnaire (CBARQ; Hsu and Serpell, 2003, JAVMA 223(9):1293-1300) was used to assess behavioral phenotypes. Owners of 228 Golden Retrievers completed the questionnaire. These dogs had been referred to our clinic for aggression problems several years earlier or they were related to aggressive dogs. In this paper, three sets of results are presented, which indicate that behavior scores from the CBARQ can be applied to genetic studies. First, factor analysis demonstrated that CBARQ items can be grouped into 10 behavioral traits, including three types of aggression: stranger-directed aggression, owner-directed aggression, and dog-directed aggression. The results were remarkably similar to those reported by Hsu and Serpell. The aggression scores showed considerable variation in our dog families, which is a prerequisite for genetic studies. Second, retrospective questions enabled us to study changes in the aggressive behavior of the dogs in the course of time. After an average time interval of 4.3 years, over 50% of the dogs had become less aggressive. Third, we analyzed data obtained with an aggression test of 83 dogs. Two out of the three CBARQ aggression factors were also found in the aggression test data.

  4. Trends in Susceptibility to Aggressive Periodontal Disease

    PubMed Central

    Shahabuddin, Nishat; Boesze-Battaglia, Kathleen; Lally, Edward T

    2016-01-01

    Aggregatibacter actinomycetemcomitans is a gram-negative microbe involved in periodontitis. Strains with varying degrees of virulence have been identified, in healthy and periodontally compromised individuals alike. Hosts mount differential immune responses to its various serotypes and virulence factors. Studies have explored host immune response in terms of antibody titers, leukocyte responses, and specific inflammatory mediators, questioning the ways in which the infectious microorganism survives. This mini-review will identify the key themes in immune response patterns of individuals both affected by and free from aggressive periodontal disease, thereby using it to understand various forms of periodontitis. PMID:28008419

  5. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    PubMed

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc.

  6. Phenotypic expansion of DGKE-associated diseases.

    PubMed

    Westland, Rik; Bodria, Monica; Carrea, Alba; Lata, Sneh; Scolari, Francesco; Fremeaux-Bacchi, Veronique; D'Agati, Vivette D; Lifton, Richard P; Gharavi, Ali G; Ghiggeri, Gian Marco; Sanna-Cherchi, Simone

    2014-07-01

    Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complement activation. The recent discovery of loss-of-function mutations in DGKE in patients with aHUS and normal complement levels challenged this observation. DGKE, encoding diacylglycerol kinase-ε, has not been implicated in the complement cascade but hypothetically leads to a prothrombotic state. The discovery of this novel mechanism has potential implications for the treatment of infants with aHUS, who are increasingly treated with complement blocking agents. In this study, we used homozygosity mapping and whole-exome sequencing to identify a novel truncating mutation in DGKE (p.K101X) in a consanguineous family with patients affected by thrombotic microangiopathy characterized by significant serum complement activation and consumption of the complement fraction C3. Aggressive plasma infusion therapy controlled systemic symptoms and prevented renal failure, suggesting that this treatment can significantly affect the natural history of this aggressive disease. Our study expands the clinical phenotypes associated with mutations in DGKE and challenges the benefits of complement blockade treatment in such patients. Mechanistic studies of DGKE and aHUS are, therefore, essential to the design of appropriate therapeutic strategies in patients with DGKE mutations.

  7. Phenotypic Expansion of DGKE-Associated Diseases

    PubMed Central

    Westland, Rik; Bodria, Monica; Carrea, Alba; Lata, Sneh; Scolari, Francesco; Fremeaux-Bacchi, Veronique; D’Agati, Vivette D.; Lifton, Richard P.; Gharavi, Ali G.; Ghiggeri, Gian Marco

    2014-01-01

    Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complement activation. The recent discovery of loss-of-function mutations in DGKE in patients with aHUS and normal complement levels challenged this observation. DGKE, encoding diacylglycerol kinase-ε, has not been implicated in the complement cascade but hypothetically leads to a prothrombotic state. The discovery of this novel mechanism has potential implications for the treatment of infants with aHUS, who are increasingly treated with complement blocking agents. In this study, we used homozygosity mapping and whole-exome sequencing to identify a novel truncating mutation in DGKE (p.K101X) in a consanguineous family with patients affected by thrombotic microangiopathy characterized by significant serum complement activation and consumption of the complement fraction C3. Aggressive plasma infusion therapy controlled systemic symptoms and prevented renal failure, suggesting that this treatment can significantly affect the natural history of this aggressive disease. Our study expands the clinical phenotypes associated with mutations in DGKE and challenges the benefits of complement blockade treatment in such patients. Mechanistic studies of DGKE and aHUS are, therefore, essential to the design of appropriate therapeutic strategies in patients with DGKE mutations. PMID:24511134

  8. Bronchiectasis: Phenotyping a Complex Disease.

    PubMed

    Chalmers, James D

    2017-03-15

    Bronchiectasis is a long-neglected disease currently experiencing a surge in interest. It is a highly complex condition with numerous aetiologies, co-morbidities and a heterogeneous disease presentation and clinical course. The past few years have seen major advances in our understanding of the disease, primarily through large real-life cohort studies. The main outcomes of interest in bronchiectasis are symptoms, exacerbations, treatment response, disease progression and death. We are now more able to identify clearly the radiological, clinical, microbiological and inflammatory contributors to these outcomes. Over the past couple of years, multidimensional scoring systems such as the Bronchiectasis Severity Index have been introduced to predict disease severity and mortality. Although there are currently no licensed therapies for bronchiectasis, an increasing number of clinical trials are planned or ongoing. While this emerging evidence is awaited, bronchiectasis guidelines will continue to be informed largely by real-life evidence from observational studies and patient registries. Key developments in the bronchiectasis field include the establishment of international disease registries and characterisation of disease phenotypes using cluster analysis and biological data.

  9. Aggression in Huntington's disease: a systematic review of rates of aggression and treatment methods.

    PubMed

    Fisher, Caroline A; Sewell, Katherine; Brown, Anahita; Churchyard, Andrew

    2014-01-01

    Aggression is commonly reported in individuals with Huntington's disease (HD). While correlating factors for aggression are often speculated about, features that are associated with, and contribute to, aggression in this population have not been clearly determined. This systematic review investigates rates of aggression and treatment options for aggression in HD. A number of key findings were revealed. Studies reporting on rates of aggression revealed that its prevalence is high, falling between 22 and 66 percent in the majority of studies. Aggression may be more common in males with HD, and is also found in higher rates in individuals who experience frequent falls, have obsessive-compulsive symptoms and suicidal ideation. There is little research investigating antecedents for aggression in HD. A wide variety of psychotropic medications have been reported in the literature to treat individuals with HD and aggressive behaviour. However, due to methodological limitations, no treatment recommendations can be made, based on the current literature. Two non-medication therapies have been investigated, behaviour support and sensory modulation intervention. However, again, due to methodological limitations with these studies, further research is needed before they can be recommended as frontline interventions. This review highlights the need for further methodologically rigorous studies investigating the treatment of aggression in HD.

  10. Exacerbation phenotyping in chronic obstructive pulmonary disease.

    PubMed

    MacDonald, Martin; Korman, Tony; King, Paul; Hamza, Kais; Bardin, Philip

    2013-11-01

    Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phenotype' AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous.

  11. A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-12-1-0535 TITLE: A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate...30Sep2014 - 29Sep2015 4. TITLE AND SUBTITLE: A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate...different between aggressive and indolent tumors. For the third year of the grant, we evaluated the gene expression of these 8 CTAs in PCa and benign

  12. Nuclear Morphometry Identifies a Distinct Aggressive Cellular Phenotype in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Glazer, Evan S.; Bartels, Peter H.; Prasad, Anil R.; Yozwiak, Michael L.; Bartels, Hubert G.; Einspahr, Janine G.; Alberts, David S.; Krouse, Robert S.

    2011-01-01

    By identifying aggressive cutaneous squamous cell carcinoma (cSCC) in patients who are at high risk for recurrences or second primaries after resection, intensive surveillance and therapy may decrease morbidity and mortality. We investigated the role of nuclear morphometry (karyometry) in differentiating between aggressive and nonaggressive cSCC. We retrospectively analyzed cSCC lesions from 40 male patients. 22 patients had evidence of aggressive cSCC (local/regional recurrence or a second primary cSCC), and 18 patients were identified with similar ages and sites of disease as control patients with nonaggressive cSCC (no evidence of recurrence, metastasis, or second primary). We performed karyometric analysis to identify nuclear features that discriminate between aggressive and nonaggressive cSCC nuclei. We used statistically significant differences (Kruskal-Wallis test P < 0.0001) to compose a quantitative aggressive classification score (proportion of aggressive nuclei from 0% to 100%). For comparisons, we used Fisher’s exact test or Student t test. The mean age was 79 ± 7 years for aggressive cSCC and 80 ± 9 years for nonaggressive cSCC (P = 0.66). We analyzed a mean of 96 nuclei in each group. The mean classification score for aggressive cSCC was significantly higher (69% ± 6%) than for nonaggressive cSCC (28% ± 5%, P = 0.00002). Overall, the classification score accurately categorized 80% of our patients (P = 0.0004). In most patients, karyometry differentiated between aggressive and nonaggressive cSCC. We found that classification scores, which provide information on individual lesions, could be used for risk stratification. PMID:21636541

  13. Characterization of Fusarium graminearum isolates recovered from wheat samples from Argentina by Fourier transform infrared spectroscopy: Phenotypic diversity and detection of specific markers of aggressiveness.

    PubMed

    Fígoli, Cecilia B; Rojo, Rodrigo; Gasoni, Laura A; Kikot, Gisele; Leguizamón, Mariana; Gamba, Raúl R; Bosch, Alejandra; Alconada, Teresa M

    2017-03-06

    Fusarium graminearum is the primary causal agent of Fusarium head blight of wheat in Argentina. This disease affects crop yields and grain quality also reducing the wheat end-use, and causing mycotoxin contamination. The aim of this work was to analyze the phenotypic characteristics associated with phenotypic diversity and aggressiveness of 34 F. graminearum sensu stricto isolates recovered from Argentinean fields in the 2008 growing season using the Fourier Transform Infrared (FTIR) dried film technology. We applied this technique also to search for spectral specific markers associated with aggressiveness. The combination of FTIR technology with hierarchical cluster analysis allowed us to determine that this population constitutes a highly diverse and heterogeneous group of fungi with significant phenotypic variance. Still, when the spectral features of a set of these isolates were compared against their aggressiveness, as measured by disease severity, thousand grains weight, and relative yield reduction, we found that the more aggressive isolates were richer in lipid content. Therefore, we could define several spectroscopic markers (>CH stretching modes in the 3000-2800 window, >CO and CO vibrational modes of esters at 1765-1707cm(-1) and 1474-900cm(-1), respectively), mostly assigned to lipid content that could be associated with F. graminearum aggressiveness. All together, by the application of FTIR techniques and simple multivariate analyses, it was possible to gain significant insights into the phenotypic characterization of F. graminearum local isolates, and to establish the existence of a direct relationship between lipid content and fungal aggressiveness. Considering that lipids have a major role as mediators in the interaction between plants and fungi our results could represent an attractive outcome in the study of Fusarium pathogenesis.

  14. The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer

    PubMed Central

    Sharma, Naomi L.; Massie, Charlie E.; Butter, Falk; Mann, Matthias; Bon, Helene; Ramos-Montoya, Antonio; Menon, Suraj; Stark, Rory; Lamb, Alastair D.; Scott, Helen E.; Warren, Anne Y.; Neal, David E.; Mills, Ian G.

    2014-01-01

    In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention. PMID:24753418

  15. A Testosterone-Related Structural Brain Phenotype Predicts Aggressive Behavior From Childhood to Adulthood

    PubMed Central

    Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N.; Hudziak, James J; Ducharme, Simon

    2015-01-01

    Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6 to 22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

  16. [Phenotypic heterogeneity of chronic obstructive pulmonary disease].

    PubMed

    Garcia-Aymerich, Judith; Agustí, Alvar; Barberà, Joan A; Belda, José; Farrero, Eva; Ferrer, Antoni; Ferrer, Jaume; Gáldiz, Juan B; Gea, Joaquim; Gómez, Federico P; Monsó, Eduard; Morera, Josep; Roca, Josep; Sauleda, Jaume; Antó, Josep M

    2009-03-01

    A functional definition of chronic obstructive pulmonary disease (COPD) based on airflow limitation has largely dominated the field. However, a view has emerged that COPD involves a complex array of cellular, organic, functional, and clinical events, with a growing interest in disentangling the phenotypic heterogeneity of COPD. The present review is based on the opinion of the authors, who have extensive research experience in several aspects of COPD. The starting assumption of the review is that current knowledge on the pathophysiology and clinical features of COPD allows us to classify phenotypic information in terms of the following dimensions: respiratory symptoms and health status, acute exacerbations, lung function, structural changes, local and systemic inflammation, and systemic effects. Twenty-six phenotypic traits were identified and assigned to one of the 6 dimensions. For each dimension, a summary is provided of the best evidence on the relationships among phenotypic traits, in particular among those corresponding to different dimensions, and on the relationship between these traits and relevant events in the natural history of COPD. The information has been organized graphically into a phenotypic matrix where each cell representing a pair of phenotypic traits is linked to relevant references. The information provided has the potential to increase our understanding of the heterogeneity of COPD phenotypes and help us plan future studies on aspects that are as yet unexplored.

  17. EXCEPTIONAL AGGRESSIVENESS OF CEREBRAL CAVERNOUS MALFORMATION DISEASE ASSOCIATED WITH PDCD10 MUTATIONS

    PubMed Central

    Rebeiz, Tania; Stockton, Rebecca A.; McDonald, David A.; Mikati, Abdul Ghani; Zhang, Lingjiao; Austin, Cecilia; Akers, Amy L.; Gallione, Carol J.; Rorrer, Autumn; Gunel, Murat; Min, Wang; De Souza, Jorge Marcondes; Lee, Connie

    2014-01-01

    Purpose The phenotypic manifestations of cerebral cavernous malformation (CCM) disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase (ROCK) mediated hyperpermeability, a potential therapeutic target, has not been established. Methods We analyze PDCD10-siRNA treated endothelial cells for stress fibers, ROCK activity and permeability. ROCK activity is assessed in CCM lesions. Brain permeability and CCM lesion burden is quantified, and clinical manifestations are assessed in prospectively enrolled subjects with PDCD10 mutations. Results We determine that PDCD10 protein suppresses endothelial stress fibers, ROCK activity and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrate robust ROCK activity in murine and human CCM vasculature, and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared to the more common KRIT1 and CCM2 familial and sporadic CCM, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features including scoliosis, cognitive disability and skin lesions, unrelated to lesion burden or bleeding. Conclusion These findings define a unique CCM disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling and the design of trials. PMID:25122144

  18. Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype1

    PubMed Central

    Bergström, Sofia Halin; Rudolfsson, Stina H; Bergh, Anders

    2016-01-01

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor–positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone. PMID:26992916

  19. The Changing Phenotype of Inflammatory Bowel Disease

    PubMed Central

    Sheehan, Donal; Shanahan, Fergus

    2016-01-01

    It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD) worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades. PMID:28050166

  20. Aggressive blood pressure control for chronic kidney disease unmasks moyamoya!

    PubMed Central

    Davis, T. Keefe; Halabi, Carmen M.; Siefken, Philp; Karmarkar, Swati; Leonard, Jeffrey

    2013-01-01

    Hypertensive crises in children or adolescents are rare, but chronic kidney disease (CKD) is a major risk factor for occurrence. Vesicoureteral reflux nephropathy is a common cause of pediatric renal failure and is associated with hypertension. Aggressive blood pressure (BP) control has been shown to delay progression of CKD and treatment is targeted for the 50th percentile for height when compared with a target below the 90th percentile for the general pediatric hypertensive patient. We present a case of an adolescent presenting with seizures and renal failure due to a hypertensive crisis. Hypertension was thought to be secondary to CKD as she had scarred echogenic kidneys due to known reflux nephropathy. However, aggressive BP treatment improved kidney function which is inconsistent with CKD from reflux nephropathy. Secondly, aggressive BP control caused transient neurological symptoms. Further imaging identified moyamoya disease. We present this case to highlight the consideration of moyamoya as a diagnosis in the setting of renal failure and hypertensive crisis. PMID:26064513

  1. Phenotypic changes of acid adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment.

    PubMed

    Damaghi, Mehdi; Gillies, Robert

    2016-09-16

    The inter- and intra-tumoral metabolic phenotypes of tumors are heterogeneous, and this is related to microenvironments that select for increased glycolysis. Increased glycolysis leads to decreased pH, and these local microenvironment effects lead to further selection. Hence, heterogeneity of phenotypes is an indirect consequence of altering microenvironments during carcinogenesis. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the acidic interior of the tumor. However, these cells eventually find themselves at the tumor edge, where they invade into the normal tissue via acid-mediated invasion. We believe acid adaptation during the evolution of cancer cells in their niche is a Rubicon that, once crossed, allows cells to invade into and outcompete normal stromal tissue. In this study, we illustrate some acid-induced phenotypic changes due to acidosis resulting in more aggressiveness and invasiveness of cancer cells.

  2. Aggression: the dominant psychological response in children with malignant disease.

    PubMed

    Kvist, S B; Rajantie, J; Kvist, M; Siimes, M A

    1991-06-01

    During the 11-yr. period of 1976 to 1986 leukemia or lymphoma treatment at the Children's Hospital, University of Helsinki was electively discontinued for the children in 90 different families. Of the 53 (59%) patients (mean age 6.4 yr. at diagnosis and 12.8 yr. at completion of questionnaires) who agreed to participate in the present study, 48 had acute lymphoblastic leukemia and five nonHodgkin lymphoma. Patients' and parents' impressions of the patients' psychological reactions during patients' prior chemotherapy were evaluated on parental and self-ratings. Also, knowledge of and presumed causes of the malignancy were studied. Patients' reactions of aggression, depression, eating disorders, hypersensitivity, phobic anxiety, death anxiety, and night terror were examined using factor analysis. Aggression, in the form of irritation and anger, was displayed more often by girls than by boys. Patients of families suffering from stress were prone to exhibit aggression in the form of mood changes, irritation, and anger. Patients with disease-related knowledge, as opposed to those less well informed, were less depressed. Discrepancies between parents' and patients' thoughts about the origin of the malignancy were noted.

  3. miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma.

    PubMed

    Lin, Chuyong; Liu, Aibin; Zhu, Jinrong; Zhang, Xin; Wu, Geyan; Ren, Pengli; Wu, Jueheng; Li, Mengfeng; Li, Jun; Song, Libing

    2014-08-06

    The strength and duration of phosphoinositide signalling from phosphatidylinositol-3-kinase (PI3K) activation to Akt is tightly balanced by phosphoinositide kinases and phosphatases. However, how phosphatase-mediated negative regulatory effects are concomitantly disrupted in cancers, which commonly exhibit constitutively activated PI3K/Akt signalling, remains undefined. Here we report that miR-508 directly suppresses multiple phosphatases, including inositol polyphosphate-5-phosphatase J (INPP5J), phosphatase and tensin homologue (PTEN) and inositol polyphosphate 4-phosphatase type I (INPP4A), resulting in constitutive activation of PI3K/Akt signalling. Furthermore, we find that overexpressing miR-508 promotes, while silencing miR-508 impairs, the aggressive phenotype of oesophageal squamous cell carcinoma (ESCC) both in vitro and in vivo. Importantly, the level of miR-508 correlates with poor survival and activated PI3K/Akt signalling in a large cohort of ESCC specimens. These findings uncover a mechanism for constitutive PI3K/Akt activation in ESCC, and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

  4. Loss of SOD3 (EcSOD) expression promotes an aggressive phenotype in human pancreatic ductal adenocarcinoma

    PubMed Central

    O’Leary, Brianne R.; Fath, Melissa A.; Bellizzi, Andrew M.; Hrabe, Jennifer E.; Button, Anna M.; Allen, Bryan G.; Case, Adam J.; Altekruse, Sean; Wagner, Brett A.; Buettner, Garry R.; Lynch, Charles F.; Hernandez, Brenda Y.; Cozen, Wendy; Beardsley, Robert A.; Keene, Jeffery; Henry, Michael D.; Domann, Frederick E.; Spitz, Douglas R.; Mezhir, James J.

    2015-01-01

    Purpose Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. The current work tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design We evaluated the prognostic significance of EcSOD in a human tissue microarray of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase inhibitor to determine the mechanism of action of EcSOD in PDA. Results Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Over-expression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. PMID:25634994

  5. Preclinical Testing of a New MR Imaging Approach to Distinguish Aggressive from Indolent Disease

    DTIC Science & Technology

    2014-06-01

    aggressiveness including histologic analysis, Ki-67 proliferative assays, lactate dehydrogenase (LDH) activity, LDH-A expression, cellularity, and micro...assay determinations of cancer aggressiveness including histologic analysis, Ki-67 proliferative assays, lactate dehydrogenase (LDH) activity, LDH-A...distinguish aggressive prostate cancers from indolent disease based on up- regulated lactate - dehydrogenase (LDH) conversion of HP-pyruvate to lactate and

  6. RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer.

    PubMed

    Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge; Ertel, Adam; Fortina, Paolo; Witkiewicz, Agnieszka K

    2015-01-01

    Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC.

  7. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  8. Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

    PubMed Central

    Mittal, Karuna; Ogden, Angela; Reid, Michelle D; Rida, Padmashree CG; Varambally, Sooryanarayana; Aneja, Ritu

    2015-01-01

    Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients. PMID:26151406

  9. A Comprehensive Evaluation of Disease Phenotype Networks for Gene Prioritization

    PubMed Central

    Li, Jianhua; Lin, Xiaoyan; Teng, Yueyang; Qi, Shouliang; Xiao, Dayu; Zhang, Jianying; Kang, Yan

    2016-01-01

    Identification of disease-causing genes is a fundamental challenge for human health studies. The phenotypic similarity among diseases may reflect the interactions at the molecular level, and phenotype comparison can be used to predict disease candidate genes. Online Mendelian Inheritance in Man (OMIM) is a database of human genetic diseases and related genes that has become an authoritative source of disease phenotypes. However, disease phenotypes have been described by free text; thus, standardization of phenotypic descriptions is needed before diseases can be compared. Several disease phenotype networks have been established in OMIM using different standardization methods. Two of these networks are important for phenotypic similarity analysis: the first and most commonly used network (mimMiner) is standardized by medical subject heading, and the other network (resnikHPO) is the first to be standardized by human phenotype ontology. This paper comprehensively evaluates for the first time the accuracy of these two networks in gene prioritization based on protein–protein interactions using large-scale, leave-one-out cross-validation experiments. The results show that both networks can effectively prioritize disease-causing genes, and the approach that relates two diseases using a logistic function improves prioritization performance. Tanimoto, one of four methods for normalizing resnikHPO, generates a symmetric network and it performs similarly to mimMiner. Furthermore, an integration of these two networks outperforms either network alone in gene prioritization, indicating that these two disease networks are complementary. PMID:27415759

  10. Nuclear maspin expression correlates with the CpG island methylator phenotype and tumor aggressiveness in colorectal cancer.

    PubMed

    Kim, Jung Ho; Cho, Nam-Yun; Bae, Jeong Mo; Kim, Kyung-Ju; Rhee, Ye-Young; Lee, Hye Seung; Kang, Gyeong Hoon

    2015-01-01

    It has been suggested that nuclear expression of maspin (mammary serine protease inhibitor; also known as SERPINB5) in colorectal cancer (CRC) is associated with proximal colonic tumor location, mucinous and poorly differentiated histology, microsatellite instability-high (MSI-H), and poor prognosis. Based on these findings, there may be a potential association between nuclear maspin expression and the CpG island methylator phenotype (CIMP) in CRC, but no study has elucidated this issue. Here, we evaluated maspin protein expression status by immunohistochemistry in 216 MSI-H CRCs. CIMP status was also determined by methylation-specific quantitative PCR method (MethyLight) using eight CIMP markers (MLH1, NEUROG1, CRABP1, CACNA1G, CDKN2A (p16), IGF2, SOCS1, and RUNX3) in 216 MSI-H CRCs. Associations between maspin expression status and various pathological, molecular, and survival data were statistically analyzed. Among the 216 MSI-H CRCs, 111 (51%) cases presented nuclear maspin-positive tumors. Nuclear maspin-positive MSI-H CRCs were significantly associated with proximal tumor location (P = 0.003), tumor budding (P < 0.001), lymphovascular invasion (P = 0.001), perineural invasion (P = 0.008), absence of peritumoral lymphoid reaction (P = 0.045), lymph node metastasis (P = 0.003), distant metastasis (P = 0.005), advanced AJCC/UICC stage (stage III/IV) (P = 0.001), and CIMP-high (CIMP-H) status (P < 0.001). Patients with nuclear maspin-positive tumors showed worse disease-free survival than patients with nuclear maspin-negative tumors (log-rank P = 0.025). In conclusion, nuclear maspin expression is molecularly associated with CIMP-H rather than MSI-H, and clinicopathologically correlates with tumor aggressiveness in CRC.

  11. Cannibalism as an interacting phenotype: precannibalistic aggression is influenced by social partners in the endangered Socorro Isopod (Thermosphaeroma thermophilum).

    PubMed

    Bleakley, B H; Welter, S M; McCauley-Cole, K; Shuster, S M; Moore, A J

    2013-04-01

    Models for the evolution of cannibalism highlight the importance of asymmetries between individuals in initiating cannibalistic attacks. Studies may include measures of body size but typically group individuals into size/age classes or compare populations. Such broad comparisons may obscure the details of interactions that ultimately determine how socially contingent characteristics evolve. We propose that understanding cannibalism is facilitated by using an interacting phenotypes perspective that includes the influences of the phenotype of a social partner on the behaviour of a focal individual and focuses on variation in individual pairwise interactions. We investigated how relative body size, a composite trait between a focal individual and its social partner, and the sex of the partners influenced precannibalistic aggression in the endangered Socorro isopod, Thermosphaeroma thermophilum. We also investigated whether differences in mating interest among males and females influenced cannibalism in mixed sex pairs. We studied these questions in three populations that differ markedly in range of body size and opportunities for interactions among individuals. We found that relative body size influences the probability of and latency to attack. We observed differences in the likelihood of and latency to attack based on both an individual's sex and the sex of its partner but found no evidence of sexual conflict. The instigation of precannibalistic aggression in these isopods is therefore a property of both an individual and its social partner. Our results suggest that interacting phenotype models would be improved by incorporating a new conditional ψ, which describes the strength of a social partner's influence on focal behaviour.

  12. Decreased HoxD10 expression promotes a proliferative and aggressive phenotype in prostate cancer.

    PubMed

    Mo, R-J; Lu, J-M; Wan, Y-P; Hua, W; Liang, Y-X; Zhuo, Y-J; Kuang, Q-W; Liu, Y-L; He, H-C; Zhong, W-D

    2017-02-19

    HoxD10 gene plays a critical role in cell proliferation in the process of tumor development. However, the protein expression level and the function of HoxD10 in prostate cancer remain unknown. Using tissue microarray, we demonstrate that the protein expression of HoxD10 is commonly decreased in prostate cancer tissues (n = 92) compared to adjacent benign prostate tissues (n = 77). Functionally, knockdown of HoxD10 resulted in significant promotion of prostate cancer cell proliferation. Moreover, knockdown of HoxD10 strikingly stimulated prostate tumor growth in a mouse xenograft model. We also found a significant association between decreased immunohistochemical staining of HoxD10 expression and higher Gleason score (P = 0.031) and advanced clinical pathological stage (P = 0.011). An analysis of the Taylor database revealed that decreased HoxD10 expression predicted worse biochemical recurrence (BCR)-free survival of PCa patients (P = 0.005) and the multivariate analyses further supported that HoxD10 might be an independent predictor for BCR-free survival (P = 0.027). Collectively, our data suggest that the loss of HoxD10 function is common and may thus result in a progressive phenotype in PCa. HoxD10 may function as a biomarker that differentiates patients with BCR disease from the ones that are not after radical prostatectomy, implicating its potential as a therapeutic target.

  13. Preclinical Testing of a New MR Imaging Approach to Distinguish Aggressive from Indolent Disease

    DTIC Science & Technology

    2015-08-01

    AWARD NUMBER: W81XWH-13-1-0128 TITLE: ““Preclinical Testing of a New MR Imaging Approach to Distinguish Aggressive from Indolent Disease...9 May 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER “Preclinical Testing of a New MR Imaging Approach to Distinguish Aggressive from Indolent...13. SUPPLEMENTARY NOTES 14. ABSTRACT The aim of this project was to develop a new MRI approach to characterize aggressive prostate cancers and

  14. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

    PubMed

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-01-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  15. Angioedema Phenotypes: Disease Expression and Classification.

    PubMed

    Wu, Maddalena Alessandra; Perego, Francesca; Zanichelli, Andrea; Cicardi, Marco

    2016-10-01

    Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring "with or without wheals." Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of "angioedema without wheals" distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.

  16. Phenotypic convergence of Menkes and Wilson disease.

    PubMed

    Bansagi, Boglarka; Lewis-Smith, David; Pal, Endre; Duff, Jennifer; Griffin, Helen; Pyle, Angela; Müller, Juliane S; Rudas, Gabor; Aranyi, Zsuzsanna; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

    2016-12-01

    Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter ATP7A. Other ATP7A mutations have been linked to juvenile occipital horn syndrome and adult-onset hereditary motor neuropathy.(1,2) About 5%-10% of the patients present with "atypical Menkes disease" characterized by longer survival, cerebellar ataxia, and developmental delay.(2) The intracellular copper transport is regulated by 2 P type ATPase copper transporters ATP7A and ATP7B. These proteins are expressed in the trans-Golgi network that guides copper to intracellular compartments, and in copper excess, it relocates copper to the plasma membrane to pump it out from the cells.(3)ATP7B mutations cause Wilson disease with dystonia, ataxia, tremor, and abnormal copper accumulation in the brain, liver, and other organs.(4).

  17. GALNT6 expression enhances aggressive phenotypes of ovarian cancer cells by regulating EGFR activity.

    PubMed

    Lin, Tzu-Chi; Chen, Syue-Ting; Huang, Min-Chuan; Huang, John; Hsu, Chia-Lang; Juan, Hsueh-Fen; Lin, Ho-Hsiung; Chen, Chi-Hau

    2017-03-28

    Ovarian cancer is the most lethal of the gynecologic malignancies. N-acetylgalactosaminyltransferase 6 (GALNT6), an enzyme that mediates the initial step of mucin type-O glycosylation, has been reported to regulate mammary carcinogenesis. However, the expression and role of GALNT6 in ovarian cancer are still unclear. Here we showed that high GALNT6 expression correlates with increased recurrence, lymph node metastasis, and chemoresistance in ovarian endometrioid and clear cell carcinomas; and higher GALNT6 levels are significantly associated with poorer patient survivals. GALNT6 knockdown with two independent siRNAs significantly suppressed viability, migration, and invasion of ovarian cancer cells. Using phospho-RTK array and Western blot analyses, we identified EGFR as a critical target of GALNT6. GALNT6 knockdown decreased phosphorylation of EGFR, whereas GALNT6 overexpression increased the phosphorylation. Lectin pull-down assays with Vicia villosa agglutinin (VVA) indicated that GALNT6 was able to modify O-glycans on EGFR. Moreover, the GALNT6-enhanced invasive behavior was significantly reversed by erlotinib, an EGFR inhibitor. Our results suggest that GALNT6 expression is associated with poor prognosis of ovarian cancer and enhances the aggressive behavior of ovarian cancer cells by regulating EGFR activity.

  18. Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells.

    PubMed

    Jiang, L; Zhou, J; Zhong, D; Zhou, Y; Zhang, W; Wu, W; Zhao, Z; Wang, W; Xu, W; He, L; Ma, Y; Hu, Y; Zhang, W; Li, J

    2017-03-13

    Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

  19. [Clinical variability of Juvenile Huntington's Disease phenotype].

    PubMed

    Błaszczyk, Magdalena; Boczarska-Jedynak, Magdalena; Rudzińska, Monika

    2015-01-01

    Huntington's disease is rare, genetically determinated, neurodegenerative disorder. It is determined by dynamic mutation of IT15 gene on short arm of 4 chromosome. Characteristic symptomatology include involuntary movements, cognitive decline and wide spectrum of mood and behaviour disorders. It typically becomes noticeable in mid-adult life, but there are reported cases of appaers of symptoms between 2 and 80 year of life. Especially interesting is juvenile Huntington's disease- the Westphal variant with the beginning in childchood (before 20 year of age) because of clinical differences causing diagnostic difficulties. It affects 5-10% of carries of the mutant gene. Symptoms became noticeable before 10 year of age only in 1% of them.

  20. The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma.

    PubMed

    Wang, Jing; Nikhil, Kumar; Viccaro, Keith; Chang, Lei; Jacobsen, Max; Sandusky, George; Shah, Kavita

    2017-03-15

    We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors in vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.

  1. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees.

    PubMed

    Liu, Hui; Robinson, Gene E; Jakobsson, Eric

    2016-06-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization.

  2. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees

    PubMed Central

    Robinson, Gene E.; Jakobsson, Eric

    2016-01-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization

  3. From genotype to phenotype in Dravet disease.

    PubMed

    Gataullina, Svetlana; Dulac, Olivier

    2017-01-01

    Dravet syndrome combines clonic generalized, focal or unilateral seizures, beginning within the first year of life, often triggered by hyperthermia whatever its cause, including pertussis vaccination. Long-lasting febrile seizures are frequent in infancy and repeat status epilepticus (SE) has negative prognostic value. Massive myoclonus, rare absences, complex partial seizures and generalized spikes may appear several years later. Myoclonic status may occur in childhood, but acute encephalopathy with febrile SE followed by ischemic lesions and psychomotor impairment, the most severe condition, occurs mainly within the first five years of life. Generalized tonic-clonic and tonic seizures in sleep predominate in adulthood. Non epileptic manifestations appear with age, including intellectual disability, ataxia and crouching gait. Incidence of SUDEP is high, whatever the age. SCN1A haploinsufficiency producing NaV1.1 dysfunction mainly affects GABAergic neurons. In cortical interneurons it explains epilepsy, in cerebellum the ataxia, in basal ganglia and motor neurons the crouching gait, in hypothalamus the thermodysregulation and sleep troubles, and dysfunction in all these structures contributes to psychomotor delay. Valproate, stiripentol, topiramate and bromide are the basis of antiepileptic treatment, whereas inhibitors of sodium channel worsen the condition. Benzodiazepines seem to facilitate acute encephalopathy when given chronically, and they should be restricted to SE. Ketogenic diet is useful in both chronic and acute conditions. Only targeting SCN1A haploinsufficiency and NaV1.1 dysfunction could improve non epileptic manifestations of this condition that deserves being considered as a disease, not only as an epilepsy syndrome.

  4. A possible cause and corresponding treatment for inflammatory, auto-immune or auto-aggressive diseases.

    PubMed

    Gracia, M C

    2007-01-01

    This article develops the idea that many inflammatory, auto-immune or auto-aggressive diseases might result from conditioned responses acquired when occasional, possibly minor pathological conditions, normal organ fatigue, or similar sensations, are reinforced by an intense neural reward coinciding, often by pure bad luck, with these minor troubles. After such conditioning, and especially in times of frustration or distress, the brain will repeatedly try to obtain the reward again by recreating, with an intensity in proportion to the degree of frustration, the sensorial pattern of the initial minor trouble, producing auto-aggressive effects. This leads naturally to the idea of trying to extinguish diseases implying self-aggression by applying negative reinforcement. This behavioural strategy has been tested for some minor or medium-severity inflammatory/auto-immune troubles and, essentially, it works, although it implies practical difficulties that are reviewed in the text. Furthermore, the experience was very limited because of the difficulty of convincing people to try for good a scarcely tested technique requiring intense mental effort and completely different from the medical treatments people are used to. The article describes the physiological-behavioural model underlying our proposal, evaluates different possibilities of treatment, and provides useful practical advice. In particular, it appears that our proposal seems best suited for diseases in which the mental abilities of the person are intact and the inflammatory aggression is clearly identifiable by its symptoms, for example pain, itching, fatigue or paralysis. Possible candidate diseases could be, for example, superficial allergies or irritations, digestive inflammatory problems, rheumatoid or circulatory troubles, or motor neurological diseases like multiple sclerosis, Guillain-Barré syndrome and possibly ALS or Parkinson. The article is completed by some guidelines on the prevention of diseases

  5. Distinct clinical phenotypes of airways disease defined by cluster analysis.

    PubMed

    Weatherall, M; Travers, J; Shirtcliffe, P M; Marsh, S E; Williams, M V; Nowitz, M R; Aldington, S; Beasley, R

    2009-10-01

    Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.

  6. Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines.

    PubMed

    Ceja-Rangel, Hugo A; Sánchez-Suárez, Patricia; Castellanos-Juárez, Emilio; Peñaroja-Flores, Rubicelia; Arenas-Aranda, Diego J; Gariglio, Patricio; Benítez-Bribiesca, Luis

    2016-09-01

    Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.

  7. The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells.

    PubMed

    Scotlandi, K; Manara, M C; Serra, M; Benini, S; Maurici, D; Caputo, A; De Giovanni, C; Lollini, P L; Nanni, P; Picci, P; Campanacci, M; Baldini, N

    1999-01-21

    The relationship between P-glycoprotein expression and malignancy is controversial. We have recently found that, in osteosarcoma, multidrug resistance (MDR) is associated with a less aggressive behavior, both in vitro and in clinical settings. In this study, we evaluated whether P-glycoprotein overexpression has a cause-effect relationship with the reduced metastatic potential of MDR cells, or rather reflects a more complex phenotype. MDR1 gene-transfected osteosarcoma cell clones, showing different levels of P-glycoprotein expression, were analysed for their in vitro characteristics and their tumorigenic and metastatic ability in athymic mice. Apart from the different levels of P-glycoprotein, no significant change in the expression of surface antigens or in the differentiative features were observed in the MDR1 gene transfectants compared to the parental cell lines or control clones, obtained by transfection with neo gene alone. In contrast to controls, however, MDR1 transfectants showed a significantly lower ability to grow in semi-solid medium and were completely unable to grow and give lung metastases in athymic mice. These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity.

  8. Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype.

    PubMed

    Tyler, Andrea D; Kirsch, Richard; Milgrom, Raquel; Stempak, Joanne M; Kabakchiev, Boyko; Silverberg, Mark S

    2016-04-01

    Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes.

  9. Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

    PubMed Central

    Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko

    2015-01-01

    CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential

  10. Identification of extreme motor phenotypes in Huntington's disease.

    PubMed

    Braisch, Ulrike; Hay, Birgit; Muche, Rainer; Rothenbacher, Dietrich; Landwehrmeyer, G Bernhard; Long, Jeffrey D; Orth, Michael

    2017-04-01

    The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits. Boundaries (2.5% and 97.5% quantiles) for extreme motor phenotypes (UHDRS total motor score (TMS) and motor age-at-onset) were estimated using quantile regression for longitudinal data. More than 15% of HD participants had an extreme TMS phenotype for at least one visit. In contrast, only about 4% of participants were consistent TMS extremes at two or more visits. Data from healthy controls revealed an upper cut-off of 13 for the TMS representing the extreme of motor ratings for a normal aging population. In HD, boundaries of motor age-at-onset based on diagnostic confidence or derived from the TMS data cut-off in controls were similar. In summary, a UHDRS TMS of more than 13 in an individual carrying the HD mutation indicates a high likelihood of motor manifestations of HD irrespective of CAG repeat length or age. The identification of motor phenotype extremes can be useful in the search for disease modifiers, for example, genetic or environmental such as medication. © 2016 Wiley Periodicals, Inc.

  11. Social cognition in Wilson's disease: A new phenotype?

    PubMed

    Peyroux, Elodie; Santaella, Nelly; Broussolle, Emmanuel; Rigard, Caroline; Favre, Emilie; Brunet, Anne-Sophie; Bost, Muriel; Lachaux, Alain; Demily, Caroline

    2017-01-01

    Studies focusing on neuropsychological impairments in Wilson's disease (WD) have highlighted that patients showing neurological signs present significant deficits in a wide range of cognitive domains. Attentional and executive impairments have also been described in people with hepatic WD. However, social cognition abilities, i.e. cognitive processes required to perceive the emotions, intentions and dispositions of other people, have not been clearly investigated in WD. In this study we examined the social cognitive functioning in 19 patients with WD depending on their clinical status-Neurological versus Non-Neurological ("hepatic") forms-compared to 20 healthy controls. For the very first time, results highlighted that patients with WD had significant impairments in the three major components of social cognition: emotion recognition, Theory of Mind and attributional style. However, these deficits differ depending on the form of the disease: patients with neurological signs showed a wide range of deficits in the three components that were assessed-results notably revealed impairments in recognizing "fear", "anger", and "disgust", a significant Theory of Mind deficit and an "aggression bias"-whereas Non-Neurological patients only showed deficits on test assessing attributional bias, with a trend to react more "aggressively" to ambiguous social situations than healthy controls, as observed in Neurological WD patients, and a specific impairment in "anger" recognition. Our findings are discussed in the light of both neurocognitive impairments and brain damages, and especially those affecting the basal ganglia, as observed in people with WD.

  12. Aggressive therapy improves cirrhosis in glycogen storage disease type IX.

    PubMed

    Tsilianidis, Laurie A; Fiske, Laurie M; Siegel, Sara; Lumpkin, Chris; Hoyt, Kate; Wasserstein, Melissa; Weinstein, David A

    2013-06-01

    Glycogen storage disease type IX (GSD IX) is described as a benign condition that often does not require treatment. Most patients with the disease are thought to outgrow the childhood manifestations, which include hepatomegaly, poor growth, and ketosis with or without hypoglycemia. Long term complications including fibrosis and cirrhosis have seldom been reported in the most common subtype, GSD IXα. We present two cases of children with GSD IXα who had fibrosis at the time of diagnosis in addition to the commonly reported disease manifestations. Structured therapy with frequent doses of uncooked cornstarch and protein supplementation was initiated, and both children responded with improved growth velocity, increased energy, decreased hepatomegaly and improved well-being. Additionally, radiographic features of fibrosis improved. We propose that GSD IXα is not a benign condition. Even in patients with a less severe presentation, consideration of a structured treatment regimen to improve quality of life appears warranted.

  13. Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo

    PubMed Central

    Zhou, P-H; Zheng, J-B; Wei, G-B; Wang, X-L; Wang, W; Chen, N-Z; Yu, J-H; Yao, J-F; Wang, H; Lu, S-Y; Sun, X-J

    2015-01-01

    Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia-inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer. PMID:26005859

  14. Type 2 Gaucher disease: phenotypic variation and genotypic heterogeneity

    PubMed Central

    Gupta, N; Oppenheim, IM; Kauvar, EF; Tayebi, N; Sidransky, E

    2010-01-01

    Gaucher disease (GD), the most common lysosomal storage disease, results from a deficiency of the lysosomal enzyme glucocerebrosidase. GD has been classified into 3 types, of which type 2 (the acute neuronopathic form) is most severe, presenting pre- or perinatally, or in the first few months of life. Traditionally, type 2 GD was considered to have the most uniform clinical phenotype when compared to other GD subtypes. However, case studies over time have demonstrated that type 2 GD, like types 1 and 3, manifests with a spectrum of phenotypes. This review includes case reports that illustrate the broad range of clinical presentations encountered in type 2 GD, as well as a discussion of associated manifestations, pathological findings, diagnostic techniques, and a review of current therapies. While type 2 GD is generally associated with severe mutations in the glucocerebrosidase gene, there is also significant genotypic heterogeneity observed. PMID:20880730

  15. Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes.

    PubMed

    Benoit, Geneviève; Machuca, Eduardo; Heidet, Laurence; Antignac, Corinne

    2010-12-01

    A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. The identification of genes involved in congenital anomalies of the kidney and in familial forms of nephrotic syndrome significantly increased our understanding of the renal development and kidney filtration barrier physiology. This review will focus on the classical phenotype and clinical heterogeneity observed in the monogenic forms of these disorders. In addition, the role of susceptibility genes in kidney diseases with a complex inheritance will also be discussed.

  16. Somatic reversion in DOCK8 immunodeficiency modulates disease phenotype

    PubMed Central

    Jing, Huie; Zhang, Qian; Zhang, Yu; Hill, Brenna J.; Dove, Christopher G.; Gelfand, Erwin W.; Atkinson, T. Prescott; Uzel, Gulbu; Matthews, Helen F.; Mustillo, Peter J.; Lewis, David B.; Kavadas, Fotini D.; Hanson, I. Celine; Kumar, Ashish R.; Geha, Raif S.; Douek, Daniel C.; Holland, Steven M.; Freeman, Alexandra F.; Su, Helen C.

    2014-01-01

    Background Autosomal recessive, loss-of-function mutations in DOCK8 cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. Objective We investigated whether reversions contributed to the variable disease expression. Methods Patients followed at the NIH Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. Results We identified 17 out of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion due to somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or in NK cells, but less so in naïve T cells or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. Conclusions In DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival, but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8 immunodeficient patients have mutable mosaic genomes that may modulate disease phenotype over time. PMID:24797421

  17. Copper phenotype in Alzheimer’s disease: dissecting the pathway

    PubMed Central

    Squitti, Rosanna; Polimanti, Renato

    2013-01-01

    Alzheimer’s disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. Unfortunately, none of these seems to clarify the complexity of the pathogenesis. In fact, diverse and independent pathogenetic pathways can be disrupted at the same time, and each contributes to disease etiology. In recent years, researchers have begun studying biometals more deeply. A number of studies have shown that metal dyshomeostasis may enhance AD onset and progression. Specifically, different authors have hypothesized that alterations in metal metabolism are associated with an increased in metal-related oxidative stress and beta-amyloid oligomer formation and precipitation. Studies conducted in vivo, in vitro, in living patients and in silico studies have demonstrated that local and systemic defects in copper metabolism are characteristic signs of AD. This strongly supports the hypothesis that copper pathways may be disrupted by the disease. More specifically, a copper phenotype can be proposed for AD, based on defects found in genes involved in copper metabolism. In this review, we describe copper dyshomeostasis in AD patients and attempt to explain the basis of the AD copper phenotype. Dissecting copper pathways, we highlight mechanisms which may be at the basis of the disease. We also discuss various associated translation outcomes. PMID:23844331

  18. Type 2 Gaucher disease: the collodion baby phenotype revisited

    PubMed Central

    Stone, D; Carey, W; Christodoulou, J; Sillence, D; Nelson, P; Callahan, M; Tayebi, N; Sidransky, E

    2000-01-01

    The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.

 PMID:10685993

  19. Fetal inhibition of inflammation improves disease phenotypes in harlequin ichthyosis.

    PubMed

    Cottle, Denny L; Ursino, Gloria M A; Ip, Sally Chi Ieng; Jones, Lynelle K; Ditommaso, Tia; Hacking, Douglas F; Mangan, Niamh E; Mellett, Natalie A; Henley, Katya J; Sviridov, Dmitri; Nold-Petry, Claudia A; Nold, Marcel F; Meikle, Peter J; Kile, Benjamin T; Smyth, Ian M

    2015-01-15

    Harlequin ichthyosis (HI) is a severe skin disease which leads to neonatal death in ∼50% of cases. It is the result of mutations in ABCA12, a protein that transports lipids required to establish the protective skin barrier needed after birth. To better understand the life-threatening newborn HI phenotype, we analysed the developing epidermis for consequences of lipid dysregulation in mouse models. We observed a pro-inflammatory signature which was characterized by chemokine upregulation in embryonic skin which is distinct from that seen in other types of ichthyosis. Inflammation also persisted in grafted HI skin. To examine the contribution of inflammation to disease development, we overexpressed interleukin-37b to globally suppress fetal inflammation, observing considerable improvements in keratinocyte differentiation. These studies highlight inflammation as an unexpected contributor to HI disease development in utero, and suggest that inhibiting inflammation may reduce disease severity.

  20. Enriched CD44(+)/CD24(-) population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC).

    PubMed

    Ma, Fei; Li, Huihui; Wang, Haijuan; Shi, Xiuqing; Fan, Ying; Ding, Xiaoyan; Lin, Chen; Zhan, Qimin; Qian, Haili; Xu, Binghe

    2014-10-28

    The mechanism underlying the aggressive behaviors of triple negative breast cancer (TNBC) is not well characterized yet. The association between cancer stem cell (CSC) population and the aggressive behaviors of TNBC has not been established. We found the CD44(+)/CD24(-) cell population was enriched in TNBC tissues and cell lines, with a higher capacity of proliferation, migration, invasion and tumorigenicity as well as lower adhesion ability. The CD44(+)/CD24(-) cell population with cancer stem cell-like properties may play an important role in the aggressive behaviors of TNBC. This discovery may lead to new therapeutic strategies targeting CD44(+)/CD24(-) cell population in TNBC.

  1. Identification of microRNAs associated with invasive and aggressive phenotype in cutaneous melanoma by next-generation sequencing.

    PubMed

    Babapoor, Sankhiros; Wu, Rong; Kozubek, James; Auidi, Donna; Grant-Kels, Jane M; Dadras, Soheil S

    2017-02-20

    A comprehensive repertoire of human microRNAs (miRNAs) that could be involved in early melanoma invasion into the dermis remains unknown. To this end, we sequenced small RNAs (18-30 nucleotides) isolated from an annotated series of invasive melanomas (average invasive depth, 2.0 mm), common melanocytic nevi, and matched normal skin (n=28). Our previously established bioinformatics pipeline identified 765 distinct mature known miRNAs and defined a set of top 40 list that clearly segregated melanomas into thin (0.75 mm) and thick (2.7 mm) groups. Among the top, miR-21-5p, let-7b-5p, let-7a-5p, miR-424-5p, miR-423-5p, miR-21-3p, miR-199b-5p, miR-182-5p, and miR-205-5p were differentially expressed between thin and thick melanomas. In a validation cohort (n=167), measured expression of miR-21-5p and miR-424-5p, not previously reported in melanoma, were significantly increased in invasive compared with in situ melanomas (P<0.0001). Increased miR-21-5p levels were significantly associated with invasive depth (P=0.038), tumor mitotic index (P=0.038), lymphovascular invasion (P=0.0036), and AJCC stage (P=0.038). In contrast, let-7b levels were significantly decreased in invasive and in situ melanomas compared with common and dysplastic nevi (P<0.0001). Decreased let-7b levels were significantly associated with invasive depth (P=0.011), Clark's level (P=0.013), ulceration (P=0.0043), and AJCC stage (P=0.011). These results define a distinct set of miRNAs associated with invasive and aggressive melanoma phenotype.Laboratory Investigation advance online publication, 20 February 2017; doi:10.1038/labinvest.2017.5.

  2. Localized severe aggressive periodontitis. Disease progression and tooth preservation: a short case report over 14 years.

    PubMed

    Pelka, Matthias; Petschelt, Anselm

    2009-04-01

    A case of a 31-year-old female with aggressive periodontitis over 14 years is presented. From 1993 to 2000, no periodontal therapy occurred; disease development and progression could be reconstructed upon radiographic findings. In 2000, full-mouth disinfection therapy and antibiotic therapy was performed, as well as regenerative surgical treatments. Seven years after surgical treatment, stable periodontal conditions and clear bone regeneration in the surgical areas was evident.

  3. Rhes suppression enhances disease phenotypes in Huntington's disease mice.

    PubMed

    Lee, John H; Sowada, Matthew J; Boudreau, Ryan L; Aerts, Andrea M; Thedens, Daniel R; Nopoulos, Peg; Davidson, Beverly L

    2014-01-01

    In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.

  4. Towards building a disease-phenotype knowledge base: extracting disease-manifestation relationship from literature

    PubMed Central

    Xu, Rong; Li, Li; Wang, QuanQiu

    2013-01-01

    Motivation: Systems approaches to studying phenotypic relationships among diseases are emerging as an active area of research for both novel disease gene discovery and drug repurposing. Currently, systematic study of disease phenotypic relationships on a phenome-wide scale is limited because large-scale machine-understandable disease–phenotype relationship knowledge bases are often unavailable. Here, we present an automatic approach to extract disease–manifestation (D-M) pairs (one specific type of disease–phenotype relationship) from the wide body of published biomedical literature. Data and Methods: Our method leverages external knowledge and limits the amount of human effort required. For the text corpus, we used 119 085 682 MEDLINE sentences (21 354 075 citations). First, we used D-M pairs from existing biomedical ontologies as prior knowledge to automatically discover D-M–specific syntactic patterns. We then extracted additional pairs from MEDLINE using the learned patterns. Finally, we analysed correlations between disease manifestations and disease-associated genes and drugs to demonstrate the potential of this newly created knowledge base in disease gene discovery and drug repurposing. Results: In total, we extracted 121 359 unique D-M pairs with a high precision of 0.924. Among the extracted pairs, 120 419 (99.2%) have not been captured in existing structured knowledge sources. We have shown that disease manifestations correlate positively with both disease-associated genes and drug treatments. Conclusions: The main contribution of our study is the creation of a large-scale and accurate D-M phenotype relationship knowledge base. This unique knowledge base, when combined with existing phenotypic, genetic and proteomic datasets, can have profound implications in our deeper understanding of disease etiology and in rapid drug repurposing. Availability: http://nlp.case.edu/public/data/DMPatternUMLS/ Contact: rxx@case.edu PMID:23828786

  5. A phenotypic model recapitulating the neuropathology of Parkinson's disease.

    PubMed

    Ferris, Craig F; Marella, Mathieu; Smerkers, Brian; Barchet, Thomas M; Gershman, Benjamin; Matsuno-Yagi, Akemi; Yagi, Takao

    2013-07-01

    This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8-9 month old, ovariectomized Long-Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11-12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5-6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2'-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the

  6. FGFR4 polymorphic variants modulate phenotypic features of Cushing disease.

    PubMed

    Nakano-Tateno, Tae; Tateno, Toru; Hlaing, Maw Maw; Zheng, Lei; Yoshimoto, Katsuhiko; Yamada, Shozo; Asa, Sylvia L; Ezzat, Shereen

    2014-04-01

    Cushing disease is a potentially lethal condition resulting from hormone excess, usually due to a small pituitary tumor that fails to respond to negative feedback inhibition. A minority of patients develop larger, more aggressive tumors of the same lineage but with modest hormone excess. Here we show that a common polymorphism in the fibroblast growth factor receptor 4 (FGFR4) transmembrane domain yields receptor isoforms with distinct properties that mediate these biological differences. Forced expression of the major FGFR4-G388 variant allele supports pY-signal transducer and activator of transcription (STAT3) responses. In contrast, expression of the minor FGFR4-R388 allele enhances STAT3 serine phosphorylation, driving cellular growth. In addition, FGFR4-R388 enhances glucocorticoid receptor phosphorylation and nuclear translocation. Consistent with these findings, glucocorticoid administration resulted in enhanced hormone negative feedback in mice with knock-in of the FGFR4 variant allele. Moreover, clinical data from patients with pituitary tumors revealed that those homozygous for the R388 allele have a higher frequency of silent corticotroph macroadenomas than FGFR4-G388 carriers, who were more likely to have small but hormonally active microadenomas. These findings demonstrate that the FGFR4 transmembrane polymorphic variants can modulate cellular growth and sensitivity to glucocorticoid hormone negative feedback through distinct STAT3 modifications of relevance to the human forms of Cushing disease.

  7. A phenotypic compound screening assay for lysosomal storage diseases.

    PubMed

    Xu, Miao; Liu, Ke; Swaroop, Manju; Sun, Wei; Dehdashti, Seameen J; McKew, John C; Zheng, Wei

    2014-01-01

    The lysosome is a vital cellular organelle that primarily functions as a recycling center for breaking down unwanted macromolecules through a series of hydrolases. Functional deficiencies in lysosomal proteins due to genetic mutations have been found in more than 50 lysosomal storage diseases that exhibit characteristic lipid/macromolecule accumulation and enlarged lysosomes. Recently, the lysosome has emerged as a new therapeutic target for drug development for the treatment of lysosomal storage diseases. However, a suitable assay for compound screening against the diseased lysosomes is currently unavailable. We have developed a Lysotracker staining assay that measures the enlarged lysosomes in patient-derived cells using both fluorescence intensity readout and fluorescence microscopic measurement. This phenotypic assay has been tested in patient cells obtained from several lysosomal storage diseases and validated using a known compound, methyl-β-cyclodextrin, in primary fibroblast cells derived from Niemann Pick C disease patients. The results demonstrate that the Lysotracker assay can be used in compound screening for the identification of lead compounds that are capable of reducing enlarged lysosomes for drug development.

  8. The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition

    PubMed Central

    Oh, Ji Hoon; Hur, Ho; Lee, Ji-Yeon; Kim, Yeejeong; Seo, Younsoo; Kim, Myoung Hee

    2017-01-01

    The gene RAE1 encodes ribonucleic acid export 1 (RAE1), which is involved in mRNA export and is known to serve as a mitotic checkpoint regulator. In addition, RAE1 haplo-insufficiency leads to chromosome missegregation and early aging-associated phenotypes. In humans, a positive correlation has been found between RAE1 copy number abnormalities and gene amplification in breast cancer cells. However, the precise functional role of RAE1 in breast cancer remains to be determined. An in silico analysis of data retrieved from GENT and cBio-Portal identified RAE1 upregulation in breast cancer tissues relative to normal breast cells. Functional studies of various cell lines showed that RAE1 induced invasive and migratory abilities by regulating epithelial-mesenchymal transition signals. A tissue microarray was constructed to demonstrate the interrelationship between clinicopathological features and RAE1 expression. Immunohistochemistry revealed a positive correlation between RAE1 expression and a high histologic grade. Furthermore, RAE1 overexpression was associated with considerably poorer disease-free survival and distant metastasis-free survival, especially in patients with oestrogen receptor-positive tumours. In summary, RAE1 may be a prognostic marker and therapeutic intervention target in malignant breast cancers. PMID:28181567

  9. The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition.

    PubMed

    Oh, Ji Hoon; Hur, Ho; Lee, Ji-Yeon; Kim, Yeejeong; Seo, Younsoo; Kim, Myoung Hee

    2017-02-09

    The gene RAE1 encodes ribonucleic acid export 1 (RAE1), which is involved in mRNA export and is known to serve as a mitotic checkpoint regulator. In addition, RAE1 haplo-insufficiency leads to chromosome missegregation and early aging-associated phenotypes. In humans, a positive correlation has been found between RAE1 copy number abnormalities and gene amplification in breast cancer cells. However, the precise functional role of RAE1 in breast cancer remains to be determined. An in silico analysis of data retrieved from GENT and cBio-Portal identified RAE1 upregulation in breast cancer tissues relative to normal breast cells. Functional studies of various cell lines showed that RAE1 induced invasive and migratory abilities by regulating epithelial-mesenchymal transition signals. A tissue microarray was constructed to demonstrate the interrelationship between clinicopathological features and RAE1 expression. Immunohistochemistry revealed a positive correlation between RAE1 expression and a high histologic grade. Furthermore, RAE1 overexpression was associated with considerably poorer disease-free survival and distant metastasis-free survival, especially in patients with oestrogen receptor-positive tumours. In summary, RAE1 may be a prognostic marker and therapeutic intervention target in malignant breast cancers.

  10. Behavioral phenotyping of mouse models of Parkinson's Disease

    PubMed Central

    Taylor, Tonya N.; Greene, James G.; Miller, Gary W.

    2010-01-01

    Parkinson's disease (PD) is a common neurodegenerative movement disorder afflicting millions of people in the United States. The advent of transgenic technologies has contributed to the development of several new mouse models, many of which recapitulate some aspects of the disease; however, no model has been demonstrated to faithfully reproduce the full constellation of symptoms seen in human PD. This may be due in part to the narrow focus on the dopamine-mediated motor deficits. As current research continues to unmask PD as a multi-system disorder, animal models should similarly evolve to include the non-motor features of the disease. This requires that typically cited behavioral test batteries be expanded. The major non-motor symptoms observed in PD patients include hyposmia, sleep disturbances, gastrointestinal dysfunction, autonomic dysfunction, anxiety, depression, and cognitive decline. Mouse behavioral tests exist for all of these symptoms and while some models have begun to be reassessed for the prevalence of this broader behavioral phenotype, the majority has not. Moreover, all behavioral paradigms should be tested for their responsiveness to L-DOPA so these data can be compared to patient response and help elucidate which symptoms are likely not dopamine-mediated. Here, we suggest an extensive, yet feasible, battery of behavioral tests for mouse models of PD aimed to better assess both non-motor and motor deficits associated with the disease. PMID:20211655

  11. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA).

    PubMed

    Gisselbrecht, C; Gaulard, P; Lepage, E; Coiffier, B; Brière, J; Haioun, C; Cazals-Hatem, D; Bosly, A; Xerri, L; Tilly, H; Berger, F; Bouhabdallah, R; Diebold, J

    1998-07-01

    Peripheral T-cell lymphomas (PTCL) have been generally reported to have a worse prognosis than B-cell lymphomas (BCL). Because of their heterogeneity and scarcity, the outcomes of the different histological subtypes have not been compared. From October 1987 to March 1993, 1,883 patients with diffuse aggressive non-Hodgkin's lymphomas (NHL) included in the LNH87 protocol could be assessed for both morphology and immunophenotyping. Among them, 288 (15%) had PTCL and 1,595 (85%) had BCL. According to the Kiel classification, most PTCL were classified as angioimmunoblastic (AIL; 23%), pleomorphic medium and large T-cell (PML; 49%), or anaplastic large cell (ALCL; 20%) lymphomas. Comparing PTCL with BCL patients, the former had more disseminated disease (78% v 58%), B symptoms (57% v 40%), bone marrow involvement (31% v 17%), skin involvement (21% v 4%), and increased beta2-microglobulin (50% v 34%), whereas BCL patients had more bulky disease (41% v 26%). According to the International Prognostic Index (IPI), PTCL and BCL scores were, respectively: 0 factors, 13% and 15%; 1 factor, 17% and 22%; 2 factors, 24% and 25%; >/=3 factors, 45% and 37% (P = .09). For BCL and PTCL, respectively, complete remission rates were 63% and 54% (P = .004); the 5-year overall survival (OS) rates were 53% and 41% (P = .0004) and event-free survival (EFS) rates were 42% and 33% (P < . 0001). Comparison of the different histological subtypes of lymphoma showed that the 5-year OS rate for T-ALCL (64%) was superior to those of other PTCL (35%) as well as diffuse large B-cell (53%) NHL. When multivariate analysis was applied using the IPI score as one factor, nonanaplastic PTCL remained an independent parameter (P = . 0004). Although the poor prognosis of non-ALCL PTCL could be due in part to the presence of adverse prognostic factors at diagnosis, this study shows that the T-cell phenotype is an independent significant factor, which should be incorporated into the definition of prognostic

  12. Aggressive Disease Course of Papillary Thyroid Carcinoma with Focal Undifferentiated Component: A Case Report.

    PubMed

    Riaz, Saima; Bashir, Humayun; Hassan, Aamna; Mushtaq, Sajid; Jamshed, Arif; Murtaza, Ahmad

    2016-10-05

    We report an aggressive papillary thyroid carcinoma (PTC) with focal undifferentiated component in a 32-year-old female. She had limited disease confined within the thyroid gland at diagnosis. Within 12 months of thyroidectomy and radioiodine ablation, thyroglobulin (Tg) levels were elevated. Second radioiodine ablative dose was given, however, stimulated Tg levels showed an upward trend with negative iodine scan within 12 months. An 18F fludeoxyglucose-avid solitary pulmonary nodule that was detected on positron emission tomography/computed tomography scan was resected followed by empiric radioiodine therapy. Within the next 10 months she developed multifocal bone metastases. The multifocal disease was rendered inoperable and treated with external beam radiation. The patient is on follow-up, and the Tg level continues to rise with local disease progression. In a small percentage of patients, PTC behaves as a very aggressive disease despite treatment. Focally undifferentiated thyroid carcinoma is an expression of the extreme end of the spectrum of differentiated thyroid carcinoma.

  13. Aggressive Disease Course of Papillary Thyroid Carcinoma with Focal Undifferentiated Component: A Case Report

    PubMed Central

    Riaz, Saima; Bashir, Humayun; Hassan, Aamna; Mushtaq, Sajid; Jamshed, Arif; Murtaza, Ahmad

    2016-01-01

    We report an aggressive papillary thyroid carcinoma (PTC) with focal undifferentiated component in a 32-year-old female. She had limited disease confined within the thyroid gland at diagnosis. Within 12 months of thyroidectomy and radioiodine ablation, thyroglobulin (Tg) levels were elevated. Second radioiodine ablative dose was given, however, stimulated Tg levels showed an upward trend with negative iodine scan within 12 months. An 18F fludeoxyglucose-avid solitary pulmonary nodule that was detected on positron emission tomography/computed tomography scan was resected followed by empiric radioiodine therapy. Within the next 10 months she developed multifocal bone metastases. The multifocal disease was rendered inoperable and treated with external beam radiation. The patient is on follow-up, and the Tg level continues to rise with local disease progression. In a small percentage of patients, PTC behaves as a very aggressive disease despite treatment. Focally undifferentiated thyroid carcinoma is an expression of the extreme end of the spectrum of differentiated thyroid carcinoma. PMID:27751976

  14. Marshall-Stickler phenotype associated with von Willebrand disease

    SciTech Connect

    MacDonald, M.R.; Baker, K.S.; Schaefer, G.B.

    1997-01-20

    We report on 6 individuals from three different kindreds with Marshall-Stickler (MS) phenotype, with characteristic orofacial abnormalities, arthropathy, deafness, and eye findings, all of whom were discovered to have a mild bleeding diathesis and coagulation-study findings consistent with mild von Willebrand disease (vWD). MS syndrome has been linked in some cases to the type II procollagen gene (COL2A1) on chromosome 12q, and to the collagen XI gene (COL11A2) on chromosome 6. The von Willebrand factor (vWF) is encoded by a 180-Kb gene located on the short arm of chromosome 12. This is the first reported association of these two disorders. 26 refs., 5 figs., 1 tab.

  15. The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

    PubMed Central

    Fu, Yi-Ping; Kohaar, Indu; Moore, Lee E.; Lenz, Petra; Figueroa, Jonine D.; Tang, Wei; Porter-Gill, Patricia; Chatterjee, Nilanjan; Scott-Johnson, Alexandra; Garcia-Closas, Montserrat; Muchmore, Brian; Baris, Dalsu; Paquin, Ashley; Ylaya, Kris; Schwenn, Molly; Apolo, Andrea B.; Karagas, Margaret R.; Tarway, McAnthony; Johnson, Alison; Mumy, Adam; Schned, Alan; Guedez, Liliana; Jones, Michael A.; Kida, Masatoshi; Monawar Hosain, GM; Malats, Nuria; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Carrato, Alfredo; Garcia-Closas, Reina; Lloreta, Josep; Wu, Xifeng; Purdue, Mark; Andriole, Gerald L.; Grubb, Robert L.; Black, Amanda; Landi, Maria T.; Caporaso, Neil E.; Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Severi, Gianluca; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Govannucci, Edward; Hunter, David; Kraft, Peter; Lindstrom, Sara; Gapstur, Susan M.; Jacobs, Eric J.; Diver, W. Ryan; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca J.; Cortessis, Victoria K.; Conti, David V.; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Haiman, Christopher A.; Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Porru, Stefano; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Grossman, H. Barton; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Fraumeni, Joseph; Chanock, Stephen J.; Hewitt, Stephen M.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila

    2014-01-01

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID:25320178

  16. Co-clustering phenome–genome for phenotype classification and disease gene discovery

    PubMed Central

    Hwang, TaeHyun; Atluri, Gowtham; Xie, MaoQiang; Dey, Sanjoy; Hong, Changjin; Kumar, Vipin; Kuang, Rui

    2012-01-01

    Understanding the categorization of human diseases is critical for reliably identifying disease causal genes. Recently, genome-wide studies of abnormal chromosomal locations related to diseases have mapped >2000 phenotype–gene relations, which provide valuable information for classifying diseases and identifying candidate genes as drug targets. In this article, a regularized non-negative matrix tri-factorization (R-NMTF) algorithm is introduced to co-cluster phenotypes and genes, and simultaneously detect associations between the detected phenotype clusters and gene clusters. The R-NMTF algorithm factorizes the phenotype–gene association matrix under the prior knowledge from phenotype similarity network and protein–protein interaction network, supervised by the label information from known disease classes and biological pathways. In the experiments on disease phenotype–gene associations in OMIM and KEGG disease pathways, R-NMTF significantly improved the classification of disease phenotypes and disease pathway genes compared with support vector machines and Label Propagation in cross-validation on the annotated phenotypes and genes. The newly predicted phenotypes in each disease class are highly consistent with human phenotype ontology annotations. The roles of the new member genes in the disease pathways are examined and validated in the protein–protein interaction subnetworks. Extensive literature review also confirmed many new members of the disease classes and pathways as well as the predicted associations between disease phenotype classes and pathways. PMID:22735708

  17. Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells.

    PubMed

    Maloberti, Paula M; Duarte, Alejandra B; Orlando, Ulises D; Pasqualini, María E; Solano, Angela R; López-Otín, Carlos; Podestá, Ernesto J

    2010-11-11

    The acyl-CoA synthetase 4 (ACSL4) is increased in breast cancer, colon and hepatocellular carcinoma. ACSL4 mainly esterifies arachidonic acid (AA) into arachidonoyl-CoA, reducing free AA intracellular levels, which is in contradiction with the need for AA metabolites in tumorigenesis. Therefore, the causal role of ACSL4 is still not established. This study was undertaken to determine the role of ACSL4 in AA metabolic pathway in breast cancer cells. The first novel finding is that ACSL4 regulates the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin in MDA-MB-231 cells. We also found that ACSL4 is significantly up-regulated in the highly aggressive MDA-MB-231 breast cancer cells. In terms of its overexpression and inhibition, ACSL4 plays a causal role in the control of the aggressive phenotype. These results were confirmed by the increase in the aggressive behaviour of MCF-7 cells stably transfected with a Tet-off ACSL4 vector. Concomitantly, another significant finding was that intramitochondrial AA levels are significantly higher in the aggressive cells. Thus, the esterification of AA by ACSL4 compartmentalizes the release of AA in mitochondria, a mechanism that serves to drive the specific lipooxygenase metabolization of the fatty acid. To our knowledge, this is the first report that ACSL4 expression controls both lipooxygenase and cyclooxygenase metabolism of AA. Thus, this functional interaction represents an integrated system that regulates the proliferating and metastatic potential of cancer cells. Therefore, the development of combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower medication doses and avoidance of side effects.

  18. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

    PubMed Central

    Zemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul-Neumann, Luitgard; Doelken, Sandra; Ehmke, Nadja; Spielmann, Malte; Øien, Nancy Christine; Schweiger, Michal R.; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna E.; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N.

    2015-01-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients’ phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics. PMID:25186178

  19. Distinct phenotypes in mixed connective tissue disease: subgroups and survival.

    PubMed

    Szodoray, P; Hajas, A; Kardos, L; Dezso, B; Soos, G; Zold, E; Vegh, J; Csipo, I; Nakken, B; Zeher, M; Szegedi, G; Bodolay, E

    2012-11-01

    The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud's phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p < 0.001), Raynaud's phenomenon (92.2%; p < 0.001) and livedo reticularis (24.6%, p < 0.001) was significantly greater than in cluster 2 and 3. In cluster 2, the incidence of ILD (98.7%; p < 0.001), myositis (77.2%; p < 0.001), and esophageal dysmotility (89.8%; p < 0.001) was significantly greater than that in cluster 1 and 3. In cluster 3, anti-CCP antibodies were present in 31 of 45 patients (68.8%) with erosions. Anti-CCP antibodies were present in 37 of 42 patients (88.0%) with erosions. PAH, angina, venous thrombosis was observed in cluster 1 and pulmonary fibrosis in cluster 2, musculosceletal damage, gastrointestinal symptoms and osteoporotic fractures were most frequent in cluster 3. Cumulative survival assessment indicated cluster 1 patients having the worst prognosis. Cluster analysis is valuable to differentiate among various subsets of MCTD and useful prognostic factor regarding the disease course.

  20. Multiple phenotypes in Huntington disease mouse neural stem cells.

    PubMed

    Ritch, James J; Valencia, Antonio; Alexander, Jonathan; Sapp, Ellen; Gatune, Leah; Sangrey, Gavin R; Sinha, Saurabh; Scherber, Cally M; Zeitlin, Scott; Sadri-Vakili, Ghazaleh; Irimia, Daniel; Difiglia, Marian; Kegel, Kimberly B

    2012-05-01

    Neural stem (NS) cells are a limitless resource, and thus superior to primary neurons for drug discovery provided they exhibit appropriate disease phenotypes. Here we established NS cells for cellular studies of Huntington's disease (HD). HD is a heritable neurodegenerative disease caused by a mutation resulting in an increased number of glutamines (Q) within a polyglutamine tract in Huntingtin (Htt). NS cells were isolated from embryonic wild-type (Htt(7Q/7Q)) and "knock-in" HD (Htt(140Q/140Q)) mice expressing full-length endogenous normal or mutant Htt. NS cells were also developed from mouse embryonic stem cells that were devoid of Htt (Htt(-/-)), or knock-in cells containing human exon1 with an N-terminal FLAG epitope tag and with 7Q or 140Q inserted into one of the mouse alleles (Htt(F7Q/7Q) and Htt(F140Q/7Q)). Compared to Htt(7Q/7Q) NS cells, HD Htt(140Q/140Q) NS cells showed significantly reduced levels of cholesterol, increased levels of reactive oxygen species (ROS), and impaired motility. The heterozygous Htt(F140Q/7Q) NS cells had increased ROS and decreased motility compared to Htt(F7Q/7Q). These phenotypes of HD NS cells replicate those seen in HD patients or in primary cell or in vivo models of HD. Huntingtin "knock-out" NS cells (Htt(-/-)) also had impaired motility, but in contrast to HD cells had increased cholesterol. In addition, Htt(140Q/140Q) NS cells had higher phospho-AKT/AKT ratios than Htt(7Q/7Q) NS cells in resting conditions and after BDNF stimulation, suggesting mutant htt affects AKT dependent growth factor signaling. Upon differentiation, the Htt(7Q/7Q) and Htt(140Q/140Q) generated numerous Beta(III)-Tubulin- and GABA-positive neurons; however, after 15 days the cellular architecture of the differentiated Htt(140Q/140Q) cultures changed compared to Htt(7Q/7Q) cultures and included a marked increase of GFAP-positive cells. Our findings suggest that NS cells expressing endogenous mutant Htt will be useful for study of mechanisms of HD

  1. Senescent phenotypes of skin fibroblasts from patients with Tangier disease

    SciTech Connect

    Matsuura, Fumihiko . E-mail: fumihiko@imed2.med.osaka-u.ac.jp; Hirano, Ken-ichi; Ikegami, Chiaki; Sandoval, Jose C.; Oku, Hiroyuki; Yuasa-Kawase, Miyako; Tsubakio-Yamamoto, Kazumi; Koseki, Masahiro; Masuda, Daisaku; Tsujii, Ken-ichi; Shimomura, Iichiro; Hori, Masatsugu; Yamashita, Shizuya; Ishigami, Masato; Nishida, Makoto

    2007-06-01

    Tangier disease (TD) is characterized by a deficiency of high density lipoprotein (HDL) in plasma and patients with TD have an increased risk for coronary artery disease (CAD). Recently, we reported that fibroblasts from TD exhibited large and flattened morphology, which is often observed in senescent cells. On the other hand, data have accumulated to show the relationship between cellular senescence and development of atherosclerotic CAD. The aim of the present study was to investigate whether TD fibroblasts exhibited cellular senescence. The proliferation of TD fibroblasts was gradually decreased at population doubling level (PDL) {approx}10 compared with control cells. TD cells practically ceased proliferation at PDL {approx}30. DNA synthesis was markedly decreased in TD fibroblasts. TD cells exhibited a higher positive rate for senescence-associated {beta}-galactosidase (SA-{beta}-gal), which is one of the biomarkers of cellular senescence in vitro. These data showed that TD cells reached cellular senescence at an earlier PDL compared with controls. Although, there was no difference in the telomere length of fibroblasts between TD and controls at the earlier passage (PDL 6), the telomere length of TD cells was shorter than that of controls at the late passage (PDL 25). Taken together, the current study demonstrates that the late-passaged TD fibroblasts showed senescent phenotype in vitro, which might be related to the increased cardiovascular manifestations in TD patients.

  2. Alcohol consumption, Lewis phenotypes, and risk of ischemic heart disease

    SciTech Connect

    Hein, H.O.; Suadicani, P.; Gyntelberg, F. . Epidemiological Research Unit); Sorenson, H. . Dept. of Chemical Immunology); Hein, H.O. . Dept. of Internal Medicine)

    1993-02-13

    The authors have previously found an increased risk of ischemic heart disease (IHD) in men with the Lewis phenotype Le(a[minus]b[minus]) and suggested that the Lewis blood group has a close genetic relation with insulin resistance. The authors have investigated whether any conventional risk factors explain the increased risk in Le(a[minus]b[minus]) men. 3,383 men aged 53-75 years were examined in 1985-86, and morbidity and mortality during the next 4 years were recorded. At baseline, the authors excluded 343 men with a history of myocardial infarction, angina pectoris, intermittent claudication, or stroke. The potential risk factors examined were alcohol consumption, physical activity, tobacco smoking, serum cotinine, serum lipids, body-mass index, blood pressure, prevalence of hypertension and non-insulin-dependent diabetes mellitus, and social class. In 280 (9.6%) men with Le(a[minus]b[minus]), alcohol was the only risk factor significantly associated with risk of IHD. There was a significant inverse dose-effect relation between alcohol consumption and risk; trend tests, with adjustment for age, were significant for fatal IHD (p=0.02), all IHD (p=0.03), and all causes of death (p=0.02). In 2649 (90.4%) men with other phenotypes, there was a limited negative association with alcohol consumption. In Le(a[minus]b[minus]) men, a group genetically at high risk of IHD, alcohol consumption seems to be especially protective. The authors suggest that alcohol consumption may modify insulin resistance in Le(a[minus]b[minus]) men.

  3. siRNA Knockdown of Ribosomal Protein Gene RPL19 Abrogates the Aggressive Phenotype of Human Prostate Cancer

    PubMed Central

    Bee, Alix; Brewer, Daniel; Beesley, Carol; Dodson, Andrew; Forootan, Shiva; Dickinson, Timothy; Gerard, Patricia; Lane, Brian; Yao, Sheng; Cooper, Colin S.; Djamgoz, Mustafa B. A.; Gosden, Christine M.; Ke, Youqiang; Foster, Christopher S.

    2011-01-01

    We provide novel functional data that posttranscriptional silencing of gene RPL19 using RNAi not only abrogates the malignant phenotype of PC-3M prostate cancer cells but is selective with respect to transcription and translation of other genes. Reducing RPL19 transcription modulates a subset of genes, evidenced by gene expression array analysis and Western blotting, but does not compromise cell proliferation or apoptosis in-vitro. However, growth of xenografted tumors containing the knocked-down RPL19 in-vivo is significantly reduced. Analysis of the modulated genes reveals induction of the non-malignant phenotype principally to involve perturbation of networks of transcription factors and cellular adhesion genes. The data provide evidence that extra-ribosomal regulatory functions of RPL19, beyond protein synthesis, are critical regulators of cellular phenotype. Targeting key members of affected networks identified by gene expression analysis raises the possibility of therapeutically stabilizing a benign phenotype generated by modulating the expression of an individual gene and thereafter constraining a malignant phenotype while leaving non-malignant tissues unaffected. PMID:21799931

  4. Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD

    PubMed Central

    2014-01-01

    Background The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes. Results We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches. Conclusion Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease severity, and genetic mechanisms. PMID:24964944

  5. Sensory modulation intervention and behaviour support modification for the treatment of severe aggression in Huntington's disease. A single case experimental design.

    PubMed

    Fisher, Caroline A; Brown, Anahita

    2015-10-13

    Aggression is common in Huntington's disease. However, at present there are no standard guidelines for managing aggression in Huntington's sufferers due to a lack of empirical research. This paper presents a case study of the treatment of very high levels of aggression with sensory modulation and behaviour support intervention in a Huntington's sufferer. The client exhibited a range of aggressive behaviours, including physical aggression to people, furniture and objects, and verbal aggression. Following an eight week baseline phase, five weeks of sensory modulation intervention were employed. A behaviour support plan was then implemented as an adjunct to the sensory intervention, with aggressive behaviour systematically audited for a further 11 weeks. The results indicate a significant reduction in reported levels of aggression during the combined sensory modulation and behaviour support phase, compared to both the baseline and the sensory modulation therapy alone phases. This case study highlights the efficacy non-pharmacological interventions may have for reducing aggression in HD.

  6. Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype

    PubMed Central

    Driss, A; Asare, KO; Hibbert, JM; Gee, BE; Adamkiewicz, TV; Stiles, JK

    2009-01-01

    More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell–cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity. PMID:20401335

  7. Deep Clinical and Neuropathological Phenotyping of Pick’s Disease

    PubMed Central

    Irwin, David J.; Brettschneider, Johannes; McMillan, Corey T.; Cooper, Felicia; Olm, Christopher; Arnold, Steven E.; Van Deerlin, Vivianna M.; Seeley, William W.; Miller, Bruce L.; Lee, Edward B.; Lee, Virginia M.-Y.; Grossman, Murray; Trojanowski, John Q.

    2015-01-01

    Objective To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick’s disease. Methods Detailed neuropathological examination using 70 μm and traditional 6 μm sections was performed using Thioflavin-S staining and immunohistochemistry for phosphorylated-tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n=5) converging evidence was obtained using antemortem neuroimaging measures of grey and white matter integrity. Results Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (Phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus and raphe nuclei (Phase II), followed by primary motor cortex and pre-cerebellar nuclei (Phase III) and finally visual cortex in the most severe (Phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18/21) but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease-duration and inversely correlated with brain-weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. Interpretation Pick’s disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration. PMID:26583316

  8. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

    PubMed Central

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie; Li, Xiaojie; Chandler-Militello, Devin; Mauceri, Joseph; Burm, Hayley B.; Toner, Michael; Osipovitch, Mikhail; Jim Xu, Qiwu; Ding, Fengfei; Wang, Fushun; Kang, Ning; Kang, Jian; Curtin, Paul C.; Brunner, Daniela; Windrem, Martha S.; Munoz-Sanjuan, Ignacio; Nedergaard, Maiken; Goldman, Steven A.

    2016-01-01

    The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder. PMID:27273432

  9. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease.

    PubMed

    Wilcock, Donna M; Hurban, Jennifer; Helman, Alex M; Sudduth, Tiffany L; McCarty, Katie L; Beckett, Tina L; Ferrell, Joshua C; Murphy, M Paul; Abner, Erin L; Schmitt, Frederick A; Head, Elizabeth

    2015-09-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.

  10. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

    PubMed

    Köhler, Sebastian; Doelken, Sandra C; Mungall, Christopher J; Bauer, Sebastian; Firth, Helen V; Bailleul-Forestier, Isabelle; Black, Graeme C M; Brown, Danielle L; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R; Eppig, Janan T; Jackson, Andrew P; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A; Jähn, Johanna; Jackson, Laird G; Kelly, Anne M; Ledbetter, David H; Mansour, Sahar; Martin, Christa L; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H; Sisodiya, Sanjay; Van Vooren, Steven; Wapner, Ronald J; Wilkie, Andrew O M; Wright, Caroline F; Vulto-van Silfhout, Anneke T; de Leeuw, Nicole; de Vries, Bert B A; Washingthon, Nicole L; Smith, Cynthia L; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J; Gkoutos, Georgios V; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E; Robinson, Peter N

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

  11. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    PubMed Central

    Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  12. Comparative analysis of a novel disease phenotype network based on clinical manifestations

    PubMed Central

    Chen, Yang; Zhang, Xiang; Zhang, Guo-qiang; Xu, Rong

    2015-01-01

    Systems approaches to analyzing disease phenotype networks in combination with protein functional interaction networks have great potential in illuminating disease pathophysiological mechanisms. While many genetic networks are readily available, disease phenotype networks remain largely incomplete. In this study, we built a large-scale Disease Manifestation Network (DMN) from 50,543 highly accurate disease-manifestation semantic relationships in the United Medical Language System (UMLS). Our new phenotype network contains 2305 nodes and 373,527 weighted edges to represent the disease phenotypic similarities. We first compared DMN with the networks representing genetic relationships among diseases, and demonstrated that the phenotype clustering in DMN reflects common disease genetics. Then we compared DMN with a widely-used disease phenotype network in previous gene discovery studies, called mimMiner, which was extracted from the textual descriptions in Online Mendelian Inheritance in Man (OMIM). We demonstrated that DMN contains different knowledge from the existing phenotype data source. Finally, a case study on Marfan syndrome further proved that DMN contains useful information and can provide leads to discover unknown disease causes. Integrating DMN in systems approaches with mimMiner and other data offers the opportunities to predict novel disease genetics. We made DMN publicly available at nlp/case.edu/public/data/DMN. PMID:25277758

  13. Mouse Genome Database: From sequence to phenotypes and disease models

    PubMed Central

    Richardson, Joel E.; Kadin, James A.; Smith, Cynthia L.; Blake, Judith A.; Bult, Carol J.

    2015-01-01

    Summary The Mouse Genome Database (MGD, www.informatics.jax.org) is the international scientific database for genetic, genomic, and biological data on the laboratory mouse to support the research requirements of the biomedical community. To accomplish this goal, MGD provides broad data coverage, serves as the authoritative standard for mouse nomenclature for genes, mutants, and strains, and curates and integrates many types of data from literature and electronic sources. Among the key data sets MGD supports are: the complete catalog of mouse genes and genome features, comparative homology data for mouse and vertebrate genes, the authoritative set of Gene Ontology (GO) annotations for mouse gene functions, a comprehensive catalog of mouse mutations and their phenotypes, and a curated compendium of mouse models of human diseases. Here, we describe the data acquisition process, specifics about MGD's key data areas, methods to access and query MGD data, and outreach and user help facilities. genesis 53:458–473, 2015. © 2015 The Authors. Genesis Published by Wiley Periodicals, Inc. PMID:26150326

  14. Factors influencing disease phenotype and penetrance in HFE haemochromatosis.

    PubMed

    Rochette, J; Le Gac, G; Lassoued, K; Férec, C; Robson, K J H

    2010-09-01

    Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes. In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders, and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous effect on iron storage.

  15. Microglial phenotypes in Parkinson's disease and animal models of the disease.

    PubMed

    Joers, Valerie; Tansey, Malú G; Mulas, Giovanna; Carta, Anna R

    2016-04-20

    Over the last decade the important concept has emerged that microglia, similar to other tissue macrophages, assume different phenotypes and serve several effector functions, generating the theory that activated microglia can be organized by their pro-inflammatory or anti-inflammatory and repairing functions. Importantly, microglia exist in a heterogenous population and their phenotypes are not permanently polarized into two categories; they exist along a continuum where they acquire different profiles based on their local environment. In Parkinson's disease (PD), neuroinflammation and microglia activation are considered neuropathological hallmarks, however their precise role in relation to disease progression is not clear, yet represent a critical challenge in the search of disease-modifying strategies. This review will critically address current knowledge on the activation states of microglia as well as microglial phenotypes found in PD and in animal models of PD, focusing on the expression of surface molecules as well as pro-inflammatory and anti-inflammatory cytokine production during the disease process. While human studies have reported an elevation of both pro- or anti-inflammatory markers in the serum and CSF of PD patients, animal models have provided insights on dynamic changes of microglia phenotypes in relation to disease progression especially prior to the development of motor deficits. We also review recent evidence of malfunction at multiple steps of NFκB signaling that may have a causal interrelationship with pathological microglia activation in animal models of PD. Finally, we discuss the immune-modifying strategies that have been explored regarding mechanisms of chronic microglial activation.

  16. Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype*

    PubMed Central

    Purushothaman, Anurag; Hurst, Douglas R.; Pisano, Claudio; Mizumoto, Shuji; Sugahara, Kazuyuki; Sanderson, Ralph D.

    2011-01-01

    Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of heparanase. High levels of HAT activity in heparanase-high cells were blocked by SST0001, an inhibitor of heparanase. Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of heparanase. These results reveal a novel mechanistic pathway driven by heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype. PMID:21757697

  17. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    NASA Astrophysics Data System (ADS)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  18. Lack of association between the TNF-α-1031genotypes and generalized aggressive periodontitis disease.

    PubMed

    Darvishi, E; Aziziaram, Z; Yari, K; Bagheri Dehbaghi, M; Kahrizi, D; Karim, H; Vaziri, S; Zargooshi, J; Ghadiri, K; Muhammadi, S; Kazemi, E; Moradi, M T; Shokrinia, M; Mohammadi, N

    2016-09-30

    Periodontal disease is one of the most prevalent inflammatory illnesses and is a main cause of tooth loss in human population. Tumor necrosis factor-α (TNF-α) gene is one of pro-inflammatory cytokines which has important role in pathogenesis of periodontal disease. The main purpose of this study is to determine genotype abundance of TNF-α-1031 gene in both groups of patients and controls, and also investigation of relation of single nucleotide polymorphism (SNP) these genotypes with periodontal disease risk. DNA was extracted from blood tissue of 31 patients and 54 controls. The TNF-α-1031 polymorphism was evaluated by polymerase chain reaction- confronting two-pair primer (PCR-CTPP) method. In the GAP group, the frequencies of TT, TC and CC genotypes were 35.48%, 61.29 and 3.23%, respectively. In controls the frequencies of TT, TC and CC genotypes were 22.22%, 72.22%, and 5.56%, respectively. Results of this study showed that there was no significant association between TNF-α (-1031 T/C promoter) gene polymorphisms and the risk of generalized aggressive periodontitis disease.

  19. Phenotypes and Pathology of Drug-Induced Liver Disease.

    PubMed

    Goodman, Zachary D

    2017-02-01

    Drug hepatotoxicity can simulate nearly any clinical syndrome or pathologic lesion that may occur in the liver, so clinical and histopathologic diagnosis of drug-induced liver injury may be difficult. Nevertheless, most drugs that are known to idiosyncratic liver injury tend to cause patterns of injury that produce characteristic phenotypes. Recognition of these patterns or phenotypes in liver biopsy material is helpful in evaluation of clinical cases of suspected drug-induced liver injury.

  20. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  1. Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients

    PubMed Central

    Karmali, Reem; Paganessi, Laura A.; Frank, Robin R.; Jagan, Sucheta; Larson, Melissa L.; Venugopal, Parameswaran; Gregory, Stephanie A.; Christopherson, Kent W.

    2013-01-01

    Early treatment of CLL/SLL does not impact survival-reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic–based prognostic model. Fifty-nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL-10, IL-5, sIL-2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL-17, IL-23, IFN-γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL-2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow-up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL-17/sIL-2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy. PMID:23136257

  2. PhenoMiner: from text to a database of phenotypes associated with OMIM diseases

    PubMed Central

    Collier, Nigel; Groza, Tudor; Smedley, Damian; Robinson, Peter N.; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

    2015-01-01

    Analysis of scientific and clinical phenotypes reported in the experimental literature has been curated manually to build high-quality databases such as the Online Mendelian Inheritance in Man (OMIM). However, the identification and harmonization of phenotype descriptions struggles with the diversity of human expressivity. We introduce a novel automated extraction approach called PhenoMiner that exploits full parsing and conceptual analysis. Apriori association mining is then used to identify relationships to human diseases. We applied PhenoMiner to the BMC open access collection and identified 13 636 phenotype candidates. We identified 28 155 phenotype-disorder hypotheses covering 4898 phenotypes and 1659 Mendelian disorders. Analysis showed: (i) the semantic distribution of the extracted terms against linked ontologies; (ii) a comparison of term overlap with the Human Phenotype Ontology (HP); (iii) moderate support for phenotype-disorder pairs in both OMIM and the literature; (iv) strong associations of phenotype-disorder pairs to known disease-genes pairs using PhenoDigm. The full list of PhenoMiner phenotypes (S1), phenotype-disorder associations (S2), association-filtered linked data (S3) and user database documentation (S5) is available as supplementary data and can be downloaded at http://github.com/nhcollier/PhenoMiner under a Creative Commons Attribution 4.0 license. Database URL: phenominer.mml.cam.ac.uk PMID:26507285

  3. PhenomeExpress: a refined network analysis of expression datasets by inclusion of known disease phenotypes.

    PubMed

    Soul, Jamie; Hardingham, Timothy E; Boot-Handford, Raymond P; Schwartz, Jean-Marc

    2015-01-29

    We describe a new method, PhenomeExpress, for the analysis of transcriptomic datasets to identify pathogenic disease mechanisms. Our analysis method includes input from both protein-protein interaction and phenotype similarity networks. This introduces valuable information from disease relevant phenotypes, which aids the identification of sub-networks that are significantly enriched in differentially expressed genes and are related to the disease relevant phenotypes. This contrasts with many active sub-network detection methods, which rely solely on protein-protein interaction networks derived from compounded data of many unrelated biological conditions and which are therefore not specific to the context of the experiment. PhenomeExpress thus exploits readily available animal model and human disease phenotype information. It combines this prior evidence of disease phenotypes with the experimentally derived disease data sets to provide a more targeted analysis. Two case studies, in subchondral bone in osteoarthritis and in Pax5 in acute lymphoblastic leukaemia, demonstrate that PhenomeExpress identifies core disease pathways in both mouse and human disease expression datasets derived from different technologies. We also validate the approach by comparison to state-of-the-art active sub-network detection methods, which reveals how it may enhance the detection of molecular phenotypes and provide a more detailed context to those previously identified as possible candidates.

  4. A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

    PubMed Central

    Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

    2011-01-01

    SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

  5. Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma.

    PubMed

    Moser, Elizabeth C; Noordijk, Evert M; van Leeuwen, Flora E; le Cessie, Saskia; Baars, Joke W; Thomas, José; Carde, Patrice; Meerwaldt, Jacobus H; van Glabbeke, Martine; Kluin-Nelemans, Hanneke C

    2006-04-01

    Cardiovascular disease frequently occurs after lymphoma therapy, but it is common in the general population too. Therefore, risk estimation requires comparison to population-based rates. We calculated risk by standardized incidence ratios (SIRs) and absolute excess risks (AERs) per 10,000 person-years based on general population rates (Continuous Morbidity Registry Nijmegen) in 476 (Dutch and Belgian) patients with aggressive non-Hodgkin lymphoma (NHL) treated with at least 6 cycles of doxorubicin-based chemotherapy in 4 European Organization for Research on Treatment of Cancer (EORTC) trials (1980-1999). Cumulative incidence of cardiovascular disease, estimated in a competing risk model, was 12% at 5 years and 22% at 10 years (median follow-up, 8.4 years). Risk of chronic heart failure appeared markedly increased (SIR, 5.4; 95% CI, 4.1-6.9) with an AER of 208 excess cases per 10 000 person-years, whereas risk of coronary artery disease matched the general population (SIR, 1.2; 95% CI, 0.8-1.8; AER, 8 per 10 000 person-years). Risk of stroke was raised (SIR, 1.8; 95% CI, 1.1-2.4; AER, 15 per 10 000 person-years), especially after additional radiotherapy (> 40 Gy). Preexisting hypertension, NHL at young age, and salvage treatment increased risk of all cardiovascular events; the effect of radiotherapy was dose dependent. In conclusion, patients are at long-term high risk of chronic heart failure after NHL treatment and need therefore life-long monitoring. In contrast, risk of coronary artery disease appeared more age dependent than treatment related.

  6. Persistent neurological damage associated with spontaneous recurrent seizures and atypical aggressive behavior of domoic acid epileptic disease.

    PubMed

    Tiedeken, Jessica A; Ramsdell, John S

    2013-05-01

    The harmful alga Pseudo-nitzschia sp. is the cause of human amnesic shellfish poisoning and the stranding of thousands of sea lions with seizures as a hallmark symptom. A human case study and epidemiological report of hundreds of stranded sea lions found individuals presenting months after recovery with a neurological disease similar to temporal lobe epilepsy. A rat model developed to establish and better predict how epileptic disease results from domoic acid poisoning demonstrated that a single episode of status epilepticus (SE), after a latent period, leads to a progressive state of spontaneous recurrent seizure (SRS) and expression of atypical aggressive behaviors. Structural damage associated with domoic acid-induced SE is prominent in olfactory pathways. Here, we examine structural damage in seven rats that progressed to epileptic disease. Diseased animals show progressive neuronal loss in the piriform cortex and degeneration of terminal fields in these layers and the posteromedial cortical amygdaloid nucleus. Animals that display aggressive behavior had additional neuronal damage to the anterior olfactory cortex. This study provides insight into the structural basis for the progression of domoic acid epileptic disease and relates to the California sea lion, where poisoned animals progress to a disease characterized by SRS and aggressive behaviors.

  7. Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek's disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. The serotonergic system m...

  8. Macrophage form, function, and phenotype in mycobacterial infection: lessons from tuberculosis and other diseases.

    PubMed

    McClean, Colleen M; Tobin, David M

    2016-10-01

    Macrophages play a central role in mycobacterial pathogenesis. Recent work has highlighted the importance of diverse macrophage types and phenotypes that depend on local environment and developmental origins. In this review, we highlight how distinct macrophage phenotypes may influence disease progression in tuberculosis. In addition, we draw on work investigating specialized macrophage populations important in cancer biology and atherosclerosis in order to suggest new areas of investigation relevant to mycobacterial pathogenesis. Understanding the mechanisms controlling the repertoire of macrophage phenotypes and behaviors during infection may provide opportunities for novel control of disease through modulation of macrophage form and function.

  9. Explaining the disease phenotype of intergenic SNP through predicted long range regulation

    PubMed Central

    Chen, Jingqi; Tian, Weidong

    2016-01-01

    Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. Recent analysis found that non-coding daSNPs were frequently located in or approximate to regulatory elements, inspiring us to try to explain the disease phenotypes of IGR daSNPs through nearby regulatory sequences. Hence, after locating the nearest distal regulatory element (DRE) to a given IGR daSNP, we applied a computational method named INTREPID to predict the target genes regulated by the DRE, and then investigated their functional relevance to the IGR daSNP's disease phenotypes. 36.8% of all IGR daSNP-disease phenotype associations investigated were possibly explainable through the predicted target genes, which were enriched with, were functionally relevant to, or consisted of the corresponding disease genes. This proportion could be further increased to 60.5% if the LD SNPs of daSNPs were also considered. Furthermore, the predicted SNP-target gene pairs were enriched with known eQTL/mQTL SNP-gene relationships. Overall, it's likely that IGR daSNPs may contribute to disease phenotypes by interfering with the regulatory function of their nearby DREs and causing abnormal expression of disease genes. PMID:27280978

  10. Prevalence of comorbidities according to predominant phenotype and severity of chronic obstructive pulmonary disease

    PubMed Central

    Camiciottoli, Gianna; Bigazzi, Francesca; Magni, Chiara; Bonti, Viola; Diciotti, Stefano; Bartolucci, Maurizio; Mascalchi, Mario; Pistolesi, Massimo

    2016-01-01

    Background In addition to lung involvement, several other diseases and syndromes coexist in patients with chronic obstructive pulmonary disease (COPD). Our purpose was to investigate the prevalence of idiopathic arterial hypertension (IAH), ischemic heart disease, heart failure, peripheral vascular disease (PVD), diabetes, osteoporosis, and anxious depressive syndrome in a clinical setting of COPD outpatients whose phenotypes (predominant airway disease and predominant emphysema) and severity (mild and severe diseases) were determined by clinical and functional parameters. Methods A total of 412 outpatients with COPD were assigned either a predominant airway disease or a predominant emphysema phenotype of mild or severe degree according to predictive models based on pulmonary functions (forced expiratory volume in 1 second/vital capacity; total lung capacity %; functional residual capacity %; and diffusing capacity of lung for carbon monoxide %) and sputum characteristics. Comorbidities were assessed by objective medical records. Results Eighty-four percent of patients suffered from at least one comorbidity and 75% from at least one cardiovascular comorbidity, with IAH and PVD being the most prevalent ones (62% and 28%, respectively). IAH prevailed significantly in predominant airway disease, osteoporosis prevailed significantly in predominant emphysema, and ischemic heart disease and PVD prevailed in mild COPD. All cardiovascular comorbidities prevailed significantly in predominant airway phenotype of COPD and mild COPD severity. Conclusion Specific comorbidities prevail in different phenotypes of COPD; this fact may be relevant to identify patients at risk for specific, phenotype-related comorbidities. The highest prevalence of comorbidities in patients with mild disease indicates that these patients should be investigated for coexisting diseases or syndromes even in the less severe, pauci-symptomatic stages of COPD. The simple method employed to phenotype and

  11. mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

    PubMed Central

    Luo, Judong; Wang, Wenjie; Tang, Yiting; Zhou, Dandan; Gao, Yi; Zhang, Qi; Zhou, Xifa; Zhu, Hui; Xing, Ligang; Yu, Jinming

    2017-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies worldwide. Radiotherapy plays a critical role in the curative management of inoperable ESCC patients. However, radioresistance restricts the efficacy of radiotherapy for ESCC patients. The molecules involved in radioresistance remain largely unknown, and new approaches to sensitize cells to irradiation are in demand. Technical advances in analysis of mRNA and methylation have enabled the exploration of the etiology of diseases and have the potential to broaden our understanding of the molecular pathways of ESCC radioresistance. In this study, we constructed radioresistant TE-1 and Eca-109 cell lines (TE-1/R and Eca-109/R, respectively). The radioresistant cells showed an increased migration ability but reduced apoptosis and cisplatin sensitivity compared with their parent cells. mRNA and methylation profiling by microarray revealed 1192 preferentially expressed mRNAs and 8841 aberrantly methylated regions between TE-1/R and TE-1 cells. By integrating the mRNA and methylation profiles, we related the decreased expression of transcription factor Sall2 with a corresponding increase in its methylation in TE-1/R cells, indicating its involvement in radioresistance. Upregulation of Sall2 decreased the growth and migration advantage of radioresistant ESCC cells. Taken together, our present findings illustrate the mRNA and DNA methylation changes during the radioresistance of ESCC and the important role of Sall2 in esophageal cancer malignancy. PMID:28367244

  12. Phenotypic insights into ADCY5‐associated disease

    PubMed Central

    Chang, Florence C.F.; Westenberger, Ana; Dale, Russell C.; Smith, Martin; Pall, Hardev S.; Perez‐Dueñas, Belen; Grattan‐Smith, Padraic; Ouvrier, Robert A.; Mahant, Neil; Hanna, Bernadette C.; Hunter, Matthew; Lawson, John A.; Max, Christoph; Sachdev, Rani; Meyer, Esther; Crimmins, Dennis; Pryor, Donald; Morris, John G.L.; Münchau, Alex; Grozeva, Detelina; Carss, Keren J.; Raymond, Lucy; Kurian, Manju A.; Klein, Christine

    2016-01-01

    ABSTRACT Background Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. Methods In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole‐exome sequencing. Results Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile‐onset action‐induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. Conclusion We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5‐associated dyskinesia may be under‐recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society PMID:27061943

  13. The changing phenotype of microglia from homeostasis to disease

    PubMed Central

    2012-01-01

    It has been nearly a century since the early description of microglia by Rio-Hortega; since then many more biological and pathological features of microglia have been recognized. Today, microglia are generally considered to be beneficial to homeostasis at the resting state through their abilities to survey the environment and phagocytose debris. However, when activated microglia assume diverse phenotypes ranging from fully inflamed, which involves the release of many pro-inflammatory cytokines, to alternatively activated, releasing anti-inflammatory cytokines or neurotrophins, the consequences to neurons can range from detrimental to supportive. Due to the different experimental sets and conditions, contradictory results have been obtained regarding the controversial question of whether microglia are “good” or “bad.” While it is well understood that the dual roles of activated microglia depend on specific situations, the underlying mechanisms have remained largely unclear, and the interpretation of certain findings related to diverse microglial phenotypes continues to be problematic. In this review we discuss the functions of microglia in neuronal survival and neurogenesis, the crosstalk between microglia and surrounding cells, and the potential factors that could influence the eventual manifestation of microglia. PMID:23210447

  14. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes.

    PubMed

    Seferović, Petar M; Paulus, Walter J

    2015-07-14

    Diabetes mellitus-related cardiomyopathy (DMCMP) was originally described as a dilated phenotype with eccentric left ventricular (LV) remodelling and systolic LV dysfunction. Recently however, clinical studies on DMCMP mainly describe a restrictive phenotype with concentric LV remodelling and diastolic LV dysfunction. Both phenotypes are not successive stages of DMCMP but evolve independently to respectively heart failure with preserved left ventricular ejection fraction (HFPEF) or reduced left ventricular ejection fraction (HFREF). Phenotype-specific pathophysiological mechanisms were recently proposed for LV remodelling and dysfunction in HFPEF and HFREF consisting of coronary microvascular endothelial dysfunction in HFPEF and cardiomyocyte cell death in HFREF. A similar preferential involvement of endothelial or cardiomyocyte cell compartments explains DMCMP development into distinct restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus (DM)-related metabolic derangements such as hyperglycaemia, lipotoxicity, and hyperinsulinaemia favour development of DMCMP with restrictive/HFPEF phenotype, which is more prevalent in obese type 2 DM patients. In contrast, autoimmunity predisposes to a dilated/HFREF phenotype, which manifests itself more in autoimmune-prone type 1 DM patients. Finally, coronary microvascular rarefaction and advanced glycation end-products deposition are relevant to both phenotypes. Diagnosis of DMCMP requires impaired glucose metabolism and exclusion of coronary, valvular, hypertensive, or congenital heart disease and of viral, toxic, familial, or infiltrative cardiomyopathy. In addition, diagnosis of DMCMP with restrictive/HFPEF phenotype requires normal systolic LV function and diastolic LV dysfunction, whereas diagnosis of DMCMP with dilated/HFREF phenotype requires systolic LV dysfunction. Treatment of DMCMP with restrictive/HFPEF phenotype is limited to diuretics and lifestyle modification, whereas DMCMP with dilated

  15. Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort

    PubMed Central

    Thomsen, Liv Cecilie V.; Melton, Phillip E.; Tollaksen, Kjersti; Lyslo, Ingvill; Roten, Linda T.; Odland, Maria L.; Strand, Kristin M.; Nygård, Ottar; Sun, Chen; Iversen, Ann-Charlotte; Austgulen, Rigmor; Moses, Eric K.; Bjørge, Line

    2015-01-01

    Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. Methods: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. Results: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02). Conclusion: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits. PMID:26259119

  16. Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.

    PubMed

    Katada, Shun; Mito, Takayuki; Ogasawara, Emi; Hayashi, Jun-Ichi; Nakada, Kazuto

    2013-09-04

    Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (ΔmtDNA), but there is no direct experimental evidence for this. To determine whether ΔmtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ΔmtDNA (mito-miceΔ). Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%. Our model mouse study clearly showed that a single ΔmtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.

  17. Mitochondrial DNA with a Large-Scale Deletion Causes Two Distinct Mitochondrial Disease Phenotypes in Mice

    PubMed Central

    Katada, Shun; Mito, Takayuki; Ogasawara, Emi; Hayashi, Jun-Ichi; Nakada, Kazuto

    2013-01-01

    Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice. PMID:23853091

  18. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases

    PubMed Central

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-01-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  19. Phenotypic impact of genomic structural variation: insights from and for human disease.

    PubMed

    Weischenfeldt, Joachim; Symmons, Orsolya; Spitz, François; Korbel, Jan O

    2013-02-01

    Genomic structural variants have long been implicated in phenotypic diversity and human disease, but dissecting the mechanisms by which they exert their functional impact has proven elusive. Recently however, developments in high-throughput DNA sequencing and chromosomal engineering technology have facilitated the analysis of structural variants in human populations and model systems in unprecedented detail. In this Review, we describe how structural variants can affect molecular and cellular processes, leading to complex organismal phenotypes, including human disease. We further present advances in delineating disease-causing elements that are affected by structural variants, and we discuss future directions for research on the functional consequences of structural variants.

  20. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression.

    PubMed

    Galbán, Craig J; Han, Meilan K; Boes, Jennifer L; Chughtai, Komal A; Meyer, Charles R; Johnson, Timothy D; Galbán, Stefanie; Rehemtulla, Alnawaz; Kazerooni, Ella A; Martinez, Fernando J; Ross, Brian D

    2012-11-01

    Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers is urgently needed to enable individualized treatment, thus improving patient outcome. We adapted the parametric response map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole-lung computed tomography (CT) scans acquired at inspiration and expiration of 194 individuals with COPD from the COPDGene study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype while providing detailed spatial information of disease distribution and location. PRM's ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients, complementing standard clinical techniques.

  1. Complex disease and phenotype mapping in the domestic dog

    PubMed Central

    Hayward, Jessica J.; Castelhano, Marta G.; Oliveira, Kyle C.; Corey, Elizabeth; Balkman, Cheryl; Baxter, Tara L.; Casal, Margret L.; Center, Sharon A.; Fang, Meiying; Garrison, Susan J.; Kalla, Sara E.; Korniliev, Pavel; Kotlikoff, Michael I.; Moise, N. S.; Shannon, Laura M.; Simpson, Kenneth W.; Sutter, Nathan B.; Todhunter, Rory J.; Boyko, Adam R.

    2016-01-01

    The domestic dog is becoming an increasingly valuable model species in medical genetics, showing particular promise to advance our understanding of cancer and orthopaedic disease. Here we undertake the largest canine genome-wide association study to date, with a panel of over 4,200 dogs genotyped at 180,000 markers, to accelerate mapping efforts. For complex diseases, we identify loci significantly associated with hip dysplasia, elbow dysplasia, idiopathic epilepsy, lymphoma, mast cell tumour and granulomatous colitis; for morphological traits, we report three novel quantitative trait loci that influence body size and one that influences fur length and shedding. Using simulation studies, we show that modestly larger sample sizes and denser marker sets will be sufficient to identify most moderate- to large-effect complex disease loci. This proposed design will enable efficient mapping of canine complex diseases, most of which have human homologues, using far fewer samples than required in human studies. PMID:26795439

  2. Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.

    PubMed

    Lo, Sarah M; Choi, Murim; Liu, Jun; Jain, Dhanpat; Boot, Rolf G; Kallemeijn, Wouter W; Aerts, Johannes M F G; Pashankar, Farzana; Kupfer, Gary M; Mane, Shrikant; Lifton, Richard P; Mistry, Pramod K

    2012-05-17

    Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

  3. The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.

    PubMed

    Zheng, Hua-Chuan; Liu, Jia-Jie; Li, Jing; Wu, Ji-Cheng; Yang, Lei; Zhao, Gui-Feng; Zhao, Xin; Jiang, Hua-Mao; Huang, Ke-Qiang; Li, Zhi-Jie

    2017-02-16

    Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc, Cyclin D1, mTOR, and Raptor. According to transcriptomic analysis, WT parafibromin suppressed PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.

  4. Phenotypic changes in acute myeloid leukaemia: implications in the detection of minimal residual disease.

    PubMed Central

    Macedo, A; San Miguel, J F; Vidriales, M B; López-Berges, M C; García-Marcos, M A; Gonzalez, M; Landolfi, C; Orfão, A

    1996-01-01

    AIM: To explore the role of phenotypic changes as possible limiting factors in the immunological detection of minimal residual disease in patients with acute myeloid leukaemia (AML). METHODS: 20 relapses were evaluated, with special attention to changes in the criteria used for the definition of a phenotype as "aberrant". In all cases the same monoclonal antibody and fluorochrome were used at diagnosis and in relapse. RESULTS: Six out of the 16 patients showed aberrant phenotypes at diagnosis. At relapse, no changes in the aberrant phenotypes were detected in most of the patients; nevertheless, in two of the four patients with asynchronous antigen expression this aberration disappeared at relapse. At diagnosis in both cases there were already small blast cell subpopulations showing the phenotype of leukaemic cells at relapse. Ten out of the 16 cases analysed showed significant changes in the expression of at least one of the markers analysed. CONCLUSIONS: At relapse in AML the "leukaemic phenotypes" usually remained unaltered, while other phenotypic features--not relevant for distinguishing leukaemic blast cells among normal progenitors--changed frequently; however, they were not a major limitation in the immunological detection of minimal residual disease. PMID:8666678

  5. Hearing impairment in Parkinson's disease: expanding the nonmotor phenotype.

    PubMed

    Vitale, Carmine; Marcelli, Vincenzo; Allocca, Roberto; Santangelo, Gabriella; Riccardi, Pasquale; Erro, Roberto; Amboni, Marianna; Pellecchia, Maria Teresa; Cozzolino, Autilia; Longo, Katia; Picillo, Marina; Moccia, Marcello; Agosti, Valeria; Sorrentino, G; Cavaliere, Michele; Marciano, Elio; Barone, Paolo

    2012-10-01

    The objective of this study was to evaluate hearing impairment in patients affected by Parkinson's disease compared with hearing scores observed in normal age- and sex-matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinson's disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinson's Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory-evoked potentials. Healthy age- and sex-matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age-dependent high-frequency hearing loss in patients with Parkinson's disease compared with both normative values and values for healthy age- and sex-matched controls (75/106 [71%], χ(2) = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ(2) = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory-evoked potentials were normal in all patients. Our patients with Parkinson's disease showed age-dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinson's disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α-synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise-induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinson's disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis.

  6. How variability in clinical phenotypes should guide research into disease mechanisms in asthma.

    PubMed

    Chung, Kian Fan; Adcock, Ian M

    2013-12-01

    Asthma is increasingly being considered as a collection of different phenotypes that present with intermittent wheezing. Unbiased approaches to classifying asthma have led to the identification of distinct phenotypes based on age of onset of disease, atopic state, disease severity or activity, degree of chronic airflow obstruction, and sputum eosinophilia. Linking phenotypes to known disease mechanism is likely to be more fruitful in determining the potential targets necessary for successful therapies of specific endotypes. A "Th2-high expression" signature from the epithelium of patients with asthma identifies a subset of patients with high eosinophilia and good therapeutic responsiveness to corticosteroids. Other characteristic traits of asthma include noneosinophilic asthma, corticosteroid insensitivity, obesity-associated, and exacerbation-prone. Further progress into asthma mechanisms will be driven by unbiased data integration of multiscale data sets from omics technologies with those phenotypic characteristics and by using mathematical modeling. This will lead to the discovery of new pathways and their integration into endotypes and also set up further hypothesis-driven research. Continued iteration through experimentation or modeling will be needed to refine the phenotypes that relate to outcomes and also delineate specific treatments for specific phenotypes.

  7. An expanded phenotype of maternal SSA/SSB antibody-associated fetal cardiac disease

    PubMed Central

    CUNEO, BETTINA F.; STRASBURGER, JANETTE F.; NIKSCH, ALISA; OVADIA, MARC; WAKAI, RONALD T.

    2010-01-01

    Objectives Conventional manifestations of fetal Sjögren’s antibodies (SSA/SSB) associated cardiac disease include atrio-ventricular block (AVB), transient sinus bradycardia, endocardial fibroelastosis (EFE) and dilated cardiomyopathy. We describe other manifestations of cardiac disease. Methods We describe three fetuses with unique myocardial and conduction system disease. Results One had isolated EFE with subsequent mitral and tricuspid valve chordal avulsion, the second had sinoatrial and infrahissian conduction system disease, and in both, neonatal progression to life threatening disease occurred. The third had sinus node dysfunction and atrial flutter. Conclusion These findings expand the clinical phenotype of maternal SSA/SSB antibody associated fetal cardiac disease. PMID:19330707

  8. CSF biomarkers in different phenotypes of Parkinson disease.

    PubMed

    Jellinger, Kurt A

    2012-04-01

    CSF biomarker studies were performed in 6 patients each with tremor-dominant (TD) and non-tremor-dominant (NT) Parkinson disease (PD) patients, 27 Alzheimer disease (AD) and 17 age-matched controls. In both NT-PD and AD patients total tau levels and the cortex tau/Aβ-42 were significantly increased compared to both TD-PD patients and controls (p < 0.01). These data in a small cohort confirm previous studies, corroborating the opinion that CSF levels of tau protein and the index total-tau/Aβ-42 may be potential markers of the severity of neurodegeneration in PD.

  9. Phenotypic, immunologic, and clinical characteristics of patients with nontuberculous mycobacterial lung disease in Korea

    PubMed Central

    2013-01-01

    Background This study aimed to elucidate the phenotypic, immunologic, and clinical characteristics of Korean patients with nontuberculous mycobacterial (NTM) lung disease and compare them with non-NTM bronchiectasis (BE) patients. Methods We prospectively recruited patients between 20 and 80 years of age who had nodular BE type NTM lung disease. Phenotypic, immunologic, and clinical characteristics were evaluated through physical examination, laboratory tests, pulmonary function tests, and radiographic examinations. Questionnaires were also answered. The results of the evaluations were compared with the results of non-NTM BE patients. Results A total of 84 patients with NTM lung disease and 47 non-NTM BE patients participated in the study. Mycobacterium avium complex lung disease and M. abscessus lung disease were most common. Patients with NTM lung disease had lower body mass index than non-NTM BE patients. Scoliosis was observed more frequently in patients with NTM lung disease than in non-NTM BE patients. Conclusions Significant similarities were seen between Korean patients with NTM lung disease and patients from other countries. Differences in phenotypic and clinical characteristics between NTM lung disease and non-NTM BE patients suggest differences in the immunopathogenesis of NTM lung disease and non-NTM BE. Trial registration information ClinicalTrials.gov Registration number; NCT01616745 PMID:24274658

  10. Refining multivariate disease phenotypes for high chip heritability

    PubMed Central

    2015-01-01

    Background Statistical genetics shows that the success of both genetic association studies and genomic prediction methods is positively associated with the heritability of the trait used in the analysis. Identifying highly heritable components of a complex disease can thus enhance genetic studies of the disease. Existing heritable component analysis methods use data from related individuals to compute linearly-combined traits to maximize heritability. Recent advances in acquiring genome-wide markers have enhanced heritability estimation using genotypic data from apparently unrelated individuals, which is referred to as the chip heritability. Novel statistical models are thus needed to identify disease components (subtypes) with high chip heritability. Methods We propose an optimization approach to identify highly heritable components of a complex disease as a function of multiple clinical variables. The heritability of the components is estimated directly from unrelated individuals using their genome-wide single nucleotide polymorphisms. The proposed approach can also model the fixed effects due to covariates, such as age and race, so that the derived traits have high chip heritability after correcting for fixed effects. A new sequential quadratic programming algorithm is developed to efficiently solve the proposed optimization problem. Results The proposed algorithm was validated both in simulations and the analysis of a real-world dataset that was aggregated from genetic studies of cocaine, opoid, and alcohol dependence. Simulation studies demonstrated that the proposed approach could identify the hypothesized component from multiple synthesized features. A case study on cocaine dependence (CD) identified a quantitative trait that achieved chip heritability of 0.86 estimated using a cross-validation process. This quantitative trait corresponded to the likelihood of an individual's membership in a CD subtype. Clinical analysis showed that the subtype enclosed

  11. Intrafamilial phenotypic variability in four families with Anderson-Fabry disease.

    PubMed

    Rigoldi, M; Concolino, D; Morrone, A; Pieruzzi, F; Ravaglia, R; Furlan, F; Santus, F; Strisciuglio, P; Torti, G; Parini, R

    2014-09-01

    We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

  12. Transcriptional Profiling of Egg Allergy and Relationship to Disease Phenotype

    PubMed Central

    Kosoy, Roman; Agashe, Charuta; Grishin, Alexander; Leung, Donald Y.; Wood, Robert A.; Sicherer, Scott H.; Jones, Stacie M.; Burks, A. Wesley; Davidson, Wendy F.; Lindblad, Robert W.; Dawson, Peter; Merad, Miriam; Kidd, Brian A.; Dudley, Joel T.; Sampson, Hugh A.

    2016-01-01

    Background Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE. Objective To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days. Results The transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-α. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-α and IFN-γ response genes, as well as genes associated with virally-infected DCs. Conclusions Transcriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis-generating mechanism to identify novel immune processes associated

  13. Danon disease: a phenotypic expression of LAMP-2 deficiency.

    PubMed

    Endo, Yukari; Furuta, Akiko; Nishino, Ichizo

    2015-03-01

    Danon disease is an X-linked disorder clinically characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Cardiomyopathy is a severe and life-threatening problem, for which cardiac transplantation is the only therapeutic option. The most striking finding in muscle biopsy samples is small basophilic granules scattered in myofibers, which are in fact small autophagic vacuoles surrounded by membranes with sarcolemmal features characterized by the recruitment of sarcolemmal proteins and acetylcholine esterase and by the presence of basal lamina on its luminal side. The mechanism underlying the formation of these autophagic vacuoles with unique sarcolemmal features (AVSF) still remains a mystery and its origin is unknown. In heart, cardiomyocytes show dramatically increased vacuolation and degenerative features, including myofibrillar disruption and lipofuscin accumulation. In brain, pale granular neurons and neurons with lipofuscin-like granules may be seen. Danon disease is caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein 2 (LAMP-2), a single-spanned transmembrane protein localized in the limiting membranes of lysosomes and late endosomes. Most mutations lead to splicing defects or protein truncation, resulting in a loss of transmembrane and/or cytoplasmic domains, leading to LAMP-2 protein deficiency. LAMP-2 is required for the maturation of autophagosomes by fusion with lysosomes; therefore, LAMP-2 deficiency leads to a failure in macroautophagy. There are three LAMP-2 isoforms, LAMP-2A, -2B, and -2C. Clinical features of Danon disease are thought to be mediated by loss of the LAMP-2B isoform which is the major isoform expressed in muscle. It is also known that LAMP-2 plays a role in chaperone-mediated autophagy and RNA- and DNA-targeting autophagy. However, the precise pathophysiological mechanism through which LAMP-2 deficiency causes Danon disease is still not fully

  14. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains.

    PubMed

    Walker, Douglas G; Lue, Lih-Fen

    2015-08-19

    Inflammatory responses in the brain, which can be demonstrated by changes in properties of microglia, the brain-resident macrophages, are a common feature of human neurodegenerative diseases. Different monocyte/macrophage phenotypes have been defined by changes in expression of cytokines, receptors and other markers as a response to different classes of stimuli. Monocytes, macrophages and microglia can have a range of phenotypes with associated properties depending on their microenvironment. Macrophage/microglia polarization states have been defined as classical activation (M1), alternative activation (M2a), type II alternative activation (M2b) or acquired deactivation (M2c). Available markers for identifying microglial phenotypes in human brains are still limited; those available provide incomplete information on the functions or polarization states of microglia observed in tissues from diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. The most widely used marker to describe activated microglia in human brains, particularly diseased brains, has been HLA-DR, the major histocompatibility complex II protein. HLA-DR-positive microglia can have a wide range of activation morphologies that are affected not only by disease pathology, but also by their differentiation states and brain regions. Two other widely used markers to identify microglia in human brains are ionized calcium binding adaptor molecule-1 and CD68. Although their expression changes in diseased brains, these markers do not show specificity for different phenotypes. Over the years there have been studies with additional markers that attempt to further define microglial properties, particularly in Alzheimer's disease brains. Most studies have employed immunohistochemical techniques to identify microglia in tissue sections, but recent advances in this field have allowed gene expression profiling of microglia upon immediate isolation from brains. We will review which markers

  15. A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease

    PubMed Central

    Cummings, Damian M.; Alaghband, Yasaman; Hickey, Miriam A.; Joshi, Prasad R.; Hong, S. Candice; Zhu, Chunni; Ando, Timothy K.; André, Véronique M.; Cepeda, Carlos; Watson, Joseph B.

    2012-01-01

    The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ∼150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ∼110, ∼160, ∼210, and ∼310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted “U-shaped” relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model. PMID:22072510

  16. Inferring drug-disease associations from integration of chemical, genomic and phenotype data using network propagation

    PubMed Central

    2013-01-01

    Background During the last few years, the knowledge of drug, disease phenotype and protein has been rapidly accumulated and more and more scientists have been drawn the attention to inferring drug-disease associations by computational method. Development of an integrated approach for systematic discovering drug-disease associations by those informational data is an important issue. Methods We combine three different networks of drug, genomic and disease phenotype and assign the weights to the edges from available experimental data and knowledge. Given a specific disease, we use our network propagation approach to infer the drug-disease associations. Results We apply prostate cancer and colorectal cancer as our test data. We use the manually curated drug-disease associations from comparative toxicogenomics database to be our benchmark. The ranked results show that our proposed method obtains higher specificity and sensitivity and clearly outperforms previous methods. Our result also show that our method with off-targets information gets higher performance than that with only primary drug targets in both test data. Conclusions We clearly demonstrate the feasibility and benefits of using network-based analyses of chemical, genomic and phenotype data to reveal drug-disease associations. The potential associations inferred by our method provide new perspectives for toxicogenomics and drug reposition evaluation. PMID:24565337

  17. Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: Shared Mechanistic and Phenotypic Traits Suggest Overlapping Disease Mechanisms.

    PubMed

    Paulin, Francisco; Doyle, Tracy J; Fletcher, Elaine A; Ascherman, Dana P; Rosas, Ivan O

    2015-01-01

    The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

  18. Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype.

    PubMed

    Jemtland, Rune; Holden, Marit; Reppe, Sjur; Olstad, Ole K; Reinholt, Finn P; Gautvik, Vigdis T; Refvem, Hilde; Frigessi, Arnoldo; Houston, Brian; Gautvik, Kaare M

    2011-08-01

    Genome-wide gene expressions in bone biopsies from patients with postmenopausal osteoporosis and healthy controls were profiled, to identify osteoporosis candidate genes. All osteoporotic patients (n = 27) in an unbiased cohort of Norwegian women presented with bone mineral density (BMD) T-scores of less than -2.5 SD and one or more confirmed low-energy fracture(s). A validation group (n = 18) had clinical and laboratory parameters intermediate to the control (n = 39) and osteoporosis groups. RNA from iliac crest bone biopsies were analyzed by Affymetrix microarrays and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Differentially expressed genes in osteoporosis versus control groups were identified using the Bayesian ANOVA for microarrays (BAMarray) method, whereas the R-package Limma (Linear Models for Microarray Data) was used to determine whether these transcripts were explained by disease, age, body mass index (BMI), or combinations thereof. Laboratory tests showed normal ranges for the cohort. A total of 609 transcripts were differentially expressed in osteoporotic patients relative to controls; 256 transcripts were confirmed for disease when controlling for age or BMI. Most of the osteoporosis susceptibility genes (80%) also were confirmed to be regulated in the same direction in the validation group. Furthermore, 217 of 256 transcripts were correlated with BMD (adjusted for age and BMI) at various skeletal sites (|r| > 0.2, p < .05). Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups. Our results identify potential osteoporosis susceptibility candidate genes adjusted for confounding factors (ie, age and BMI) with or without a significant correlation with BMD.

  19. Complex Inheritance of ABCA4 Disease: Four Mutations in a Family with Multiple Macular Phenotypes

    PubMed Central

    Lee, Winston; Xie, Yajing (Angela); Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H.; Lupski, James R.; Allikmets, Rando

    2015-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes. PMID:26527198

  20. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    ERIC Educational Resources Information Center

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  1. Genetic Variants Synthesize to Produce Paneth Cell Phenotypes that Define Subtypes of Crohn’s Disease

    PubMed Central

    VanDussen, Kelli L.; Liu, Ta-Chiang; Li, Dalin; Towfic, Fadi; Modiano, Nir; Winter, Rachel; Haritunians, Talin; Taylor, Kent D.; Dhall, Deepti; Targan, Stephan R.; Xavier, Ramnik J.; McGovern, Dermot P. B.; Stappenbeck, Thaddeus S.

    2014-01-01

    Background & Aims Genetic susceptibility loci for Crohn’s disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features. PMID:24076061

  2. Heritability of Chronic Obstructive Pulmonary Disease and Related Phenotypes in Smokers

    PubMed Central

    Cho, Michael H.; Castaldi, Peter J.; Hersh, Craig P.; Silverman, Edwin K.

    2013-01-01

    Rationale: Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have shown that spirometric phenotypes are heritable. Objectives: To assess the heritability and coheritability of four major COPD-related phenotypes (measurements of FEV1, FEV1/FVC, percent emphysema, and percent gas trapping), and COPD affection status in smokers of non-Hispanic white and African American descent using a population design. Methods: Single-nucleotide polymorphisms from genome-wide association studies chips were used to calculate the relatedness of pairs of individuals and a mixed model was adopted to estimate genetic variance and covariance. Measurements and Main Results: In the non-Hispanic whites, estimated heritabilities of FEV1 and FEV1/FVC were both about 37%, consistent with estimates in the literature from family-based studies. For chest computed tomography scan phenotypes, estimated heritabilities were both close to 25%. Heritability of COPD affection status was estimated as 37.7% in both populations. Conclusions: This study suggests that a large portion of the genetic risk of COPD is yet to be discovered and gives rationale for additional genetic studies of COPD. The estimates of coheritability (genetic covariance) for pairs of the phenotypes suggest considerable overlap of causal genetic loci. PMID:23972146

  3. Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations

    PubMed Central

    Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

    2016-01-01

    MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD. PMID:26849207

  4. Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations.

    PubMed

    Shi, Hongbo; Zhang, Guangde; Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

    2016-01-01

    MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD.

  5. Severe pulmonary hypertension in lung disease: phenotypes and response to treatment.

    PubMed

    Brewis, Melanie J; Church, Alistair C; Johnson, Martin K; Peacock, Andrew J

    2015-11-01

    Pulmonary hypertension (PH) due to lung disease (World Health Organization (WHO) group 3) is common, but severe PH, arbitrarily defined as mean pulmonary artery pressure ≥35 mmHg is reported in only a small proportion. Whether these should be treated as patients in WHO group 1 (i.e. pulmonary arterial hypertension) with PH-targeted therapies is unknown. We compared the phenotypic characteristics and outcomes of 118 incident patients with severe PH and lung disease with 74 idiopathic pulmonary arterial hypertension (IPAH) patients, all treated with pulmonary vasodilators. Lung disease patients were older, more hypoxaemic, and had lower gas transfer, worse New York Heart Association functional class and lower 6-min walking distance (6MWD) than IPAH patients. Poorer survival in those with lung disease was driven by the interstitial lung disease (ILD) cohort. In contrast to IPAH, where significant improvements in 6MWD and N-terminal pro-brain natruiretic peptide (NT-proBNP) occurred, PH therapy in severe PH lung disease did not lead to improvement in 6MWD or functional class, but neither was deterioration seen. NT-proBNP decreased from 2200 to 1596 pg·mL(-1) (p=0.015). Response varied by lung disease phenotype, with poorer outcomes in patients with ILD and emphysema with preserved forced expiratory volume in 1 s. Further study is required to investigate whether vasodilator therapy may delay disease progression in severe PH with lung disease.

  6. Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations.

    PubMed

    Olivotto, Iacopo; d'Amati, Giulia; Basso, Cristina; Van Rossum, Albert; Patten, Monica; Emdin, Michele; Pinto, Yigal; Tomberli, Benedetta; Camici, Paolo G; Michels, Michelle

    2015-04-01

    Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at the myofilament level, a number of downstream maladaptive mechanisms, ranging from microvascular dysfunction and ischaemia to myocardial fibrosis and from diastolic dysfunction to abnormal sympathetic activation and arrhythmogenesis, seem to recur in sarcomeric cardiomyopathies, independent of the presenting phenotype. The extent and rate at which each of these features occur and evolve may be radically different in each form of cardiomyopathy, determining a clinical heterogeneity that is not only cross-sectional, but also longitudinal, i.e. time-related. Timely and sensitive detection of these long-term modifications in the clinical setting is a key to preventing advanced disease and identifying novel therapeutic targets. The present review evaluates the contribution of contemporary technology to pre-clinical diagnosis, characterization of phenotypes, and assessment of disease progression in sarcomere cardiomyopathies, including echocardiography, positron emission tomography, magnetic resonance, pathology, and circulating biomarkers.

  7. Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

    PubMed

    Cohen, Mark; Appleby, Brian; Safar, Jiri G

    2016-01-01

    Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

  8. Association of immunological cell profiles with specific clinical phenotypes of scleroderma disease.

    PubMed

    López-Cacho, José Manuel; Gallardo, Soledad; Posada, Manuel; Aguerri, Miriam; Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos; Cárdaba, Blanca

    2014-01-01

    This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4(+) and CD8(+) T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies.

  9. Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease

    PubMed Central

    Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos

    2014-01-01

    This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID:24818126

  10. Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

    PubMed Central

    Wang, Zhaohui; Ren, Hong; Shen, Pingyan; Wang, Weiming; Xu, Yaowen; Ni, Liyan; Yu, Xialian; Chen, Xiaonong; Zhang, Wen; Yang, Li; Li, Xiao; Xu, Jing; Chen, Nan

    2016-01-01

    Numerous α-galactosidase A (α-gal A) gene (GLA) mutations have been identified in Fabry disease (FD), but studies on genotype-phenotype correlation are limited. This study evaluated the features of GLA gene mutations and genotype-phenotype relationship in Chinese FD patients. Gene sequencing results, demographic information, clinical history, and laboratory findings were collected from 73 Chinese FD patients. Totally 47 mutations were identified, including 23 novel mutations which might be pathogenic. For male patients, those with frameshift and nonsense mutations presented the classical FD, whereas those with missense mutations presented both of classical and atypical phenotypes. Interestingly, two male patients with missense mutation p.R356G from two unrelated families, and two with p.R301Q from one family presented different phenotypes. A statistically significant association was found between the levels of α-gal A enzyme activity and ocular changes in males, though no significant association was found between residual enzyme activity level and genotype or clinical phenotypes. For female patients, six out of seven with frameshift mutations and one out of nine with missense mutation presented the classical FD, and α-gal A activity in those patients was found to be significantly lower than that of patients with atypical phenotypes (13.73 vs. 46.32 nmol/ml/h/mg). Our findings suggest that the α-gal A activity might be associated with the clinical severity in female patients with FD. But no obvious associations between activity level of α-gal A and genotype or clinical phenotypes were found for male patients. PMID:27560961

  11. Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases.

    PubMed

    Ferreiro, A; Estournet, B; Chateau, D; Romero, N B; Laroche, C; Odent, S; Toutain, A; Cabello, A; Fontan, D; dos Santos, H G; Haenggeli, C A; Bertini, E; Urtizberea, J A; Guicheney, P; Fardeau, M

    2000-11-01

    Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity ("minicores") in muscle fibers. The dinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis ("classical" form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD.

  12. The mouse genome database: genotypes, phenotypes, and models of human disease.

    PubMed

    Bult, Carol J; Eppig, Janan T; Blake, Judith A; Kadin, James A; Richardson, Joel E

    2013-01-01

    The laboratory mouse is the premier animal model for studying human biology because all life stages can be accessed experimentally, a completely sequenced reference genome is publicly available and there exists a myriad of genomic tools for comparative and experimental research. In the current era of genome scale, data-driven biomedical research, the integration of genetic, genomic and biological data are essential for realizing the full potential of the mouse as an experimental model. The Mouse Genome Database (MGD; http://www.informatics.jax.org), the community model organism database for the laboratory mouse, is designed to facilitate the use of the laboratory mouse as a model system for understanding human biology and disease. To achieve this goal, MGD integrates genetic and genomic data related to the functional and phenotypic characterization of mouse genes and alleles and serves as a comprehensive catalog for mouse models of human disease. Recent enhancements to MGD include the addition of human ortholog details to mouse Gene Detail pages, the inclusion of microRNA knockouts to MGD's catalog of alleles and phenotypes, the addition of video clips to phenotype images, providing access to genotype and phenotype data associated with quantitative trait loci (QTL) and improvements to the layout and display of Gene Ontology annotations.

  13. Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation.

    PubMed

    Angeli, Aikaterina; Mencacci, Niccolo E; Duran, Raquel; Aviles-Olmos, Iciar; Kefalopoulou, Zinovia; Candelario, Joseph; Rusbridge, Sarah; Foley, Jennifer; Pradhan, Priyanka; Jahanshahi, Marjan; Zrinzo, Ludvic; Hariz, Marwan; Wood, Nicholas W; Hardy, John; Limousin, Patricia; Foltynie, Tom

    2013-09-01

    Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

  14. Opportunities for collaborative phenotyping for disease resistance traits in a large beef cattle resource population.

    PubMed

    Thallman, R M; Kuehn, L A; Allan, M F; Bennett, G L; Koohmaraie, M

    2008-01-01

    The Germplasm Evaluation (GPE) Project at the US Meat Animal Research Center (USMARC) is planned to produce about 3,000 calves per year in support of the following objectives: identification and validation of genetic polymorphisms related to economically relevant traits (ERT), estimation of breed and heterosis effects among 16 breeds for ERT, and estimation of genetic correlations among ERT and physiological indicator traits (PIT). Opportunities exist for collaboration in the development and collection of PIT phenotypes for disease resistance. Other areas of potential collaboration include detailed diagnosis (identification of disease causing organisms, etc.) of treated animals, collaborative development of epidemiological statistical models that would extract more information from the records of diagnoses and treatments, or pharmacogenetics. Concentrating a variety of different phenotypes and research approaches on the same population makes each component much more valuable than it would be individually.

  15. From genotype to phenotype; clinical variability in Lesch-Nyhan disease. The role of epigenetics.

    PubMed

    Trigueros Genao, M; Torres, R J

    2014-11-01

    Lesch-Nyhan disease is a rare genetic disease characterized by a deficiency in the function of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Patients affected by this disease experience hyperuricemia, motor disorders, mental retardation and, in the most severe cases, self-mutilation. Its clinical manifestations depend on the enzymatic activity of HGPRT, which is classically linked to the type of alteration in the HGPRT gene. More than 400 mutations of this gene have been found. At present, one of the controversial aspects of the disease is the relationship between the genotype and phenotype; cases have been described lacking a mutation, such as the patient presented in this article, as well as families who despite sharing the same genetic defect show disorders with differing severity. Epigenetic processes, which modify the genetic expression without changing the sequence of the deoxyribonucleic acid (DNA), could explain the clinical variability observed in this disease.

  16. Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

    PubMed Central

    Sun, Xingshen; Sui, Hongshu; Fisher, John T.; Yan, Ziying; Liu, Xiaoming; Cho, Hyung-Ju; Joo, Nam Soo; Zhang, Yulong; Zhou, Weihong; Yi, Yaling; Kinyon, Joann M.; Lei-Butters, Diana C.; Griffin, Michelle A.; Naumann, Paul; Luo, Meihui; Ascher, Jill; Wang, Kai; Frana, Timothy; Wine, Jeffrey J.; Meyerholz, David K.; Engelhardt, John F.

    2010-01-01

    Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments. PMID:20739752

  17. Association between Manganese Superoxide Dismutase (MnSOD Val-9Ala) genotypes with the risk of generalized aggressive periodontitis disease.

    PubMed

    Kazemi, E; Moradi, M-T; Yari, K; Mousavi, S A R; Kahrizi, D

    2015-12-19

    Generalized aggressive periodontitis (GAP) is a subtype of periodontal diseases that characterized by rapid destruction of periodontal supporting tissues. The MnSOD Val-9Ala mutation of manganese superoxide dismutase gene (MnSOD Val-9Ala) and its correlation with periodontal diseases has been studied in different populations. The purpose of this study was to investigate the possible association of MnSODVal-9Ala polymorphism with periodontitis disease in sample of GAP patients in Iran for the first time. Following a GAP examination, 50 GAP patients and 100 healthy individuals were recruited. Genomic DNA was extracted from peripheral blood leukocytes and the MnSODVal-9Ala polymorphismwas detected using PCR-RFLP method. The frequency of Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 25, 66 and 9%, respectively. In periodontitis patients, frequencies were as Ala/Ala (12%), Ala/Val (50%) and Val/Val (38%) genotypes. There was a significant positive association between distribution of MnSOD Val-9Ala genotypes and the risk of periodontitis disease (p<0.05). Our results indicated that MnSOD Val-9Ala gene polymorphism has a positive association with the risk of periodontitis disease.

  18. TGF-β Regulates DNA Methyltransferase Expression in Prostate Cancer, Correlates with Aggressive Capabilities, and Predicts Disease Recurrence

    PubMed Central

    Helfand, Brian T.; Jang, Thomas L.; Sharma, Vidit; Kozlowski, James; Kuzel, Timothy Michael; Zhu, Lihua J.; Yang, Ximing J.; Javonovic, Borko; Guo, Yinglu; Lonning, Scott; Harper, Jay; Teicher, Beverly A.; Brendler, Charles; Yu, Nengwang; Catalona, William J.; Lee, Chung

    2011-01-01

    Background DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy. Methodology/Principal Findings We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer. Conclusions and Significance Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after

  19. Pharmacological HIF2α inhibition improves VHL disease-associated phenotypes in zebrafish model.

    PubMed

    Metelo, Ana Martins; Noonan, Haley R; Li, Xiang; Jin, Youngnam; Baker, Rania; Kamentsky, Lee; Zhang, Yiyun; van Rooijen, Ellen; Shin, Jordan; Carpenter, Anne E; Yeh, Jing-Ruey; Peterson, Randall T; Iliopoulos, Othon

    2015-05-01

    Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl(-/-) mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl(-/-) embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease.

  20. Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia.

    PubMed

    Cacabelos, Ramón

    2004-12-01

    More than 180 genes distributed across the human genome are potentially involved in the pathogenesis of Alzheimer's disease (AD). The AD population shows a higher genetic variation rate than the control population. Significant differences in allelic distribution and frequency exist when AD-related polygenic clusters are compared with other forms of dementia, indicating that the genetic component in neurodegenerative dementia differs from that of other CNS disorders. The characterization of AD genotype-related phenotypic profiles reveals substantial differences in biological markers among AD clusters associated with different genes and/or allelic combinations. AD and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in their major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometric values, cardiovascular function, blood pressure, lipid metabolism, uric acid metabolism, peripheral calcium homeostasis, liver function, alkaline phosphatase, lactate dehydrogenase, red and white blood cells, regional brain atrophy, and brain blood flow velocity. Functional genomic studies incorporating apolipoprotein E (APOE)-related changes in biological markers extended the difference between AD and DVC by up to 57%. Structural genomic studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS, and PRNP, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate in the range of 30-80%, depending upon genes and genetic clusters. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1 to 3%. The main phenotypic differences in AD are genotype dependent, indicating a powerful

  1. Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease Phenotypes

    PubMed Central

    Yao, Chen; Chen, Brian H.; Joehanes, Roby; Otlu, Burcak; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Tastan, Oznur; Cupples, L. Adrienne; Meigs, James B.; Fox, Caroline S.; Freedman, Jane E.; Courchesne, Paul; O’Donnell, Christopher J.; Munson, Peter J.; Keles, Sunduz; Levy, Daniel

    2015-01-01

    Background Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. Methods and Results We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10−8) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. Conclusions Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD. PMID:25533967

  2. Multi-dimensional phenotyping: towards a new taxonomy for airway disease.

    PubMed

    Wardlaw, A J; Silverman, M; Siva, R; Pavord, I D; Green, R

    2005-10-01

    All the real knowledge which we possess, depends on methods by which we distinguish the similar from the dissimilar. The greater the number of natural distinctions this method comprehends the clearer becomes our idea of things. The more numerous the objects which employ our attention the more difficult it becomes to form such a method and the more necessary. Classification is a fundamental part of medicine. Diseases are often categorized according to pre-20th century descriptions and concepts of disease based on symptoms, signs and functional abnormalities rather than on underlying pathogenesis. Where the aetiology of disease has been revealed (for example in the infectious diseases) a more precise classification has become possible, but in the chronic inflammatory diseases, and in the inflammatory airway diseases in particular, where pathogenesis has been stubbornly difficult to elucidate, we still use broad descriptive terms such as asthma and chronic obstructive pulmonary disease, which defy precise definition because they encompass a wide spectrum of presentations and physiological and cellular abnormalities. It is our contention that these broad-brush terms have outlived their usefulness and that we should be looking to create a new taxonomy of airway disease-a taxonomy that more closely reflects the spectrum of phenotypes that are encompassed within the term airway inflammatory diseases, and that gives full recognition to late 20th and 21st century insights into the disordered physiology and cell biology that characterizes these conditions in the expectation that these will map more closely to both aetiology and response to treatment. Development of this taxonomy will require a much more complete and sophisticated correlation of the many variables that make up a condition than has been usual to employ in an approach that encompasses multi-dimensional phenotyping and uses complex statistical tools such as cluster analysis.

  3. Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease.

    PubMed

    Penco, Silvana; Lunetta, Christian; Mosca, Lorena; Maestri, Eleonora; Avemaria, Francesca; Tarlarini, Claudia; Patrosso, Maria Cristina; Marocchi, Alessandro; Corbo, Massimo

    2011-05-01

    We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.

  4. Exploring and Exploiting Disease Interactions from Multi-Relational Gene and Phenotype Networks

    PubMed Central

    Davis, Darcy A.; Chawla, Nitesh V.

    2011-01-01

    The availability of electronic health care records is unlocking the potential for novel studies on understanding and modeling disease co-morbidities based on both phenotypic and genetic data. Moreover, the insurgence of increasingly reliable phenotypic data can aid further studies on investigating the potential genetic links among diseases. The goal is to create a feedback loop where computational tools guide and facilitate research, leading to improved biological knowledge and clinical standards, which in turn should generate better data. We build and analyze disease interaction networks based on data collected from previous genetic association studies and patient medical histories, spanning over 12 years, acquired from a regional hospital. By exploring both individual and combined interactions among these two levels of disease data, we provide novel insight into the interplay between genetics and clinical realities. Our results show a marked difference between the well defined structure of genetic relationships and the chaotic co-morbidity network, but also highlight clear interdependencies. We demonstrate the power of these dependencies by proposing a novel multi-relational link prediction method, showing that disease co-morbidity can enhance our currently limited knowledge of genetic association. Furthermore, our methods for integrated networks of diverse data are widely applicable and can provide novel advances for many problems in systems biology and personalized medicine. PMID:21829475

  5. rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis

    PubMed Central

    Chen, Wei-Chiao; Wei, James Cheng-Chung; Lu, Hsing-Fang; Wong, Henry Sung-Ching; Woon, Peng Yeong; Hsu, Yu-Wen; Huang, Jin-Ding; Chang, Wei-Chiao

    2017-01-01

    Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs) were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In conclusion, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype. PMID:28054948

  6. Does geographical location influence the phenotype of Fabry disease in women in Europe?

    PubMed

    Barba-Romero, M-A; Deegan, P; Giugliani, R; Hughes, D

    2010-02-01

    This study examines the relationship between phenotype and geographical location of patients with Fabry disease in Europe. Data were taken from patients enrolled in the Fabry Outcome Survey (FOS), as of October 2007. A modified version of the Mainz Severity Score Index (FOS-MSSI) was used to classify patients according to the severity of disease. European patients were grouped depending on country of residence (northern or southern European countries). Results are presented from 762 patients enrolled in FOS in Europe (357 men and 405 women); 66% lived in northern and 34% in southern countries. Median age at onset of symptoms of Fabry disease was similar in both sexes. No differences in disease severity were seen among men, according to place of residence; however, women living in northern countries had higher severity scores (p < 0.001) than those in southern countries. In men and women, FOS-MSSI scores increased with age, irrespective of place of residence. The results suggest that expression of different phenotypic features in Fabry disease in women living in Europe may be influenced by extra-genetic or epigenetic factors. These factors might be related to dietary or environmental influences that differ according to the patient's country of residence.

  7. Carboxypeptidase N-Deficient Mice Present With Polymorphic Disease Phenotypes on Induction of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Hu, Xianzhen; Wetsel, Rick A; Ramos, Theresa N.; Mueller-Ortiz, Stacey L.; Schoeb, Trenton R.; Barnum, Scott R.

    2015-01-01

    Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease. In this study we used CPN−/− mice in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Unexpectedly, we observed several EAE disease phenotypes in CPN−/− mice compared to wild type mice. The majority of CPN−/− mice died within five to seven days after disease induction, before displaying clinical signs of disease. The remaining mice presented with either mild EAE or did not develop EAE. In addition, CPN−/− mice injected with complete or incomplete Freund's adjuvant died within the same time frame and in similar numbers as those induced for EAE. Overall, the course of EAE in CPN−/− mice was significantly delayed and attenuated compared to wild type mice. Spinal cord histopathology in CPN−/− mice revealed meningeal, but not parenchymal leukocyte infiltration, and minimal demyelination. Our results indicate that CPN plays an important role in EAE development and progression and suggests that multiple CPN ligands contribute to the disease phenotypes we observed. PMID:24028840

  8. Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis.

    PubMed

    Hu, Xianzhen; Wetsel, Rick A; Ramos, Theresa N; Mueller-Ortiz, Stacey L; Schoeb, Trenton R; Barnum, Scott R

    2014-02-01

    Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease. In this study we used CPN(-/-) mice in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Unexpectedly, we observed several EAE disease phenotypes in CPN(-/-) mice compared to wild type mice. The majority of CPN(-/-) mice died within five to seven days after disease induction, before displaying clinical signs of disease. The remaining mice presented with either mild EAE or did not develop EAE. In addition, CPN(-/-) mice injected with complete or incomplete Freund's adjuvant died within the same time frame and in similar numbers as those induced for EAE. Overall, the course of EAE in CPN(-/-) mice was significantly delayed and attenuated compared to wild type mice. Spinal cord histopathology in CPN(-/-) mice revealed meningeal, but not parenchymal leukocyte infiltration, and minimal demyelination. Our results indicate that CPN plays an important role in EAE development and progression and suggests that multiple CPN ligands contribute to the disease phenotypes we observed.

  9. Gene-metabolite network analysis in different nonalcoholic fatty liver disease phenotypes

    PubMed Central

    Liu, Xiao-Lin; Ming, Ya-Nan; Zhang, Jing-Yi; Chen, Xiao-Yu; Zeng, Min-De; Mao, Yi-Min

    2017-01-01

    We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high-fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations. PMID:28082742

  10. Phenotypic expansion of the supernumerary derivative (22) chromosome syndrome: VACTERL and Hirschsprung's disease.

    PubMed

    Prieto, Juan C; Garcia, Nilda M; Elder, Frederick F; Zinn, Andrew R; Baker, Linda A

    2007-11-01

    Phenotypically healthy carriers of the balanced 11;22 translocation, the most frequent non-Robertsonian constitutional translocation known in human beings, are at risk of having a progeny with supernumerary derivative (22)t(11;22) syndrome [der(22) syndrome]. We present the cases of 2 male patients with supernumerary der(22) syndrome [47,XY,+der(22)t(11;22)(q23;q11.2)mat], yielding partial trisomy for 22pter-q11 and 11q23-qter. These cases expand the phenotype of the der(22) syndrome, with the first case highlighting the phenotypic overlap of VACTERL and the second adding Hirschsprung's disease and intestinal malrotation to the list of associated anorectal anomalies. Because der(22) syndrome and cat eye syndrome (partial tetrasomy of 22q11) share a similar region of extra dosage on 22q11 and both typically manifest an anorectal phenotype, a dosage-sensitive gene for anorectal anomalies may be present in this locus.

  11. Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report

    PubMed Central

    2011-01-01

    Background Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNAGln T4336C). Case presentation Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD. PMID:22023810

  12. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  13. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    PubMed Central

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

  14. The interpretation of disease phenotypes to identify TSE strains following murine bioassay: characterisation of classical scrapie.

    PubMed

    Beck, Katy E; Vickery, Christopher M; Lockey, Richard; Holder, Thomas; Thorne, Leigh; Terry, Linda A; Denyer, Margaret; Webb, Paul; Simmons, Marion M; Spiropoulos, John

    2012-11-01

    Mouse bioassay can be readily employed for strain typing of naturally occurring transmissible spongiform encephalopathy cases. Classical scrapie strains have been characterised historically based on the established methodology of assessing incubation period of disease and the distribution of disease-specific vacuolation across the brain following strain stabilisation in a given mouse line. More recent research has shown that additional methods could be used to characterise strains and thereby expand the definition of strain "phenotype". Here we present the phenotypic characteristics of classical scrapie strains isolated from 24 UK ovine field cases through the wild-type mouse bioassay. PrPSc immunohistochemistry (IHC), paraffin embedded tissue blots (PET-blot) and Western blotting approaches were used to determine the neuroanatomical distribution and molecular profile of PrPSc associated with each strain, in conjunction with traditional methodologies. Results revealed three strains isolated through each mouse line, including a previously unidentified strain. Moreover IHC and PET-blot methodologies were effective in characterising the strain-associated types and neuroanatomical locations of PrPSc. The use of Western blotting as a parameter to define classical scrapie strains was limited. These data provide a comprehensive description of classical scrapie strain phenotypes on isolation through the mouse bioassay that can provide a reference for further scrapie strain identification.

  15. Extending Injury- and Disease-Resistant CNS Phenotypes by Repetitive Epigenetic Conditioning

    PubMed Central

    Gidday, Jeffrey M.

    2015-01-01

    Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist – in effect, expanding conditioning’s “therapeutic window” – would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1–3 days) protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances post-ischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious but also practical, adaptive epigenetics-based treatments for individuals with neurological disease. PMID:25784897

  16. Phenotype-optimized sequence ensembles substantially improve prediction of disease-causing mutation in cystic fibrosis.

    PubMed

    Masica, David L; Sosnay, Patrick R; Cutting, Garry R; Karchin, Rachel

    2012-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with a phenotypic spectrum that includes cystic fibrosis (CF). The disease liability of some common CFTR mutations is known, but rare mutations are seen in too few patients to categorize unequivocally, making genetic diagnosis difficult. Computational methods can predict the impact of mutation, but prediction specificity is often below that required for clinical utility. Here, we present a novel supervised learning approach for predicting CF from CFTR missense mutation. The algorithm begins by constructing custom multiple sequence alignments called phenotype-optimized sequence ensembles (POSEs). POSEs are constructed iteratively, by selecting sequences that optimize predictive performance on a training set of CFTR mutations of known clinical significance. Next, we predict CF disease liability from a different set of CFTR mutations (test-set mutations). This approach achieves improved prediction performance relative to popular methods recently assessed using the same test-set mutations. Of clinical significance, our method achieves 94% prediction specificity. Because databases such as HGMD and locus-specific mutation databases are growing rapidly, methods that automatically tailor their predictions for a specific phenotype may be of immediate utility. If the performance achieved here generalizes to other systems, the approach could be an excellent tool to help establish genetic diagnoses.

  17. Physical therapy assessment tools to evaluate disease progression and phenotype variability in Golden Retriever muscular dystrophy.

    PubMed

    Gaiad, T P; Silva, M B; Silva, G C A; Caromano, F A; Miglino, M A; Ambrósio, C E

    2011-10-01

    Dogs suffering from Golden Retriever muscular dystrophy (GRMD) present symptoms that are similar to human patients with Duchenne muscular dystrophy (DMD). Phenotypic variability is common in both cases and correlates with disease progression and response to therapy. Physical therapy assessment tools were used to study disease progression and assess phenotypic variability in dogs with GRMD. At 5 (T0), 9 (T1), 13 (T2) and 17 (T3)months of age, the physical features, joint ranges of motion (ROM), limb and thorax circumferences, weight and creatine kinase (CK) levels were assessed in 11 dogs with GRMD. Alterations of physical features were higher at 13 months, and different disease progression rates were observed. Passive ROM decreased until 1 year old, which was followed by a decline of elbow and tarsal ROM. Limb and thorax circumferences, which were corrected for body weight, decreased significantly between T0 and T3. These measurements can be used to evaluate disease progression in dogs with GRMD and to help discover new therapies for DMD patients.

  18. Distribution and Phenotype of Epstein-Barr Virus-Infected Cells in Inflammatory Bowel Disease

    PubMed Central

    Spieker, Tilmann; Herbst, Hermann

    2000-01-01

    Little is known about Epstein-Barr virus (EBV) infection of colon mucosa, particularly in inflammatory bowel diseases. Crohn’s disease and ulcerative colitis are thought to differ in T-helper lymphocyte composition and cytokine secretion patterns. Some of the implicated cytokines are growth factors for EBV-infected cells. We examined colon mucosa for differences in the distribution and phenotype of EBV-infected cells. Colon tissues with Crohn’s disease (n = 31) or ulcerative colitis (n = 25) and controls (n = 60) were characterized by in situ hybridization and immunohistology for six EBV gene products as indicators of latent and replicative EBV infection. The cells were additionally phenotyped by combined detection of the EBV transcripts and B- or T-cell antigens. B lymphocytes predominated as the site of latent EBV infection in the colon and were most numerous in ulcerative colitis. In active ulcerative colitis, EBV-positive lymphocytes accumulated under and within the epithelium and displayed evidence for replicative infection. The patterns of mucosal EBV gene expression indicate local impairment of virus-specific T-cell responses in active ulcerative colitis. Detection of EBV may help to discriminate between active ulcerative colitis and other inflammatory bowel diseases. Colon mucosa is a potential site of EBV replication and may be relevant for EBV transmission. PMID:10880375

  19. Is Chronic Obstructive Pulmonary Disease Caused by Wood Smoke a Different Phenotype or a Different Entity?

    PubMed

    Torres-Duque, Carlos A; García-Rodriguez, María Carmen; González-García, Mauricio

    2016-08-01

    Around 40% of the world's population continue using solid fuel, including wood, for cooking or heating their homes. Chronic exposure to wood smoke is a risk factor for developing chronic obstructive pulmonary disease (COPD). In some regions of the world, this can be a more important cause of COPD than exposure to tobacco smoke from cigarettes. Significant differences between COPD associated with wood smoke (W-COPD) and that caused by smoking (S-COPD) have led some authors to suggest that W-COPD should be considered a new COPD phenotype. We present a review of the differences between W-COPD and S-COPD. On the premise that wood smoke and tobacco smoke are not the same and the physiopathological mechanisms they induce may differ, we have analyzed whether W-COPD can be considered as another COPD phenotype or a distinct nosological entity.

  20. Network Modules of the Cross-Species Genotype-Phenotype Map Reflect the Clinical Severity of Human Diseases

    PubMed Central

    Han, Seong Kyu; Kim, Inhae; Hwang, Jihye; Kim, Sanguk

    2015-01-01

    Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases. However, genetic variations uncovered from patient populations do not provide enough information to understand the mechanisms underlying the progression and clinical severity of human diseases. Moreover, building a high-resolution genotype-phenotype map is difficult due to the diverse genetic backgrounds of the human population. We built a cross-species genotype-phenotype map to explain the clinical severity of human genetic diseases. We developed a data-integrative framework to investigate network modules composed of human diseases mapped with gene essentiality measured from a model organism. Essential and nonessential genes connect diseases of different types which form clusters in the human disease network. In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes. Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases. Our results reveal that the genotype-phenotype map of a model organism can facilitate the identification of human disease-gene associations and predict human disease progression. PMID:26301634

  1. Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Six unique arylsulfatase B gene alleles causing variable disease phenotypes

    SciTech Connect

    Isbrandt, D.; Arlt, G.; Figura, K. von; Peters, C.; Brooks, D.A.; Hopwood, J.J.

    1994-03-01

    Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase B (ASB), also known as N-acetylgalactosamine-4-sulfatase. Multiple clinical phenotypes of this autosomal recessively inherited disease have been described. Recent isolation and characterization of the human ASB gene facilitated the analysis of molecular defects underlying the different phenotypes. Conditions for PCR amplification of the entire open reading frame from genomic DNA and for subsequent direct automated DNA sequencing of the resulting DNA fragments were established. Besides two polymorphisms described elsewhere that cause methionine-for-valine substitutions in the arylsulfatase B gene, six new mutations in six patients were detected: four point mutations resulting in amino acid substitutions, a 1-bp deletion, and a 1-bp insertion. The point mutations were two G-to-A and two T-to-C transitions. The G-to-A transitions cause an arginine-for-glycine substitution at residue 144 in a homoallelic patient with a severe disease phenotype and a tyrosine-for-cysteine substitution at residue 521 in a potentially heteroallelic patient with the severe form of the disease. The T-to-C transitions cause an arginine-for-cysteine substitution at amino acid residue 192 in a homoallelic patient with mild symptoms and a proline-for-leucine substitution at amino acid 321 in a homoallelic patient with the intermediate form. The insertion between nucleotides T1284 and G1285 resulted in a loss of the 100 C-terminal amino acids of the wild-type protein and in the deletion of nucleotide C1577 in a 39-amino-acid C-terminal extension of the ASB polypeptide. Both mutations were detected in homoallelic patients with the severe form of the disease. Expression of mutant cDNAs encoding the four amino acid substitutions and the deletion resulted in reduction of both ASB protein levels and arylsulfatase enzyme activity. 25 refs., 4 figs.

  2. Pre-clinical cognitive phenotypes for Alzheimer's disease: a latent profile approach

    PubMed Central

    Hayden, Kathleen M.; Kuchibhatla, Maragatha; Romero, Heather R.; Plassman, Brenda L.; Burke, James R.; Browndyke, Jeffrey N.; Welsh-Bohmer, Kathleen A.

    2013-01-01

    Background Cognitive profiles for pre-clinical Alzheimer's disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. Objective(s) The aim of this work is to evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. Methods The National Alzheimer's Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 NIA funded Alzheimer's Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (n=3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Results Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post-hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Conclusions Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; however comparable results can be achieved with very sensitive tests and contrast scores. PMID:24080384

  3. Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

    PubMed Central

    Lovasz, Barbara Dorottya; Lakatos, Laszlo; Horvath, Agnes; Szita, Istvan; Pandur, Tunde; Mandel, Michael; Vegh, Zsuzsanna; Golovics, Petra Anna; Mester, Gabor; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Kiss, Lajos Sandor; Lakatos, Peter Laszlo

    2013-01-01

    AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn’s disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long

  4. Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer

    PubMed Central

    Gomez-Roman, Natividad; Sahasrabudhe, Neha Mohan; McGregor, Fiona; Chalmers, Anthony J.; Cassidy, Jim; Plumb, Jane

    2016-01-01

    The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1β re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer. PMID:26967059

  5. Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography?

    PubMed

    Szilagyi, Andew; Xue, Xiaoqing

    2016-11-01

    Geographic patterns with diminishing rates from north to south toward the equator have been described for a number of diseases, putatively related largely to "western" lifestyle. Among these the inflammatory bowel diseases; Crohn's (CD) and Ulcerative colitis (UC) have been prominent in sharing distributions with a number of autoimmune diseases. One of the interesting associations is the epidemiologic similarity with multiple sclerosis (MS). However, in addition, at least some of these diseases also correlated inversely with lactase non persistent population (LNP) distributions. It is hypothesized that MS should also have an inverse relationship with LNP. We provide support for this by comparing published MS, CD, UC and LNP national rates to the beginning of the new millennium. Possible links among these diseases may be an evolutionary signature of new genes which may have accompanied emergence of lactase persistence millennia ago. The emergent phenotypic dichotomy also forced different assimilation responses to lactose digestion. While intestinal retention of lactase results in direct host enzymatic digestion, in LNP persons intestinal bacterial metabolism of lactose impacts on the host micro-flora. These microbial changes may play some role in altering rates of diseases including IBD and MS. However, since the late 20th century previously observed patterns are changing. Although industrialization is considered to play an important modifying role, the rising rates of obesity with an emphasis on diet, and microfloral pathogenesis, but with an independent geographic pattern may also facilitate altering rates and geographic distributions of both of these and other diseases.

  6. Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.

    PubMed

    Miller, James R C; Träger, Ulrike; Andre, Ralph; Tabrizi, Sarah J

    2015-01-01

    Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

  7. Modeling disease using three dimensional cell culture: multi-lumen and inverted cyst phenotypes.

    PubMed

    Monteleon, Christine L; D'Souza-Schorey, Crislyn

    2012-06-01

    Three-dimensional cell culture provides a unique system to investigate intrinsic mechanisms and micro environmental cues involved in the morphogenesis of epithelial glandular architectures. While this culture system allows insight into normal tissue development, it is also is readily amenable to manipulations that permit cellular modeling of various disease states. Here, we discuss a range of cellular and genetic alterations that result in two distinct cyst phenotypes, the multi-lumen cyst and the inverted cyst, both of which involve defects in cell polarity and lumen formation. Multi-lumen cyst formation results from disturbances in the mechanisms that regulate cell polarity, apical assembly, and the rate of lumen clearance. In the inverted cyst, the apical domain is oriented adjacent to the matrix, markedly affecting the morphogenic cues the matrix provides for cystogenesis. Both of these abnormal glandular phenotypes are highly reminiscent of histological patterns used to classify a number of diseases. A better understanding of the causes of multi-lumen and inverted cysts will provide insights into the origin and progression of epithelial diseases, potentially leading to the development of new therapies.

  8. Distinctive Menkes disease variant with occipital horns: Delineation of natural history and clinical phenotype

    SciTech Connect

    Proud, V.K.; Mussell, H.G.; Percy, A.K.

    1996-10-02

    To delineate further the clinical spectrum of Menkes disease, an X-linked recessive disorder of copper transport, we studied 4 related males, ranging in age from 4-38 years, with a unique phenotype that combines manifestations of classical and mild Menkes disease and occipital horn syndrome (OHS). The propositus, an 18-year-old man, was evaluated following an intracerebral hemorrhage at age 15 years and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, failure to thrive, and diarrhea from infancy; seizures from age 3 years; and abnormal hair (pili torti) and face, cutis laxa, and multiple joint dislocations. Radiographic abnormalities included occipital exostoses, tortuous cerebral blood vessels with multiple branch occlusions, and hammer-shaped clavicles. Biochemical studies demonstrated reduced copper and ceruloplasmin levels in serum, and abnormal plasma catecholamine ratios. We reported previously the molecular defect in this family, a splice-site mutation that predicts formation of approximately 20% of the normal Menkes gene product. Here, we detail the clinical course and physical features and radiographic findings in these 4 individuals, and compare their phenotype with classical and mild Menkes and OHS. Unusual Menkes disease variants such as this may escape recognition due to anomalies that appear inconsistent with the diagnosis, particularly prolonged survival and later onset of seizures. Males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport. 28 refs., 8 figs.

  9. Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression.

    PubMed

    Leung, M; Piatkov, I; Rochester, C; Boyages, S C; Leong, R W L

    2009-02-01

    Severe cytopenias in patients with autoimmune conditions treated with azathioprine are well-recognized. Thiopurine methyltransferase (TPMT) enzymatic activity is subject to individual and ethnic variability. Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe and potentially fatal haematopoietic toxicity. Studies have shown that essentially all TPMT-deficient patients will develop haematopoietic toxicity on administration of conventional thiopurine dosages (6-mercaptopurine, azathioprine). Therefore, screening for TPMT polymorphisms in patients before prescribing thiopurine drugs has been proposed. However, despite normal in vitro enzymatic activity, cytopenia may still occur in vivo. This is the case report of an Asian patient with Crohn disease harbouring a rare TPMT mutation on DNA sequencing, who developed neutropenic sepsis and anaemia after a flare of Crohn disease. The report illustrates the importance of monitoring for cytopenia in the setting of active inflammatory disease despite prior normal phenotyping, the role of predictive pharmacogenetics and the limitations of TPMT phenotype assays that may result in misclassification of at-risk patients.

  10. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia

    PubMed Central

    Stitziel, Nathan O.; Fouchier, Sigrid W.; Sjouke, Barbara; Peloso, Gina M.; Moscoso, Alessa M.; Auer, Paul L.; Goel, Anuj; Gigante, Bruna; Barnes, Timothy A.; Melander, Olle; Orho-Melander, Marju; Duga, Stefano; Sivapalaratnam, Suthesh; Nikpay, Majid; Martinelli, Nicola; Girelli, Domenico; Jackson, Rebecca D.; Kooperberg, Charles; Lange, Leslie A.; Ardissino, Diego; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Reilly, Muredach P.; Rader, Daniel J.; de Faire, Ulf; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J.; Charnas, Lawrence; Altshuler, David; Gabriel, Stacey; Kastelein, John J.P.; Defesche, Joep C.; Nederveen, Aart J.; Kathiresan, Sekar; Hovingh, G. Kees

    2014-01-01

    Objective Autosomal recessive hypercholesterolemia (ARH) is a rare inherited disorder characterized by extremely high total and low-density lipoprotein cholesterol levels that has been previously linked to mutations in LDLRAP1. We identified a family with ARH not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular etiology of ARH in this family. Approach and Results We used exome sequencing to assess all protein coding regions of the genome in three family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Since homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease (CESD), we performed directed follow-up phenotyping by non-invasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of CESD. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27,000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. Conclusions By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent CESD in the affected individuals from this kindred and addressed an outstanding question regarding risk of cardiovascular disease in LIPA E8SJM heterozygous carriers. PMID:24072694

  11. Basophil phenotypes in chronic idiopathic urticaria in relation to disease activity and autoantibodies.

    PubMed

    Eckman, John A; Hamilton, Robert G; Gober, Laura M; Sterba, Patricia M; Saini, Sarbjit S

    2008-08-01

    Potentially pathogenic IgG autoantibodies to IgE or its receptor, Fc epsilonRIalpha, have been detected in approximately 40% of chronic idiopathic urticaria (CIU) patients. CIU patients' basophils display distinct altered Fc epsilonRIalpha-mediated degranulation. CIU patients with basophil histamine release in response to polyclonal goat anti-human IgE > or = 10% are classified as CIU responders (CIU-R) and < 10% are CIU non-responders (CIU-NR). We compared the presence of autoantibodies to basophil degranulation phenotypes and to disease status (active or inactive). Sera were collected from non-CIU subjects and CIU subjects who participated in a longitudinal study of disease severity and had defined basophil degranulation phenotypes. Immunoenzymetric assays (IEMA) quantified IgG anti-Fc epsilonRIalpha and anti-IgE. IgG anti-Fc epsilonRIalpha antibody was detected in 57% of CIU-R (n=35), 55% of CIU-NR (n=29), and 57% of non-CIU subjects (n=23), whereas IgG anti-IgE was present in 43% of CIU-R, 45% of CIU-NR, and 30% of non-CIU subjects. Both the autoantibody levels and the functional basophil phenotype remained stable in subjects with active disease (n=16), whereas there was an enhancement in basophil function as subjects evolved into a state of remission (n=6), which appears independent of the presence of autoantibody. IEMAs detected a similar frequency of autoantibodies in CIU-R, CIU-NR, and non-CIU subjects. Basophil function may be independent of IEMA-detected autoantibodies.

  12. Phenotypic and Genotypic Characteristics of Neisseria meningitidis Disease-Causing Strains in Argentina, 2010

    PubMed Central

    Sorhouet-Pereira, Cecilia; Efron, Adriana; Gagetti, Paula; Faccone, Diego; Regueira, Mabel; Corso, Alejandra; Gabastou, Jean-Marc; Ibarz-Pavón, Ana Belén

    2013-01-01

    Phenotypic and genotypic characterization of 133 isolates of Neisseria meningitidis obtained from meningococcal disease cases in Argentina during 2010 were performed by the National Reference Laboratory as part of a project coordinated by the PAHO within the SIREVA II network. Serogroup, serotype, serosubtype and MLST characterization were performed. Minimum Inhibitory Concentration to penicillin, ampicillin, ceftriaxone, rifampin, chloramphenicol, tetracycline and ciprofloxacin were determined and interpreted according to CLSI guidelines. Almost 49% of isolates were W135, and two serotype:serosubtype combinations, W135∶2a:P1.5,2:ST-11 and W135∶2a:P1.2:ST-11 accounted for 78% of all W135 isolates. Serogroup B accounted for 42.1% of isolates, and was both phenotypically and genotypically diverse. Serogroup C isolates represented 5.3% of the dataset, and one isolate belonging to the ST-198 complex was non-groupable. Isolates belonged mainly to the ST-11 complex (48%) and to a lesser extent to the ST-865 (18%), ST-32 (9,8%) and the ST-35 complexes (9%). Intermediate resistance to penicillin and ampicillin was detected in 35.4% and 33.1% of isolates respectively. Two W135∶2a:P1.5,2:ST-11:ST-11 isolates presented resistance to ciprofloxacin associated with a mutation in the QRDR of gyrA gene Thr91-Ile. These data show serogroup W135 was the first cause of disease in Argentina in 2010, and was strongly associated with the W135∶2a:P1.5,2:ST-11 epidemic clone. Serogroup B was the second cause of disease and isolates belonging to this serogroup were phenotypically and genotypically diverse. The presence of isolates with intermediate resistance to penicillin and the presence of fluorquinolone-resistant isolates highlight the necessity and importance of maintaining and strengthening National Surveillance Programs. PMID:23483970

  13. Aggressive Behavior

    MedlinePlus

    ... Listen Español Text Size Email Print Share Aggressive Behavior Page Content Article Body My child is sometimes very aggressive. What is the best ... once they are quiet and still reinforces this behavior, so your child learns that time out means “quiet and still.” ...

  14. A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

    PubMed

    Hölter, Sabine M; Stromberg, Mary; Kovalenko, Marina; Garrett, Lillian; Glasl, Lisa; Lopez, Edith; Guide, Jolene; Götz, Alexander; Hans, Wolfgang; Becker, Lore; Rathkolb, Birgit; Rozman, Jan; Schrewed, Anja; Klingenspor, Martin; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wursta, Wolfgang; Gillis, Tammy; Wakimoto, Hiroko; Seidman, Jonathan; MacDonald, Marcy E; Cotman, Susan; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Lee, Jong-Min; Wheeler, Vanessa C

    2013-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

  15. A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

    PubMed Central

    Kovalenko, Marina; Garrett, Lillian; Glasl, Lisa; Lopez, Edith; Guide, Jolene; Götz, Alexander; Hans, Wolfgang; Becker, Lore; Rathkolb, Birgit; Rozman, Jan; Schrewed, Anja; Klingenspor, Martin; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wursta, Wolfgang; Gillis, Tammy; Wakimoto, Hiroko; Seidman, Jonathan; MacDonald, Marcy E.; Cotman, Susan; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Lee, Jong-Min; Wheeler, Vanessa C.

    2013-01-01

    Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing. PMID:24278347

  16. Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

    PubMed

    Pietropaolo, Susanna; Feldon, Joram; Yee, Benjamin K

    2008-08-01

    The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

  17. Retraction: "Activated K-Ras and INK4a/Arf Deficiency Promote Aggressiveness of Pancreatic Cancer by Induction of EMT Consistent With Cancer Stem Cell Phenotype" by Wang et al.

    PubMed

    2016-10-01

    The above article, published online on November 23, 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 4B and C to be inappropriately manipulated and re-labeled. Literature Cited Wang Z, Ali S, Banerjee S, Bao B, Li Y, Azmi AS, Korc M, Sarkar FH. 2013. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J Cell Physiol 228:556-562; doi: 10.1002/jcp.24162.

  18. Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts

    PubMed Central

    Laschkolnig, Anja; Kollerits, Barbara; Lamina, Claudia; Meisinger, Christa; Rantner, Barbara; Stadler, Marietta; Peters, Annette; Koenig, Wolfgang; Stöckl, Andrea; Dähnhardt, Doreen; Böger, Carsten A.; Krämer, Bernhard K.; Fraedrich, Gustav; Strauch, Konstantin; Kronenberg, Florian

    2014-01-01

    Aims The relevance of lipoprotein(a) [Lp(a)] concentrations and low-molecular-weight (LMW) apo(a) phenotypes in peripheral arterial disease (PAD) has only been investigated by few studies. Therefore, we analysed this association in three independent cohorts and performed a Mendelian Randomization approach using instrumental variable regression. Methods and results Lp(a) concentrations, apo(a) phenotypes, and one SNP in the LPA gene (rs10455872) were measured in the CAVASIC study, including 241 male patients with intermittent claudication and 246 age- and diabetes-matched controls as well as in the two population-based studies KORA F3 (n = 3184) and KORA F4 (n = 3080). In KORA F3/F4, 109/80 persons suffered from intermittent claudication, 200/144 from PAD, and 128/103 showed an ankle–brachial index (ABI) <0.9. In CAVASIC, adjusted logistic regression analyses revealed significant associations between an increase of log-Lp(a) per one standard deviation (SD) (OR = 1.28, P = 0.02) as well as LMW apo(a) phenotypes and symptomatic PAD (OR = 1.65, P = 0.03). Linear regression models with continuous ABI showed a significant association in the combined analyses of KORA F3/F4: an increase in log-Lp(a) per one SD (β = −0.006, P = 0.005) and the presence of LMW apo(a) phenotypes (β = −0.011, P = 0.02) or the minor allele of rs10455872 (ß = −0.016, P = 0.03) were associated with a decrease in ABI in the fully adjusted linear and instrumental variable regression models. Conclusion Analyses in three independent populations showed significant associations of Lp(a) concentrations, LMW apo(a) phenotypes, and rs10455872 with PAD. This points to a causal relationship between Lp(a) and PAD since the genetically determined apo(a) phenotypes and SNP alleles are indeed associated with PAD. PMID:24760552

  19. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  20. PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases.

    PubMed

    Buske, Orion J; Girdea, Marta; Dumitriu, Sergiu; Gallinger, Bailey; Hartley, Taila; Trang, Heather; Misyura, Andriy; Friedman, Tal; Beaulieu, Chandree; Bone, William P; Links, Amanda E; Washington, Nicole L; Haendel, Melissa A; Robinson, Peter N; Boerkoel, Cornelius F; Adams, David; Gahl, William A; Boycott, Kym M; Brudno, Michael

    2015-10-01

    The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered.

  1. Implications for managed care for improving outcomes in Parkinson's disease: balancing aggressive treatment with appropriate care.

    PubMed

    Chen, Jack J

    2011-10-01

    Disability in Parkinson's disease (PD) is due not only to progressive impairment in balance, gait, and motor-related tasks, but also to several nonmotor symptoms affecting autonomic, neuropsychiatric, and sensory functions. The prevalence of PD in the United States is rising due to the expanding elderly population. Direct medical costs associated with PD are significant and influenced by level of disability and associated complexity of management. As new treatments are made available, reevaluation of treatment benefits and paradigms is warranted, for both motor and nonmotor symptoms of PD, to better manage outcomes. In addition to evaluation of symptomatic therapies for PD, attention to advances in disease-modifying therapies and to management of nonmotor symptoms should be an integral component of PD surveillance in the managed care environment.

  2. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain

    PubMed Central

    Varnum, Megan M.; Ikezu, Tsuneya

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function and memory formation. There is no therapeutic that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states using AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules like interleukin-4 and CD200 have proven to be important anti-inflammatory molecules in the regulation of neuroinflammation in the brain, and they will be discussed in detail for their therapeutic potential. PMID:22710659

  3. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain.

    PubMed

    Varnum, Megan M; Ikezu, Tsuneya

    2012-08-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function. There is no therapy that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states in AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules such as interleukin-4 and CD200 have proven to be important anti-inflammatory mediators in the regulation of neuroinflammation in the brain, which will be discussed in detail for their therapeutic potential.

  4. Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington's disease in vitro model.

    PubMed

    Lee, Mijung; Liu, Tian; Im, Wooseok; Kim, Manho

    2016-08-01

    Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the aggregation of mutant Huntingtin (mHtt). Adipose-derived stem cells (ASCs) have a potential for use in the treatment of incurable disorders, including HD. ASCs secrete various neurotrophic factors and microvesicles, and modulate hostile microenvironments affected by disease through paracrine mechanisms. Exosomes are small vesicles that transport nucleic acid and protein between cells. Here, we investigated the therapeutic role of exosomes from ASCs (ASC-exo) using in vitro HD model by examining pathological phenotypes of this model. Immunocytochemistry result showed that ASC-exo significantly decreases mHtt aggregates in R6/2 mice-derived neuronal cells. Western blot result further confirmed the reduction in mHtt aggregates level by ASC-exo treatment. ASC-exo up-regulates PGC-1, phospho-CREB and ameliorates abnormal apoptotic protein level in an in vitro HD model. In addition, MitoSOX Red, JC-1 and cell viability assay showed that ASC-exo reduces mitochondrial dysfunction and cell apoptosis of in vitro HD model. These findings suggest that ASC-exo has a therapeutic potential for treating HD by modulating representative cellular phenotypes of HD.

  5. Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP).

    PubMed

    Sedor, John R; Madhavan, Sethu M; Kim, Jane H; Konieczkowski, Martha

    2011-01-01

    Normal function of the glomerular filtration barrier requires wild-type differentiation of the highly specialized glomerular epithelial cell, the podocyte. Podocytes express three distinct domains, consisting of a cell body, primary processes, and secondary foot processes (FP). These FP express slit diaphragms, which are highly specialized cell-cell contacts critical for filtration-barrier function. Foot processes are dynamic structures that reorganize within minutes through actin cytoskeletal rearrangement. Glomerular diseases are characterized by a persistent simplification in podocyte domain structure with loss of FP, a phenotype described as FP effacement. The generation of such phenotypic plasticity requires that signaling pathways in subcellular compartments be integrated dynamically for a cell to respond appropriately to information flow from its microenvironment. We have identified a LIM-domain-containing protein, Wilm's tumor interacting protein (WTIP), that regulates podocyte actin dynamics to maintain stable cell contacts. After glomerular injury, the WTIP molecule shuttles to the podocyte nucleus in response to changes in slit-diaphragm assembly, and changes gene transcription to permit podocyte remodeling. Defining regulatory pathways of podocyte differentiation identifies novel, druggable targets for chronic kidney diseases characterized by glomerular scarring.

  6. Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek’s disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    1. Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals and birds. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. 2. Our obje...

  7. Childhood-onset systemic lupus erythematosus in Singapore: clinical phenotypes, disease activity, damage, and autoantibody profiles.

    PubMed

    Tan, J H T; Hoh, S F; Win, M T M; Chan, Y H; Das, L; Arkachaisri, T

    2015-08-01

    Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterized by immune dysregulation affecting patients less than 18 years old. One-fifth of SLE cases are diagnosed during childhood. cSLE presents differently from adults and has a more severe and aggressive course. We describe the clinical and antibody profiles in our cSLE Singapore cohort. All cSLE patients who satisfied the 1997 American College of Rheumatology diagnostic criteria were captured in our lupus registry from January 2009 to January 2014. Data including demographic, cumulative clinical, serologic data, and damage indices were collected. Adjusted mean SLEDAI-2K (AMS) was used to summarize disease activity over multiple visits. Cluster analysis using non-hierarchical K-means procedure was performed on eight selected antibodies. The 64 patients (female:male ratio 5:1; Chinese 45.3%, Malay 28.1%, Indian 9.4%, and other races 17.2%) had a mean onset age of 11.5 years (range 2.1-16.7) and mean age at diagnosis was 11.9 years (range 2.6-18.0). Our study demonstrated differences in clinical manifestations for which hematologic involvement was the most common manifestation with less renal disease and uncommon neurologic manifestation as compared to other cSLE cohorts reported in our region. Antibody clusters were identified in our cohort but their clinical association/discrimination and outcome prediction required further validation study. Outcomes of our cohort in regard to disease activity after therapy and organ damages were comparable if not better to other cSLE cohorts elsewhere. Steroid-related damage, including symptomatic multifocal avascular necrosis and cataract, were not uncommon locally. Infection remains the major cause of death for the continent. Nevertheless, the five year survival rate of our cohort (98.4%) was high.

  8. Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort

    PubMed Central

    Talman, Paul; Duong, Thi; Vucic, Steve; Mathers, Susan; Venkatesh, Svetha; Henderson, Robert; Rowe, Dominic; Schultz, David; Edis, Robert; Needham, Merrilee; Macdonnell, Richard; McCombe, Pamela; Birks, Carol; Kiernan, Matthew

    2016-01-01

    Objective To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia. Methods Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death. Design Prospective observational cohort study. Participants 1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015. Results 5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12 months for the ALS phenotypes, 18 months for the flail limb phenotypes and 19 months for PLS. Riluzole treatment was started in 78–85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12 months in the ALS phenotypes and 15–18 months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8–36% of ALS phenotypes and 2–9% of the flail phenotypes. Non-invasive ventilation was started in 16–22% of ALS phenotypes and 21–29% of flail phenotypes. Conclusions The establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries. PMID:27694488

  9. Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena.

    PubMed

    Ocio, Enrique M; Sanchez-Guijo, Fermin M; Diez-Campelo, Maria; Castilla, Cristina; Blanco, Oscar J; Caballero, Dolores; San Miguel, Jesus F

    2005-04-01

    Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune-related disorders are rare complications of MCD. We report on an MCD case in a 23-year-old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8). After 8 courses of the anti-CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti-CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune-related disorders are associated.

  10. Switching to BCL-6 Negativity in Relapsed Diffuse Large B Cell Lymphoma Correlated with More Aggressive Disease Course.

    PubMed

    Todorović, Milena; Balint, Bela; Andjelic, Bosko; Radisavljevic, Ziv; Mihaljevic, Biljana

    2014-12-01

    Diffuse large B-cell lymphoma (DLBCL) is the most frequent, complex and heterogeneous lymphoma of adulthood. Heterogeneity is expressed at clinical, genetic, and molecular levels. It is known that BCL-6 expression is a favorable prognostic factor in DLBCL. However, the underlying mechanisms of BCL-6 expression in DLBCL relapse are not yet elucidated. Here, we present so far undescribed clinical phenomenon of switching BCL-6(+) protein expression into BCL-6(-) expression in 19 of 41 relapsed DLBCL patients. The switch in relapsed DLBCL was associated with more aggressive clinical course of the disease. Bone marrow infiltration and high IPI risk were more often present in BCL-6(-) patients. Significantly increased biochemical parameters, such as LDH, beta-2 macroglobulin, CRP, and ferritin have been found, as well as significantly decreased serum Fe, TIBC, and hemoglobin. A Ki-67 proliferation marker was considerably high in relapsed DLBCL, but without significant differences between BCL-6(+) and BCL-6(-) groups of patients. Thus, switching of the positive into negative BCL-6 expression during DLBCL relapse could be used as a prognostic factor and a valuable criterion for treatment decision.

  11. Chronic Obstructive Pulmonary Disease Exacerbations in the COPDGene Study: Associated Radiologic Phenotypes

    PubMed Central

    Kazerooni, Ella A.; Lynch, David A.; Liu, Lyrica X.; Murray, Susan; Curtis, Jeffrey L.; Criner, Gerard J.; Kim, Victor; Bowler, Russell P.; Hanania, Nicola A.; Anzueto, Antonio R.; Make, Barry J.; Hokanson, John E.; Crapo, James D.; Silverman, Edwin K.; Martinez, Fernando J.; Washko, George R.

    2011-01-01

    Purpose: To test the hypothesis—given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)—that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease. Materials and Methods: This research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a −950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements. Results: In a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047). Conclusion: Greater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10

  12. Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management

    PubMed Central

    Ballas, Samir K.; Kesen, Muge R.; Goldberg, Morton F.; Lutty, Gerard A.; Dampier, Carlton; Osunkwo, Ifeyinwa; Wang, Winfred C.; Hoppe, Carolyn; Hagar, Ward; Darbari, Deepika S.; Malik, Punam

    2012-01-01

    The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes. PMID:22924029

  13. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    PubMed

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II.

  14. Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management.

    PubMed

    Ballas, Samir K; Kesen, Muge R; Goldberg, Morton F; Lutty, Gerard A; Dampier, Carlton; Osunkwo, Ifeyinwa; Wang, Winfred C; Hoppe, Carolyn; Hagar, Ward; Darbari, Deepika S; Malik, Punam

    2012-01-01

    The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

  15. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2

    PubMed Central

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer’s disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world’s literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years ± 7.8 (range 39–75) and mean age at death of 64.2 years ± 9.8 (range 43–88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer’s disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging

  16. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.

    PubMed

    Jayadev, Suman; Leverenz, James B; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D

    2010-04-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel

  17. Advances in huntington disease drug discovery: novel approaches to model disease phenotypes.

    PubMed

    Bard, Jonathan; Wall, Michael D; Lazari, Ovadia; Arjomand, Jamshid; Munoz-Sanjuan, Ignacio

    2014-02-01

    Huntington disease is a monogenic, autosomal dominant, progressive neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in exon 1 of the huntingtin (HTT) gene; age of onset of clinical symptoms inversely correlates with expanded CAG repeat length. HD leads to extensive degeneration of the basal ganglia, hypothalamic nuclei, and selected cortical areas, and a wide range of molecular mechanisms have been implicated in disease pathology in animal or cellular models expressing mutated HTT (mHTT) proteins, either full-length or amino-terminal fragments. However, HD cellular models that recapitulate the slow progression of the disease have not been available due to the toxicity of overexpressed exogenous mHTT or to limitations with using primary cells for long-term studies. Most investigations of the effects of mHTT relied on cytotoxicity or aggregation end points in heterologous systems or in primary embryonic neuroglial cultures derived from HD mouse models. More innovative approaches are currently under active investigation, including screening using electrophysiological endpoints, as well as the recent use of primary blood mononuclear cells and of human embryonic stem cells derived from a variety of HD research participants. Here we describe how these cellular systems are being used to investigate HD biology as well as to identify mechanisms with therapeutic potential.

  18. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes

    PubMed Central

    de Bie, P; Muller, P; Wijmenga, C; Klomp, L W J

    2007-01-01

    The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper‐transporting P‐type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper‐induced trafficking, post‐translational modifications and protein–protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders. PMID:17717039

  19. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.

    PubMed Central

    Andresen, B S; Olpin, S; Poorthuis, B J; Scholte, H R; Vianey-Saban, C; Wanders, R; Ijlst, L; Morris, A; Pourfarzam, M; Bartlett, K; Baumgartner, E R; deKlerk, J B; Schroeder, L D; Corydon, T J; Lund, H; Winter, V; Bross, P; Bolund, L; Gregersen, N

    1999-01-01

    Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid beta-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established. PMID:9973285

  20. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease.

    PubMed

    Lee, Soojin; Bang, Se Min; Hong, Yoon Ki; Lee, Jang Ho; Jeong, Haemin; Park, Seung Hwan; Liu, Quan Feng; Lee, Im-Soon; Cho, Kyoung Sang

    2016-03-01

    Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca(2+)-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula), a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi), exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  1. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease

    PubMed Central

    Lee, Soojin; Bang, Se Min; Hong, Yoon Ki; Lee, Jang Ho; Jeong, Haemin; Park, Seung Hwan; Liu, Quan Feng; Lee, Im-Soon; Cho, Kyoung Sang

    2016-01-01

    ABSTRACT Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca2+-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula), a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi), exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  2. Expanding genotype/phenotype of neuromuscular diseases by comprehensive target capture/NGS

    PubMed Central

    Tian, Xia; Liang, Wen-Chen; Feng, Yanming; Wang, Jing; Zhang, Victor Wei; Chou, Chih-Hung; Huang, Hsien-Da; Lam, Ching Wan; Hsu, Ya-Yun; Lin, Thy-Sheng; Chen, Wan-Tzu

    2015-01-01

    Objective: To establish and evaluate the effectiveness of a comprehensive next-generation sequencing (NGS) approach to simultaneously analyze all genes known to be responsible for the most clinically and genetically heterogeneous neuromuscular diseases (NMDs) involving spinal motoneurons, neuromuscular junctions, nerves, and muscles. Methods: All coding exons and at least 20 bp of flanking intronic sequences of 236 genes causing NMDs were enriched by using SeqCap EZ solution-based capture and enrichment method followed by massively parallel sequencing on Illumina HiSeq2000. Results: The target gene capture/deep sequencing provides an average coverage of ∼1,000× per nucleotide. Thirty-five unrelated NMD families (38 patients) with clinical and/or muscle pathologic diagnoses but without identified causative genetic defects were analyzed. Deleterious mutations were found in 29 families (83%). Definitive causative mutations were identified in 21 families (60%) and likely diagnoses were established in 8 families (23%). Six families were left without diagnosis due to uncertainty in phenotype/genotype correlation and/or unidentified causative genes. Using this comprehensive panel, we not only identified mutations in expected genes but also expanded phenotype/genotype among different subcategories of NMDs. Conclusions: Target gene capture/deep sequencing approach can greatly improve the genetic diagnosis of NMDs. This study demonstrated the power of NGS in confirming and expanding clinical phenotypes/genotypes of the extremely heterogeneous NMDs. Confirmed molecular diagnoses of NMDs can assist in genetic counseling and carrier detection as well as guide therapeutic options for treatable disorders. PMID:27066551

  3. The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

    PubMed Central

    PAPAGIORGIS, PETROS C.; ZIZI, ADAMANTIA E.; TSELENI, SOPHIA; OIKONOMAKIS, IOANNIS N.; NIKITEAS, NIKOLAOS I.

    2012-01-01

    The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, well-differentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to

  4. Gene Therapy Shows Promise for Aggressive Lymphoma

    MedlinePlus

    ... fullstory_163824.html Gene Therapy Shows Promise for Aggressive Lymphoma Over one-third of patients appeared disease- ... 2017 (HealthDay News) -- An experimental gene therapy for aggressive non-Hodgkin lymphoma beat back more than a ...

  5. Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Moore, Bethany B.; Fry, Chris; Zhou, Yueren; Murray, Susan; Han, MeiLan K.; Martinez, Fernando J.; Flaherty, Kevin R.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts. PMID:25580363

  6. Attenuation of disease phenotype through alternative translation initiation in low-penetrance retinoblastoma.

    PubMed

    Sánchez-Sánchez, Francisco; Ramírez-Castillejo, Carmen; Weekes, Daniel B; Beneyto, Magdalena; Prieto, Félix; Nájera, Carmen; Mittnacht, Sibylle

    2007-02-01

    Hereditary predisposition to retinoblastoma (RB) is caused by germline mutations in the retinoblastoma 1 (RB1) gene and transmits as an autosomal dominant trait. In the majority of cases disease develops in greater than 90% of carriers. However, reduced penetrance with a large portion of disease-free carrier is seen in some families. Unambiguous identification of the predisposing mutation in these families is important for accurate risk prediction in relatives and their genetic counseling but also provides conceptual information regarding the relationship between the RB1 genotype and the disease phenotype. In this study we report a novel mutation detected in 10 individuals of an extended family, only three of whom are affected by RB disease. The mutation comprises a 23-basepair (bp) duplication in the first exon of RB1 (c.43_65dup) producing a frameshift in exon 1 and premature chain termination in exon 2. Mutations resulting in premature chain termination classically are associated with high penetrance disease, as message translation may not generate functional product and nonsense mediated RNA decay (NMD) frequently eliminates the mutant transcript. However, appreciable NMD does not follow from the mutation described here and transcript expression in tissue culture cells and translation in vitro reveals that alternative in-frame translation start sites involving Met113 and possibly Met233 are used to generate truncated RB1 products (pRB94 and pRB80), known and suspected to exhibit tumor suppressor activity. These results strongly suggest that modulation of disease penetrance in this family is achieved by internal translation initiation. Our observations provide the first example for rescue of a chain-terminating mutation in RB1 through alternative translation initiation.

  7. Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity.

    PubMed

    Bamodu, Oluwaseun Adebayo; Huang, Wen-Chien; Tzeng, David T W; Wu, Alexander; Wang, Liang Shun; Yeh, Chi-Tai; Chao, Tsu-Yi

    2015-08-10

    Triple-negative breast cancer (TNBC) is chemotherapy-refractory and associated with poor clinical prognosis. Doxorubicin (Doxo), a class I anthracycline and first-line anticancer agent, effective against a wide spectrum of neoplasms including breast carcinoma, is associated with several cumulative dose-dependent adverse effects, including cardiomyopathy, typhilitis, and acute myelotoxicity. This study evaluated the usability of Ovatodiolide (Ova) in sensitizing TNBC cells to Doxo cytotoxicity, so as to reduce Doxo effective dose and consequently its adverse effects. TNBC cell lines MDA-MB-231 and HS578T were used. Pre-treatment of the TNBC cells with 10 µM Ova 24 h before Doxo administration increased the Doxo anticancer effect (IC50 1.4 µM) compared to simultaneous treatment with Doxo ( IC50 1.8 µM), or Doxo alone (IC50 9.2 µM). Intracellular accumulation of Doxo was lowest in Ova pre-treated cells at all Doxo concentrations, when compared with Doxo or simultaneously treated cells. In comparison to the Doxo-only group, cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5 µM Ova and 1.25 µM Doxo showed increased percentage of cells arrested at G0/G1; however, pre-treatment with the same concentration of Ova 24 h before Doxo showed greater tumor growth inhibition, with a 2.4-fold increased percentage of cells in G0/G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells also lost their cancer stem cell-like phenotype evidenced by significant dissolution, necrosis of formed mammospheres. Taken together, these findings indicate that Ova sensitizes TNBC cells to Doxo and potentiates doxorubicin-induced elimination of the TNBC cancer stem cell-like phenotype.

  8. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

    PubMed Central

    Soriano, Sirena; Calap-Quintana, Pablo; Llorens, José Vicente; Al-Ramahi, Ismael; Gutiérrez, Lucía; Martínez-Sebastián, María José; Botas, Juan; Moltó, María Dolores

    2016-01-01

    Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets. PMID:27433942

  9. The relationship between the phenotype of Parkinson's disease and levodopa-induced dyskinesia.

    PubMed

    Zhang, Yu-Han; Tang, Bei-Sha; Song, Chen-Yuan; Xu, Qian; Lou, Ming-Xin; Liu, Zhen-Hua; Yu, Ren-He; Yan, Xin-Xiang; Guo, Ji-Feng

    2013-11-27

    Levodopa has been demonstrated to be an effective medication for Parkinson's disease (PD), but its long-term use is complicated by the subsequent development of dyskinesias. Few studies have distinguished distinct PD subtypes associated with the occurrence of Levodopa-Induced Dyskinesia (LID). Therefore, we performed a retrospective analysis to determine if the specific phenotype of PD and other epidemiological factors are associated with the development of LID. Of 367 PD patients taking levodopa, 101 of them developed LID. Multivariate logistic regression analysis demonstrated that initial tremor-dominant manifestation was associated with a reduced risk of LID, independent of other risk factors, such as age at the onset of PD, the duration and dose of levodopa.

  10. Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

    PubMed Central

    Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill; Cree, Bruce A. C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

    2016-01-01

    IMPORTANCE Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0–1.4] and 0 [−0.3 to 0.5], respectively; P = 1.8 × 10−27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset

  11. Mutagenesis and phenotyping resources in zebrafish for studying development and human disease

    PubMed Central

    Varshney, Gaurav Kumar

    2014-01-01

    The zebrafish (Danio rerio) is an important model organism for studying development and human disease. The zebrafish has an excellent reference genome and the functions of hundreds of genes have been tested using both forward and reverse genetic approaches. Recent years have seen an increasing number of large-scale mutagenesis projects and the number of mutants or gene knockouts in zebrafish has increased rapidly, including for the first time conditional knockout technologies. In addition, targeted mutagenesis techniques such as zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short sequences (CRISPR) or CRISPR-associated (Cas), have all been shown to effectively target zebrafish genes as well as the first reported germline homologous recombination, further expanding the utility and power of zebrafish genetics. Given this explosion of mutagenesis resources, it is now possible to perform systematic, high-throughput phenotype analysis of all zebrafish gene knockouts. PMID:24162064

  12. Phenotypic spectrum of the Tubulin-related Disorders and Functional Implications of Disease-causing Mutations

    PubMed Central

    Tischfield, Max A.; Cederquist, Gustav Y.; Gupta, Mohan L.; Engle, Elizabeth C.

    2011-01-01

    A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, and axon guidance and maintenance have recently been attributed to missense mutations in the genes that encode α– and β-tubulin isotypes TUBA1A, TUBA8, TUBB2B, and TUBB3, all of which putatively co-assemble into neuronal microtubules. The resulting nervous system malformations can include different types of cortical malformations, defects in commissural fiber tracts, and degeneration of motor and sensory axons. Many clinical phenotypes and brain malformations are shared among the various mutations regardless of structural location and/or isotype, while others segregate with distinct amino acids or functional domains within tubulin. Collectively, these disorders provide novel paradigms for understanding the biological functions of microtubules and their core components in normal health and disease. PMID:21292473

  13. Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway.

    PubMed

    Zheng, Kehong; Zhou, Xinying; Yu, Jinlong; Li, Qiang; Wang, Hui; Li, Mingyi; Shao, Ziyun; Zhang, Feifei; Luo, Yuhao; Shen, Zetao; Chen, Fei; Shi, Fujun; Cui, Chunhui; Zhao, Dachuan; Lin, Zhiqun; Zheng, Wei; Zou, Zhaowei; Huang, Zonghai; Zhao, Liang

    2016-06-28

    The Wnt/β-catenin pathway is known to contribute to colorectal cancer (CRC) progression, although little is known about the contribution of β-catenin on this process. We investigated the role of miR-490-3p, which was recently reported to suppress tumorigenesis through its effect on Wnt/β-catenin signaling. We found that hypermethylation of the miR-490-3p promoter down-regulates miR-490-3p expression in CRC tissue. Gain- and loss-of-function assays in vitro and in vivo reveal that miR-490-3p suppresses cancer cell proliferation by inducing apoptosis and inhibits cell invasiveness by repressing the initiation of epithelial-to-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. The frequently rearranged in advanced T-cell lymphomas (FRAT1) protein was identified as a direct target of miR-490-3p and contributes to its tumor-suppressing effects. miR-490-3p appears to have an inhibitory effect on β-catenin expression in nuclear fractions of CRC cells, whereas FRAT1 expression is associated with the accumulation of β-catenin in the nucleus of cells, which could be weakened by transfection with miR-490-3p. Our findings suggest that the miR-490-3p/FRAT1/β-catenin axis is important in CRC progression and provides new insight into the molecular mechanisms underlying CRC. They may help to confirm the pathway driving CRC aggressiveness and serve for the development of a novel miRNA-targeting anticancer therapy.

  14. Chronic obstructive pulmonary disease phenotype desaturator with hypoxic vascular remodelling and pulmonary hypertension obtained by cluster analysis

    PubMed Central

    2012-01-01

    Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). This article discusses and refines the concept of desaturator phenotypes in COPD with pulmonary hypertension (PH) obtained by cluster analysis and presents a pattern of phenotypic markers that could be used as a framework for future diagnosis and research. Nocturnal oxygen desaturation results in sleep disturbances which predispose to nocturnal cardiac dysrhythmias, PH and possibly nocturnal death, particularly during acute exacerbations. We assume that in patients with COPD at least two factors play a role in PH: the severity of pulmonary impairment, and the severity of systemic nocturnal hypoxaemia due to reduced pulmonary functions. Establishing a common language for future research will facilitate our understanding and management of such a disease. This knowledge could lead to different pharmacological treatments and other interventions directed at specific phenotypic groups. PMID:23127203

  15. Infections associated with chronic granulomatous disease: linking genetics to phenotypic expression.

    PubMed

    Ben-Ari, Josef; Wolach, Ofir; Gavrieli, Ronit; Wolach, Baruch

    2012-08-01

    Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-γ is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state.

  16. Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

    PubMed

    Bravo-Alonso, Irene; Navarrete, Rosa; Arribas-Carreira, Laura; Perona, Almudena; Abia, David; Couce, María Luz; García-Cazorla, Angels; Morais, Ana; Domingo, Rosario; Ramos, María Antonia; Swanson, Michael A; Van Hove, Johan L K; Ugarte, Magdalena; Pérez, Belén; Pérez-Cerdá, Celia; Rodríguez-Pombo, Pilar

    2017-02-28

    The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

  17. Erwinia amylovora strains isolated in Romania from outbreaks of fire blight disease: phenotypic characterization.

    PubMed

    Măruţescu, Luminita; Sesan, Tatiana-Eugenia; Manole, Filofteia

    2008-01-01

    The fire blight disease was described for the first time in Romania, in 1992. Since then by continuous spreading, this disease has caused severe damages of the fruit trees production, particularly of the pear and quince orchards in different regions of the country, being advantaged by certain weather conditions (high temperatures and humidity). An epidemiological surveillance of this disease that was spreading over different regions of the country, has been instituted since 2002. During the year 2005 a total number of 785 samples were collected from the affected areas. The isolation and identification of Erwinia (E.) amylovora were performed on NSA and King's media and by indirect immunofluorescence (IFA) assay using monoclonal antiserum. Four hundred and fifty strains proved levan-type colonies on sucrose nutrient-agar and were IF-positive. Biochemical characterization of 46 selected strains, by help of the API 20E system, revealed a great homogeneity, for 80% of the strains, belonging to one of the two major API 20E profiles described for E. amylovora, the 20% remaining strains showing minor differences. Hypersensitivity test performed on tobacco leaves was positive. Six of the selected strains were susceptible to streptomycin. The present study can be considered as the first attempt of phenotypic characterization of E. amylovora strains isolated from Romanian area.

  18. Common phenotype and different non-HLA genes in Graves' disease and alopecia areata.

    PubMed

    Taketomo, Yasunori; Noso, Shinsuke; Babaya, Naru; Hiromine, Yoshihisa; Ito, Hiroyuki; Kanto, Kousei; Niwano, Fumimaru; Oiso, Naoki; Kawada, Akira; Kawabata, Yumiko; Ikegami, Hiroshi

    2017-02-01

    Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1(∗)15:01-DQB1(∗)06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc<0.002, respectively), but not with AA, even in TRAb-positive patients. The difference in the association between GD and AA suggests that the CTLA4 and TSHR are not main factors contributing to determining common genetic basis among GD and AA.

  19. Genotype-phenotype correlations in von Hippel-Lindau (VHL) disease: Predisposition to pheochromocytoma

    SciTech Connect

    Maher, E.R.; Crossey, P.A.; Richards, F.M.

    1994-09-01

    VHL disease is a dominantly inherited familial cancer syndrome predisposing to a variety of neoplasms, most frequently retinal and CNS haemangioblastoma, renal cell carcinoma, and pheochromocytoma. Marked interfamilial differences in predisposition to pheochromocytoma are recognized. We identified germline mutations in 85 unrelated VHL disease patients (22 large germline deletions, 44 different intragenic mutations: 21 missense, 6 nonsense, 16 deletions or insertions, 1 splice donor site mutation), and correlated this information with phenotype in 65 kindreds. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma but only 2 of 12 families with pheochromocytoma ({chi}{sup 2}=12.33 p<0.01). Of 12 families with pheochromocytoma, 10 had missense mutations compared to 13 of 53 kindreds without pheochromocytoma ({chi}{sup 2}=12.33 p<0.001). 5% of kindreds with large deletions or intragenic mutations predicted to cause a truncated protein were pheochromocytoma positive, compared to 43% of kindreds with misense mutations. In particular, substitution of an arginine at codon 238 (Arg{yields}Trp or Arg{yields}Gln) was associated with a high risk (62%) of pheochromocytoma. The identification of germline mutations in VHL disease not only allows presymptomatic diagnosis, but can also indicate the risk of pheochromocytoma. In addition these results provide a basis for screening for VHL gene mutations in patients with familial or sporadic pheochromocytoma. To date, VHL gene mutations have been identified in 2 families with familial pheochromocytoma.

  20. BDNF Overexpression in the Forebrain Rescues Huntington’s Disease Phenotypes in YAC128 Mice

    PubMed Central

    Xie, Yuxiang; Hayden, Michael R.; Xu, Baoji

    2010-01-01

    Huntington’s disease (HD) is caused by an expansion of the polyglutamine tract at the amino-terminus of huntingtin. This mutation reduces levels of brain-derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis. Here we report that overexpression of BDNF in the forebrain rescues many disease phenotypes in YAC128 mice that express a full-length human huntingtin mutant with a 128-glutamine tract. The Bdnf transgene, under the control of the promoter for α subunit of Ca2+/calmodulin-dependent protein kinase II, greatly increased BDNF levels in the cerebral cortex and striatum. BDNF overexpression in YAC128 mice prevented loss and atrophy of striatal neurons and motor dysfunction, normalized expression of the striatal dopamine receptor D2 and enkephalin, and improved procedural learning. Furthermore, quantitative analyses of Golgi-impregnated neurons revealed a decreased spine density and abnormal spine morphology in striatal neurons of YAC128 mice, which was also reversed by increasing BDNF levels in the striatum. These results demonstrate that reduced striatal BDNF plays a crucial role in the HD pathogenesis and suggest that attempts to restore striatal BDNF level may have therapeutic effects to the disease. PMID:21048129

  1. Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease.

    PubMed

    Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R; Hamilton, Kristen; Grunberg, Neil E; Ariyannur, Prasanth S; Gahl, William A; Anikster, Yair; Mog, Steven; Hallows, William C; Denu, John M; Namboodiri, Aryan M A

    2010-06-01

    Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease.

  2. Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

    PubMed Central

    Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

    2011-01-01

    Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. PMID:21416485

  3. Cognitive phenotypes in parkinson's disease differ in terms of brain-network organization and connectivity.

    PubMed

    Lopes, Renaud; Delmaire, Christine; Defebvre, Luc; Moonen, Anja J; Duits, Annelien A; Hofman, Paul; Leentjens, Albert F G; Dujardin, Kathy

    2017-03-01

    Cognitive deficits are common in Parkinson's disease and we suspect that dysfunctions of connected brain regions can be the source of these deficits. The aim of the present study was to investigate changes in whole-brain intrinsic functional connectivity according to differences in cognitive profiles in Parkinson's disease. 119 participants were enrolled and divided into four groups according to their cognitive phenotypes (determined by a cluster analysis): (i) 31 cognitively intact patients (G1), (ii) 31 patients with only slight mental slowing (G2), (iii) 43 patients with mild to moderate deficits mainly in executive functions (G3), (iv) 14 patients with severe deficits in all cognitive domains (G4-5). Rs-fMRI whole-brain connectivity was examined by two complementary approaches: graph theory for studying network functional organization and network-based statistics (NBS) for exploring functional connectivity amongst brain regions. After adjustment for age, duration of formal education and center of acquisition, there were significant group differences for all functional organization indexes: functional organization decreased (G1 > G2 > G3 > G4-5) as cognitive impairment worsened. Between-group differences in functional connectivity (NBS corrected, P < 0.01) mainly concerned the ventral prefrontal, parietal, temporal and occipital cortices as well as the basal ganglia. In Parkinson's disease, brain network organization is progressively disrupted as cognitive impairment worsens, with an increasing number of altered connections between brain regions. We observed reduced connectivity in highly associative areas, even in patients with only slight mental slowing. The association of slowed mental processing with loss of connectivity between highly associative areas could be an early marker of cognitive impairment in Parkinson's disease and may contribute to the detection of prodromal forms of Parkinson's disease dementia. Hum Brain Mapp 38

  4. Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force

    PubMed Central

    Soto, M.; Abushakra, S.; Cummings, J.; Siffert, J.; Robert, P.; Vellas, B.; Lyketsos, C.G.

    2015-01-01

    BACKGROUND The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID:26413494

  5. Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel

    PubMed Central

    Al-Hamed, Mohamed H; Kurdi, Wesam; Alsahan, Nada; Alabdullah, Zainab; Abudraz, Rania; Tulbah, Maha; Alnemer, Maha; Khan, Rubina; Al-Jurayb, Haya; Alahmed, Ahmed; Tahir, Asma I; Khalil, Dania; Edwards, Noel; Al Abdulaziz, Basma; Binhumaid, Faisal S; Majid, Salma; Faquih, Tariq; El-Kalioby, Mohamed; Abouelhoda, Mohamed; Altassan, Nada; Monies, Dorota; Meyer, Brian; Sayer, John A; Albaqumi, Mamdouh

    2016-01-01

    Background Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease. Methods To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated. Results In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort. Conclusions In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians. PMID:26862157

  6. The c-MET Network as Novel Prognostic Marker for Predicting Bladder Cancer Patients with an Increased Risk of Developing Aggressive Disease

    PubMed Central

    Jeong, Phildu; Kim, Seon-Kyu; Kim, Seon-Young; Yan, Chunri; Seo, Sung Phil; Lee, Sang Keun; Kim, Jayoung; Kim, Wun-Jae

    2015-01-01

    Previous studies have shown that c-MET is overexpressed in cases of aggressive bladder cancer (BCa). Identification of crosstalk between c-MET and other RTKs such as AXL and PDGFR suggest that c-MET network genes (c-MET-AXL-PDGFR) may be clinically relevant to BCa. Here, we examine whether expression of c-MET network genes can be used to identify BCa patients at increased risk of developing aggressive disease. In vitro analysis, c-MET knockdown suppressed cell proliferation, invasion, and migration, and increased sensitivity to cisplatin-induced apoptosis. In addition, c-MET network gene (c-MET, AXL, and PDGFR) expression allowed discrimination of BCa tissues from normal control tissues and appeared to predict poor disease progression in non-muscle invasive BCa patients and poor overall survival in muscle invasive BCa patients. These results suggest that c-MET network gene expression is a novel prognostic marker for predicting which BCa patients have an increased risk of developing aggressive disease. These genes might be a useful marker for co-targeting therapy, and are expected to play an important role in improving both response to treatment and survival of BCa patients. PMID:26225770

  7. The c-MET Network as Novel Prognostic Marker for Predicting Bladder Cancer Patients with an Increased Risk of Developing Aggressive Disease.

    PubMed

    Kim, Young-Won; Yun, Seok Joong; Jeong, Phildu; Kim, Seon-Kyu; Kim, Seon-Young; Yan, Chunri; Seo, Sung Phil; Lee, Sang Keun; Kim, Jayoung; Kim, Wun-Jae

    2015-01-01

    Previous studies have shown that c-MET is overexpressed in cases of aggressive bladder cancer (BCa). Identification of crosstalk between c-MET and other RTKs such as AXL and PDGFR suggest that c-MET network genes (c-MET-AXL-PDGFR) may be clinically relevant to BCa. Here, we examine whether expression of c-MET network genes can be used to identify BCa patients at increased risk of developing aggressive disease. In vitro analysis, c-MET knockdown suppressed cell proliferation, invasion, and migration, and increased sensitivity to cisplatin-induced apoptosis. In addition, c-MET network gene (c-MET, AXL, and PDGFR) expression allowed discrimination of BCa tissues from normal control tissues and appeared to predict poor disease progression in non-muscle invasive BCa patients and poor overall survival in muscle invasive BCa patients. These results suggest that c-MET network gene expression is a novel prognostic marker for predicting which BCa patients have an increased risk of developing aggressive disease. These genes might be a useful marker for co-targeting therapy, and are expected to play an important role in improving both response to treatment and survival of BCa patients.

  8. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

    PubMed

    Alcalay, Roy N; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Mejia Santana, Helen; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L; Lubarr, Naomi; San Luciano, Marta; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

    2013-12-01

    The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

  9. Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease.

    PubMed

    Rodrigues, Filipe Brogueira; Byrne, Lauren; McColgan, Peter; Robertson, Nicola; Tabrizi, Sarah J; Leavitt, Blair R; Zetterberg, Henrik; Wild, Edward J

    2016-10-01

    Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = -0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of

  10. Phenotypic variation amongst genotypically homogeneous Legionella pneumophila serogroup 1 isolates: implications for the investigation of outbreaks of Legionnaires' disease.

    PubMed Central

    Harrison, T. G.; Saunders, N. A.; Haththotuwa, A.; Hallas, G.; Birtles, R. J.; Taylor, A. G.

    1990-01-01

    One hundred and seventy-nine isolates of Legionella pneumophila serogroup 1, obtained from a site associated with an outbreak of Legionnaires' disease, were examined by monoclonal antibody subgrouping, restriction fragment length polymorphism typing, restriction endonuclease analysis and plasmid content. Nine distinct phenotypes were detected but at the genotypic level all strains were closely related. The data presented indicate that phenotypic variation of a single parent strain can occur within an environmental site. The implications of these findings are discussed in relation to the investigation of outbreaks of Legionnaires' disease. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:1969803

  11. A transgenic zebrafish model expressing KIT-D816V recapitulates features of aggressive systemic mastocytosis.

    PubMed

    Balci, Tugce B; Prykhozhij, Sergey V; Teh, Evelyn M; Da'as, Sahar I; McBride, Eileen; Liwski, Robert; Chute, Ian C; Leger, Daniel; Lewis, Stephen M; Berman, Jason N

    2014-10-01

    Systemic mastocytosis (SM) is a rare myeloproliferative disease without curative therapy. Despite clinical variability, the majority of patients harbour a KIT-D816V mutation, but efforts to inhibit mutant KIT with tyrosine kinase inhibitors have been unsatisfactory, indicating a need for new preclinical approaches to identify alternative targets and novel therapies in this disease. Murine models to date have been limited and do not fully recapitulate the most aggressive forms of SM. We describe the generation of a transgenic zebrafish model expressing the human KIT-D816V mutation. Adult fish demonstrate a myeloproliferative disease phenotype, including features of aggressive SM in haematopoeitic tissues and high expression levels of endopeptidases, consistent with SM patients. Transgenic embryos demonstrate a cell-cycle phenotype with corresponding expression changes in genes associated with DNA maintenance and repair, such as reduced dnmt1. In addition, epcam was consistently downregulated in both transgenic adults and embryos. Decreased embryonic epcam expression was associated with reduced neuromast numbers, providing a robust in vivo phenotypic readout for chemical screening in KIT-D816V-induced disease. This study represents the first zebrafish model of a mast cell disease with an aggressive adult phenotype and embryonic markers that could be exploited to screen for novel agents in SM.

  12. Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design.

    PubMed

    Soto, Maria; Andrieu, Sandrine; Nourhashemi, Fati; Ousset, Pierre Jean; Ballard, Clive; Robert, Philippe; Vellas, Bruno; Lyketsos, Constantine G; Rosenberg, Paul B

    2014-09-16

    ABSTRACT Background: The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods: We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results: We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions: This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.

  13. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia.

    PubMed

    Cui, Bing; Chen, Liguang; Zhang, Suping; Mraz, Marek; Fecteau, Jessie-F; Yu, Jian; Ghia, Emanuela M; Zhang, Ling; Bao, Lei; Rassenti, Laura Z; Messer, Karen; Calin, George A; Croce, Carlo M; Kipps, Thomas J

    2014-07-24

    High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.

  14. APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Manocha, Gunjan D.; Floden, Angela M.; Rausch, Keiko; Kulas, Joshua A.; McGregor, Brett A.; Rojanathammanee, Lalida; Puig, Kelley R.; Puig, Kendra L.; Karki, Sanjib; Nichols, Michael R.; Darland, Diane C.; Porter, James E.

    2016-01-01

    Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid β (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP−/−) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP−/− cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP−/− mice compared with wild-type mice. The mAPP−/− mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aβ plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease. SIGNIFICANCE STATEMENT A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid β (Aβ) peptide within plaques robustly invested with reactive microglia. This supports the notion that Aβ stimulation of microglial activation is one source of brain inflammatory changes during disease. Aβ is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Aβ are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Aβ production to drive the microgliosis associated with AD brains. PMID:27511018

  15. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

    PubMed Central

    Rutherford, Nicola J.; Heckman, Michael G.; DeJesus-Hernandez, Mariely; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Rayaprolu, Sruti; Stewart, Heather; Finger, Elizabeth; Volkening, Kathryn; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Knopman, David S.; Kretzschmar, Hans A.; Neumann, Manuela; Caselli, Richard J.; White, Charles L.; Mackenzie, Ian R.; Petersen, Ronald C.; Strong, Michael J.; Miller, Bruce L.; Boeve, Bradley F.; Uitti, Ryan J.; Boylan, Kevin; Wszolek, Zbigniew K.; Graff-Radford, Neill R.; Dickson, Dennis W.; Ross, Owen A.; Rademakers, Rosa

    2012-01-01

    Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers. PMID:22840558

  16. Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice.

    PubMed

    Lebreton, Fanny; Cayzac, Sebastien; Pietropaolo, Susanna; Jeantet, Yannick; Cho, Yoon H

    2015-01-01

    In hereditary neurodegenerative Huntington's disease (HD), there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG) together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4 Hz) power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD.

  17. Phenotypic Diversity of Sickle Cell Disease in Patients with a Double Heterozygosity for Hb S and Hb D-Punjab.

    PubMed

    Torres, Lidiane S; Okumura, Jéssika V; Belini-Júnior, Édis; Oliveira, Renan G; Nascimento, Patrícia P; Silva, Danilo G H; Lobo, Clarisse L C; Oliani, Sonia M; Bonini-Domingos, Claudia R

    2016-09-01

    Phenotypic heterogeneity for sickle cell disease is associated to several genetic factors such as genotype for sickle cell disease, β-globin gene cluster haplotypes and Hb F levels. The coinheritance of Hb S (HBB: c.20A > T) and Hb D-Punjab (HBB: c.364G > C) results in a double heterozygosity, which constitutes one of the genotypic causes of sickle cell disease. This study aimed to assess the phenotypic diversity of sickle cell disease presented by carriers of the Hb S/Hb D-Punjab genotype and the Bantu [- + - - - -] haplotype. We evaluated medical records from 12 patients with sickle cell disease whose Hb S/Hb D-Punjab genotype and Bantu haplotype were confirmed by molecular analysis. Hb S and Hb D-Punjab levels were quantified by chromatographic analysis. Mean concentrations of Hb S and Hb D-Punjab were 44.8 ± 2.3% and 43.3 ± 1.8%, respectively. Painful crises were present in eight (66.7%) patients evaluated, representing the most common clinical event. Acute chest syndrome (ACS) was the second most prevalent manifestation, occurring in two individuals (16.7%). Three patients were asymptomatic, while another two exhibited greater diversity of severe clinical manifestations. Medical records here analyzed reported a significant clinical diversity in sickle cell disease ranging from the absence of symptoms to wide phenotypic variety. The sickle cell disease genotype, Bantu haplotype and hemoglobin (Hb) levels did not influence the clinical diversity. Thus, we concluded that the phenotypic variation in sickle cell disease was present within a specific genotype for disease regardless of the β-globin gene cluster haplotypes.

  18. The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice.

    PubMed

    Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney; Rakoczy, Sharlene G; Taglialatela, Giulio; Brown-Borg, Holly M; Combs, Colin K

    2016-04-01

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  19. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching.

    PubMed

    Howe, Douglas G; Bradford, Yvonne M; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-04

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, 'Fish' records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search.

  20. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

    PubMed Central

    Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-01

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

  1. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.

    PubMed

    Vinchi, Francesca; Costa da Silva, Milene; Ingoglia, Giada; Petrillo, Sara; Brinkman, Nathan; Zuercher, Adrian; Cerwenka, Adelheid; Tolosano, Emanuela; Muckenthaler, Martina U

    2016-01-28

    Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease.

  2. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease

    PubMed Central

    Vinchi, Francesca; Costa da Silva, Milene; Ingoglia, Giada; Petrillo, Sara; Brinkman, Nathan; Zuercher, Adrian; Cerwenka, Adelheid; Tolosano, Emanuela

    2016-01-01

    Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease. PMID:26675351

  3. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple negative MDA-MB-231 human breast cancer cells

    PubMed Central

    Browne, Gillian; Dragon, Julie A.; Hong, Deli; Messier, Terri L.; Gordon, Jonathan A. R.; Farina, Nicholas H.; Boyd, Joseph R.; VanOudenhove, Jennifer J.; Perez, Andrew W.; Zaidi, Sayyed K.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

    2016-01-01

    The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer. PMID:26749280

  4. Molecular basis of mast cell disease.

    PubMed

    Soucie, Erinn; Brenet, Fabienne; Dubreuil, Patrice

    2015-01-01

    Mastocytosis is an incurable and sometimes fatal haematological disorder grossly described as the accumulation of abnormal mast cells in the bone marrow and other organs causing tissue and organ damage. The clinical manifestations of this disease are extremely variable; disease phenotypes range from indolent to aggressive, and often present with associated non-mast cell haematological disorders (AHNMD), mainly myeloproliferative neoplasm and myelodysplastic syndromes. Recent efforts to genetically dissect the mechanisms that define aggressive and non-aggressive mastocytosis have generated a list of recurrent somatic mutations in mastocytosis patients that are associated with and may predict the evolution towards aggressive disease phenotypes. Here we review these mutations and discuss the molecular mechanisms associated with these mutations in an effort to better understand the biology of this disease and to predict its onset and evolution, with the ultimate goal of devising new and improved treatment strategies.

  5. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.

    PubMed

    Yang, Shao H; Chang, Sandy Y; Ren, Shuxun; Wang, Yibin; Andres, Douglas A; Spielmann, H Peter; Fong, Loren G; Young, Stephen G

    2011-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.

  6. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    PubMed

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  7. Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes

    PubMed Central

    Kurbegovic, Almira; Côté, Olivier; Couillard, Martin; Ward, Christopher J.; Harris, Peter C.; Trudel, Marie

    2010-01-01

    While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild-type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from ∼2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1TAG mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and ∼15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1TAG mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1TAG mouse model demonstrates that overexpression of wild-type Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD. PMID:20053665

  8. Abberant protein synthesis in G2019S LRRK2 Drosophila Parkinson disease-related phenotypes

    PubMed Central

    Martin, Ian; Abalde-Atristain, Leire; Kim, Jungwoo Wren; Dawson, Ted M; Dawson, Valina L

    2014-01-01

    LRRK2 mutations are a frequent cause of familial Parkinson disease (PD) and are also found in a number of sporadic PD cases. PD-linked G2019S and I2020T mutations in the kinase domain of LRRK2 result in elevated kinase activity, which is required for the toxicity of these pathogenic variants in cell and animal models of PD. We recently reported that LRRK2 interacts with and phosphorylates a number of mammalian ribosomal proteins, several of which exhibit increased phosphorylation via both G2019S and I2020T LRRK2. Blocking the phosphorylation of ribosomal protein s15 through expression of phospho-deficient T136A s15 prevents age-associated locomotor deficits and dopamine neuron loss caused by G2019S LRRK2 expression in Drosophila indicating that s15 is a pathogenic LRRK2 substrate. We previously described that G2019S LRRK2 causes an induction of bulk mRNA translation that is blocked by T136A s15 or the protein synthesis inhibitor anisomycin. Here, we report the protective effects of the eIF4E/eIF4G interaction inhibitor 4EGI-1, in preventing neurodegenerative phenotypes in G2019S LRRK2 flies, and discuss how our findings and those of other groups provide a framework to begin investigating the mechanistic impact of LRRK2 on translation. PMID:25483009

  9. The Use of Kosher Phenotyping for Mapping QTL Affecting Susceptibility to Bovine Respiratory Disease

    PubMed Central

    Eitam, Harel; Yishay, Moran; Schiavini, Fausta; Soller, Morris; Bagnato, Alessandro; Shabtay, Ariel

    2016-01-01

    Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle, caused by multiple pathogens that become more virulent in response to stress. As clinical signs often go undetected and various preventive strategies failed, identification of genes affecting BRD is essential for selection for resistance. Selective DNA pooling (SDP) was applied in a genome wide association study (GWAS) to map BRD QTLs in Israeli Holstein male calves. Kosher scoring of lung adhesions was used to allocate 122 and 62 animals to High (Glatt Kosher) and Low (Non-Kosher) resistant groups, respectively. Genotyping was performed using the Illumina BovineHD BeadChip according to the Infinium protocol. Moving average of -logP was used to map QTLs and Log drop was used to define their boundaries (QTLRs). The combined procedure was efficient for high resolution mapping. Nineteen QTLRs distributed over 13 autosomes were found, some overlapping previous studies. The QTLRs contain polymorphic functional and expression candidate genes to affect kosher status, with putative immunological and wound healing activities. Kosher phenotyping was shown to be a reliable means to map QTLs affecting BRD morbidity. PMID:27077383

  10. The Use of Kosher Phenotyping for Mapping QTL Affecting Susceptibility to Bovine Respiratory Disease.

    PubMed

    Lipkin, Ehud; Strillacci, Maria Giuseppina; Eitam, Harel; Yishay, Moran; Schiavini, Fausta; Soller, Morris; Bagnato, Alessandro; Shabtay, Ariel

    2016-01-01

    Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle, caused by multiple pathogens that become more virulent in response to stress. As clinical signs often go undetected and various preventive strategies failed, identification of genes affecting BRD is essential for selection for resistance. Selective DNA pooling (SDP) was applied in a genome wide association study (GWAS) to map BRD QTLs in Israeli Holstein male calves. Kosher scoring of lung adhesions was used to allocate 122 and 62 animals to High (Glatt Kosher) and Low (Non-Kosher) resistant groups, respectively. Genotyping was performed using the Illumina BovineHD BeadChip according to the Infinium protocol. Moving average of -logP was used to map QTLs and Log drop was used to define their boundaries (QTLRs). The combined procedure was efficient for high resolution mapping. Nineteen QTLRs distributed over 13 autosomes were found, some overlapping previous studies. The QTLRs contain polymorphic functional and expression candidate genes to affect kosher status, with putative immunological and wound healing activities. Kosher phenotyping was shown to be a reliable means to map QTLs affecting BRD morbidity.

  11. Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.

    PubMed

    Tazir, Meriem; Bellatache, Mounia; Nouioua, Sonia; Vallat, Jean-Michel

    2013-06-01

    The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT.

  12. Resting-state functional connectivity of subthalamic nucleus in different Parkinson's disease phenotypes.

    PubMed

    Wang, Zhan; Chen, Huimin; Ma, Huizi; Ma, Lingyan; Wu, Tao; Feng, Tao

    2016-12-15

    Previous studies showed that the subthalamic nucleus (STN) plays a crucial role in Parkinson's disease (PD) pathophysiology. During rest, PD phenotypes exhibit different STN functional connectivity. STN functional connectivity was examined in 31 PD patients [12 tremor-dominant (TD) and 19 posture instability gait difficulty (PIGD)] and 22 healthy controls (HC). Compared with controls and PIGD patients, the TD patients exhibited higher functional connectivity between the bilateral STN and the left cerebellar anterior lobe. Compared with the TD and HC groups, in the PIGD subgroup functional connectivity was lower between the left putamen and the STN, as well as between the pons and the STN. In the PIGD subgroup, functional connectivity was greater between the STN and bilateral occipital lobe, which positively correlated with PIGD scores in PD patients. Additionally, STN-cerebellum connectivity positively correlated with the tremor score, and STN-putamen connectivity negatively correlated with the PIGD score in PD patients. PD subtypes with distinguished STN functional connectivity might explain the various pathophysiological mechanisms in tremor and gait disorders. Increased coupling between the STN and cerebellum might underlie the neural substrate of PD tremors. Lower functional connectivity between the STN and putamen might underpin PD gait and posture disturbances, while higher functional connectivity between the STN and visual cortex might play a compensatory role.

  13. Increased Epicardial Adipose Tissue Is Associated with the Airway Dominant Phenotype of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Higami, Yuichi; Ogawa, Emiko; Ryujin, Yasushi; Goto, Kenichi; Seto, Ruriko; Wada, Hiroshi; Tho, Nguyen Van; Lan, Le Thi Tuyet; Paré, Peter D.; Nakano, Yasutaka

    2016-01-01

    Background Epicardial adipose tissue (EAT) has been shown to be a non-invasive marker that predicts the progression of cardiovascular disease (CVD). It has been reported that the EAT volume is increased in patients with chronic obstructive pulmonary disease (COPD). However, little is known about which phenotypes of COPD are associated with increased EAT. Methods One hundred and eighty smokers who were referred to the clinic were consecutively enrolled. A chest CT was used for the quantification of the emphysematous lesions, airway lesions, and EAT. These lesions were assessed as the percentage of low attenuation volume (LAV%), the square root of airway wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) and the EAT area, respectively. The same measurements were made on 225 Vietnamese COPD patients to replicate the results. Results Twenty-six of the referred patients did not have COPD, while 105 were diagnosed as having COPD based on a FEV1/FVC<0.70. The EAT area was significantly associated with age, BMI, FEV1 (%predicted), FEV1/FVC, self-reported hypertension, self-reported CVD, statin use, LAV%, and √Aaw at Pi10 in COPD patients. The multiple regression analyses showed that only BMI, self-reported CVD and √Aaw at Pi10 were independently associated with the EAT area (R2 = 0.51, p<0.0001). These results were replicated in the Vietnamese population. Conclusions The EAT area is independently associated with airway wall thickness. Because EAT is also an independent predictor of CVD risk, these data suggest a mechanistic link between the airway predominant form of COPD and CVD. PMID:26866482

  14. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease.

    PubMed

    Ossenkoppele, Rik; Cohn-Sheehy, Brendan I; La Joie, Renaud; Vogel, Jacob W; Möller, Christiane; Lehmann, Manja; van Berckel, Bart N M; Seeley, William W; Pijnenburg, Yolande A; Gorno-Tempini, Maria L; Kramer, Joel H; Barkhof, Frederik; Rosen, Howard J; van der Flier, Wiesje M; Jagust, William J; Miller, Bruce L; Scheltens, Philip; Rabinovici, Gil D

    2015-11-01

    Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, "visual variant," n=93), logopenic variant primary progressive aphasia (lvPPA, "language variant," n=74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n=114) and late age-of-onset (LOAD, >65 years, n=114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n=80). Even at the earliest clinical stage (CDR=0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD.

  15. Loss of Secreted Frizzled-Related Protein 4 Correlates with an Aggressive Phenotype and Predicts Poor Outcome in Ovarian Cancer Patients

    PubMed Central

    Nixdorf, Sheri; Ford, Caroline E.; Olivier, Jake; Caduff, Rosmarie; Scurry, James P.; Guertler, Rea; Hornung, Daniela; Mueller, Renato; Fink, Daniel A.; Hacker, Neville F.; Heinzelmann-Schwarz, Viola A.

    2012-01-01

    Background Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. Methodology/Principal Findings We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Conclusions/Significance Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets. PMID:22363760

  16. HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes.

    PubMed

    Cui, J; Xia, T; Xie, D; Gao, Y; Jia, Z; Wei, D; Wang, L; Huang, S; Quan, M; Xie, K

    2016-09-08

    Hepatocyte growth factor (HGF)/Met signaling has critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. The mechanistic role of cross talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including retrovirus-associated DNA sequences/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA.

  17. Phenotypic & Genotypic Characteristics of Inflammatory Bowel Disease (IBD) in French-Canadians: comparison with a large North American repository

    PubMed Central

    Bhat, Mamatha; Nguyen, Geoffrey C.; Pare, Pierre; Lahaie, Raymond; Deslandres, Colette; Bernard, Edmond-Jean; Aumais, Guy; Jobin, Gilles; Wild, Gary; Cohen, Albert; Langelier, Diane; Brant, Steven; Dassopoulos, Themistocles; McGovern, Dermot; Torres, Esther; Duerr, Richard; Regueiro, Miguel; Silverberg, Mark S; Steinhart, Hillary; Griffiths, Anne M.; Elkadri, Abdul; Cho, Judy; Proctor, Deborah; Goyette, Philippe; Rioux, John; Bitton, Alain

    2009-01-01

    BACKGROUND Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French-Canadians, the most prominent founder population in North America. METHODS Using well-characterized phenotype data in the NIDDK-IBD Genetics Consortium repository on IBD patients, we compared phenotypic characteristics of 202 French-Canadians to those of 1287 other Caucasian patients. These included: diagnosis, anatomical location, disease behaviour, extraintestinal manifestations, surgical history, and family history of IBD. RESULTS French-Canadian CD patients were less likely to have stricturing disease (11 vs 21%, P=0.005; OR 0.45, 95% CI: 0.24– 0.85). Using a stringent definition of ethnicity (3 out of 4 grandparents being French-Canadian, as opposed to self-report, n= 148), French-Canadians had a tendency towards developing fistulizing CD (37% vs 28%, p= 0.07), and there was an increased prevalence of sacroiliitis among French-Canadians with IBD (4% vs 2%, p=0.045). Among French-Canadians, the numbers of current smokers in CD (40 vs 25%, p=0.006) and former smokers in UC (35% vs 20%, p=0.03) were significantly higher. The prevalence of one of the three main variant NOD2 SNPs among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French-Canadians (75% versus 0%, P=0.006). CONCLUSION French-Canadians exhibit an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to management of IBD in this population. PMID:19513023

  18. Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.

    PubMed

    Brownjohn, Philip W; Smith, James; Portelius, Erik; Serneels, Lutgarde; Kvartsberg, Hlin; De Strooper, Bart; Blennow, Kaj; Zetterberg, Henrik; Livesey, Frederick J

    2017-03-06

    Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation.

  19. Effect of the IL-1 Receptor Antagonist Kineret® on Disease Phenotype in mdx Mice

    PubMed Central

    Benny Klimek, Margaret E.; Sali, Arpana; Rayavarapu, Sree; Van der Meulen, Jack H.; Nagaraju, Kanneboyina

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked muscle disease caused by mutations in the dystrophin gene. The pathology of DMD manifests in patients with progressive muscle weakness, loss of ambulation and ultimately death. One of the characteristics of DMD is muscle inflammation, and dystrophin-deficient skeletal muscles produce higher levels of the pro-inflammatory cytokine interleukin 1β (IL-1β) in response to toll like receptor (TLR) stimulation compared to controls; therefore, blocking the IL-1β pathway could improve the disease phenotype in mdx mice, a mouse model of DMD. Kineret® or IL-1Ra is a recombinant IL-1 receptor antagonist approved by the FDA for treating rheumatoid arthritis. To determine the efficacy of IL-1Ra in a DMD model, we administered subcutaneous injections of saline control or IL-1Ra (25 mg/kg/day) to mdx mice daily for 45 days beginning at 5 weeks of age. Functional and histological parameters were measured at the conclusion of the study. IL-1Ra only partially inhibited this signaling pathway in this study; however, there were still interesting observations to be noted. For example, although not significantly changed, splenocytes from the IL-1Ra-treated group secreted less IL-1β after LPS stimulation compared to control mice indicating a blunted response and incomplete inhibition of the pathway (37% decrease). In addition, normalized forelimb grip strength was significantly increased in IL-1Ra-treated mice. There were no changes in EDL muscle-specific force measurements, histological parameters, or motor coordination assessments in the dystrophic mice after IL-1Ra treatment. There was a significant 27% decrease in the movement time and total distance traveled by the IL-1Ra treated mice, correlating with previous studies examining effects of IL-1 on behavior. Our studies indicate partial blocking of IL-1β with IL-1Ra significantly altered only a few behavioral and strength related disease parameters; however, treatment with

  20. Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD).

    PubMed

    Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino

    2011-08-01

    Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS.

  1. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    PubMed

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

  2. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

    PubMed Central

    Jin, Meiling; Xie, Yuansheng; Chen, Zhiqiang; Liao, Yujie; Li, Zuoxiang; Hu, Panpan; Qi, Yan; Yin, Zhiwei; Li, Qinggang; Fu, Ping; Chen, Xiangmei

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning. PMID:27782177

  3. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies.

    PubMed

    Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D

    2012-02-01

    Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

  4. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

    PubMed Central

    Acland, Gregory M.

    2014-01-01

    Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision. PMID:22065099

  5. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    PubMed

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

  6. Suppression of Heregulin-β1/HER2-Modulated Invasive and Aggressive Phenotype of Breast Carcinoma by Pterostilbene via Inhibition of Matrix Metalloproteinase-9, p38 Kinase Cascade and Akt Activation

    PubMed Central

    Pan, Min-Hsiung; Lin, Ying-Ting; Lin, Chih-Li; Wei, Chi-Shiang; Ho, Chi-Tang; Chen, Wei-Jen

    2011-01-01

    Invasive breast cancer is the major cause of death among females and its incidence is closely linked to HER2 (human epidermal growth factor receptor 2) overexpression. Pterostilbene, a natural analog of resveratrol, exerts its cancer chemopreventive activity similar to resveratrol by inhibiting cancer cell proliferation and inducing apoptosis. However, the anti-invasive effect of pterostilbene on HER2-bearing breast cancer has not been evaluated. Here, we used heregulin-β1 (HRG-β1), a ligand for HER3, to transactivate HER2 signaling. We found that pterostilbene was able to suppress HRG-β1-mediated cell invasion, motility and cell transformation of MCF-7 human breast carcinoma through down-regulation of matrix metalloproteinase-9 (MMP-9) activity and growth inhibition. In parallel, pterostilbene also inhibited protein and mRNA expression of MMP-9 driven by HRG-β1, suggesting that pterostilbene decreased HRG-β1-mediated MMP-9 induction via transcriptional regulation. Examining the signaling pathways responsible for HRG-β1-associated MMP-9 induction and growth inhibition, we observed that pterostilbene, as well as SB203580 (p38 kinase inhibitor), can abolish the phosphorylation of p38 mitogen-activated protein kinase (p38 kinase), a downstream HRG-β1-responsive kinase responsible for MMP-9 induction. In addition, HRG-β1-driven Akt phosphorylation required for cell proliferation was also suppressed by pterostilbene. Taken together, our present results suggest that pterostilbene may serve as a chemopreventive agent to inhibit HRG-β1/HER2-mediated aggressive and invasive phenotype of breast carcinoma through down-regulation of MMP-9, p38 kinase and Akt activation. PMID:19617202

  7. Antennal phenotype of Mexican haplogroups of the Triatoma dimidiata complex, vectors of Chagas disease.

    PubMed

    May-Concha, Irving; Guerenstein, Pablo G; Ramsey, Janine M; Rojas, Julio C; Catalá, Silvia

    2016-06-01

    Triatoma dimidiata (Latreille) is a species complex that spans North, Central, and South America and which is a key vector of all known discrete typing units (DTU) of Trypanosoma cruzi, the etiologic agent of Chagas disease. Morphological and genetic studies indicate that T. dimidiata is a species complex with three principal haplogroups (hg) in Mexico. Different markers and traits are still inconclusive regarding if other morphological differentiation may indicate probable behavioral and vectorial divergences within this complex. In this paper we compared the antennae of three Mexican haplogroups (previously verified by molecular markers ND4 and ITS-2) and discussed possible relationships with their capacity to disperse and colonized new habitats. The abundance of each type of sensillum (bristles, basiconics, thick- and thin-walled trichoids) on the antennae of the three haplogroups, were measured under light microscopy and compared using Kruskal-Wallis non-parametric and multivariate non-parametric analyses. Discriminant analyses indicate significant differences among the antennal phenotype of haplogroups either for adults and some nymphal stages, indicating consistency of the character to analyze intraspecific variability within the complex. The present study shows that the adult antennal pedicel of the T. dimidiata complex have abundant chemosensory sensilla, according with good capacity for dispersal and invasion of different habitats also related to their high capacity to adapt to conserved as well as modified habitats. However, the numerical differences among the haplogroups are suggesting variations in that capacity. The results here presented support the evidence of T. dimidiata as a species complex but show females and males in a different way. Given the close link between the bug's sensory system and its habitat and host-seeking behavior, AP characterization could be useful to complement genetic, neurological and ethological studies of the closely

  8. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease.

    PubMed

    de Wee, Eva M; Sanders, Yvonne V; Mauser-Bunschoten, Eveline P; van der Bom, Johanna G; Degenaar-Dujardin, Manon E L; Eikenboom, Jeroen; de Goede-Bolder, Arja; Laros-van Gorkom, Britta A P; Meijer, Karina; Hamulyák, Karly; Nijziel, Marten R; Fijnvandraat, Karin; Leebeek, Frank W G

    2012-10-01

    We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

  9. Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease.

    PubMed

    Dave, Kuldip D; De Silva, Shehan; Sheth, Niketa P; Ramboz, Sylvie; Beck, Melissa J; Quang, Changyu; Switzer, Robert C; Ahmad, Syed O; Sunkin, Susan M; Walker, Dan; Cui, Xiaoxia; Fisher, Daniel A; McCoy, Aaron M; Gamber, Kevin; Ding, Xiaodong; Goldberg, Matthew S; Benkovic, Stanley A; Haupt, Meredith; Baptista, Marco A S; Fiske, Brian K; Sherer, Todd B; Frasier, Mark A

    2014-10-01

    Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development.

  10. Brugada Syndrome and Early Repolarisation: Distinct Clinical Entities or Different Phenotypes of the Same Genetic Disease?

    PubMed Central

    Caputo, Maria Luce; Regoli, François; Moccetti, Tiziano; Brugada, Pedro; Auricchio, Angelo

    2016-01-01

    Brugada and early repolarisation (ER) syndromes are currently considered two distinct inherited electrical disorders with overlapping clinical and electrocardiographic features. A considerable number of patients diagnosed with ER syndrome have a genetic mutation related to Brugada syndrome (BrS). Due to the high variable phenotypic manifestation, patients with BrS may present with inferolateral repolarisation abnormalities only, resembling the ER pattern. Moreover, the complex genotype–phenotype interaction in BrS can lead to the occurrence of mixed phenotypes with ER syndrome. The first part of this review focuses on specific clinical and electrocardiographic features of BrS and ER syndrome, highlighting the similarity shared by the two primary electrical disorders. The genetic background, with emphasis on the complexity of genotype–phenotype interaction, is explored in the second part of this review. PMID:27617086

  11. Simultaneous Modeling of Disease Status and Clinical Phenotypes To Increase Power in Genome-Wide Association Studies.

    PubMed

    Bilow, Michael; Crespo, Fernando; Pan, Zhicheng; Eskin, Eleazar; Eyheramendy, Susana

    2017-03-01

    Genome-wide association studies have identified thousands of variants implicated in dozens of complex diseases. Most studies collect individuals with and without disease and search for variants with different frequencies between the groups. For many of these studies, additional disease traits are also collected. Jointly modeling clinical phenotype and disease status is a promising way to increase power to detect true associations between genetics and disease. In particular, this approach increases the potential for discovering genetic variants that are associated with both a clinical phenotype and a disease. Standard multivariate techniques fail to effectively solve this problem, because their case-control status is discrete and not continuous. Standard approaches to estimate model parameters are biased due to the ascertainment in case-control studies. We present a novel method that resolves both of these issues for simultaneous association testing of genetic variants that have both case status and a clinical covariate. We demonstrate the utility of our method using both simulated data and the Northern Finland Birth Cohort data.

  12. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

    PubMed

    Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J; Lopez, Rachel; Rosa Garrido, Manuel; Kim, Joseph; Wisniewski, Nicholas; Rau, Christoph D; Wang, Jessica J; Weiss, James N; Wang, Yibin; Lusis, Aldons J; Vondriska, Thomas M

    2016-08-01

    Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.

  13. Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

    PubMed Central

    2015-01-01

    Prion diseases are a heterogeneous group of neurodegenerative disorders affecting various mammals including humans. Prion diseases are characterized by a misfolding of the host-encoded prion protein (PrPC) into a pathological isoform termed PrPSc. In wild-type mice, PrPC is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and PrPSc typically accumulates in diffuse nonamyloid deposits with gray matter spongiosis. By contrast, when mice lacking the GPI anchor are infected with the same prion inoculum, PrPSc accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis. In order to evaluate whether different host biochemical pathways were implicated in these two phenotypically distinct prion disease models, we utilized a proteomics approach. In both models, infected mice displayed evidence of a neuroinflammatory response and complement activation. Proteins involved in cell death and calcium homeostasis were also identified in both phenotypes. However, mitochondrial pathways of apoptosis were implicated only in the nonamyloid form, whereas metal binding and synaptic vesicle transport were more disrupted in the amyloid phenotype. Thus, following infection with a single prion strain, PrPC anchoring to the plasma membrane correlated not only with the type of PrPSc deposition but also with unique biochemical pathways associated with pathogenesis. PMID:25140793

  14. Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells

    PubMed Central

    Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha; Jang, Yoon-Young

    2016-01-01

    Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults. PMID:27570479

  15. Systematic review of rheumatic disease phenotypes and outcomes in the Indigenous populations of Canada, the USA, Australia and New Zealand.

    PubMed

    Hurd, Kelle; Barnabe, Cheryl

    2017-04-01

    We performed a systematic review designed to characterize clinical phenotypes and outcomes in Indigenous populations with rheumatic disease to enhance the understanding of how rheumatic disease presents in Indigenous populations and allow for better projection of the healthcare needs of the communities affected. A systematic search was performed in medical (Medline, EMBASE, CINAHL), Indigenous and conference abstract databases (to June 2015). Search terms for Indigenous populations were combined with terms for inflammatory arthritis conditions, connective tissue disorders, crystal arthritis and osteoarthritis. Studies were included if they reported on disease features, disease activity measures, or patient-reported outcomes in Canadian, American, Australian or New Zealand Indigenous populations. Data were extracted in duplicate, and a narrative summary was prepared. A total of 5269 titles and abstracts were reviewed, of which 504 underwent full-text review and 85 met inclusion criteria. Nearly all the studies described outcomes in the North American populations (n = 77), with only four studies from Australia and four studies from New Zealand. The majority of studies were in rheumatoid arthritis (n = 31) and systemic lupus erythematosus (n = 19). Indigenous patients with rheumatoid arthritis had higher disease activity and reported more significant impact on patient-reported outcomes and quality of life than non-Indigenous patients. Spondyloarthropathy features were described in North American populations, with most patients having advanced manifestations. In systemic lupus erythematosus, nephritis was more frequent in Indigenous populations. Gout and osteoarthritis were more severe in New Zealand Maori populations. The existing literature supports differences in disease phenotype and severity in Indigenous populations of Canada, America, Australia and New Zealand. We encourage investigators in this area of research to undertake contemporary studies that

  16. Systematic drug repositioning for a wide range of diseases with integrative analyses of phenotypic and molecular data.

    PubMed

    Iwata, Hiroaki; Sawada, Ryusuke; Mizutani, Sayaka; Yamanishi, Yoshihiro

    2015-02-23

    Drug repositioning, or the application of known drugs to new indications, is a challenging issue in pharmaceutical science. In this study, we developed a new computational method to predict unknown drug indications for systematic drug repositioning in a framework of supervised network inference. We defined a descriptor for each drug-disease pair based on the phenotypic features of drugs (e.g., medicinal effects and side effects) and various molecular features of diseases (e.g., disease-causing genes, diagnostic markers, disease-related pathways, and environmental factors) and constructed a statistical model to predict new drug-disease associations for a wide range of diseases in the International Classification of Diseases. Our results show that the proposed method outperforms previous methods in terms of accuracy and applicability, and its performance does not depend on drug chemical structure similarity. Finally, we performed a comprehensive prediction of a drug-disease association network consisting of 2349 drugs and 858 diseases and described biologically meaningful examples of newly predicted drug indications for several types of cancers and nonhereditary diseases.

  17. Elucidating the genotype-phenotype relationships and network perturbations of human shared and specific disease genes from an evolutionary perspective.

    PubMed

    Begum, Tina; Ghosh, Tapash Chandra

    2014-10-05

    To date, numerous studies have been attempted to determine the extent of variation in evolutionary rates between human disease and nondisease (ND) genes. In our present study, we have considered human autosomal monogenic (Mendelian) disease genes, which were classified into two groups according to the number of phenotypic defects, that is, specific disease (SPD) gene (one gene: one defect) and shared disease (SHD) gene (one gene: multiple defects). Here, we have compared the evolutionary rates of these two groups of genes, that is, SPD genes and SHD genes with respect to ND genes. We observed that the average evolutionary rates are slow in SHD group, intermediate in SPD group, and fast in ND group. Group-to-group evolutionary rate differences remain statistically significant regardless of their gene expression levels and number of defects. We demonstrated that disease genes are under strong selective constraint if they emerge through edgetic perturbation or drug-induced perturbation of the interactome network, show tissue-restricted expression, and are involved in transmembrane transport. Among all the factors, our regression analyses interestingly suggest the independent effects of 1) drug-induced perturbation and 2) the interaction term of expression breadth and transmembrane transport on protein evolutionary rates. We reasoned that the drug-induced network disruption is a combination of several edgetic perturbations and, thus, has more severe effect on gene phenotypes.

  18. Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

    PubMed

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-04-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

  19. Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother.

    PubMed

    Manoura, Antonia; Korakaki, Eftychia; Hatzidaki, Eleftheria; Saitakis, Emmanuel; Maraka, Sofia; Papamastoraki, Isabella; Matalliotakis, Emmanuel; Foundouli, Kaliopi; Giannakopoulou, Christine

    2007-01-01

    Very few people do not express any Kell antigens on their red blood cells (K0 phenotype). They can be immunized by transfusion or pregnancy and develop antibodies against Kell system antigens. These maternal antibodies can cause severe hemolytic disease of the fetus/newborn, as a result of the suppression of erythropoiesis and hemolysis. Multiple intrauterine transfusions in the management of severe hemolytic disease have been shown to cause erythropoietic suppression as well. Recombinant erythropoietin has been successfully used in the management of late anemia of infants with Rh hemolytic disease and in 1 case of KEL1 (Kell)-associated hemolytic disease. The authors present the case of severe hemolytic disease of a newborn due to KEL5 (Ku) isoimmunization of his K0 phenotype mother. Regular intrauterine transfusions were performed to manage the severe fetal anemia (Hb 3 g/dL). A male infant was born at the 36th week of gestation having normal hemoglobin (15.8 g/dL) and developed only mild hyperbilirubinemia. On the 15th day of life, the infant's hematocrit had fallen to 27.3%, with low reticulocyte count and low erythropoietin level. The infant was managed successfully with recombinant erythropoietin.

  20. Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

    PubMed Central

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V.; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-01-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. PMID:25880443

  1. Developing a Manually Annotated Clinical Document Corpus to Identify Phenotypic Information for Inflammatory Bowel Disease

    PubMed Central

    South, Brett R; Shen, Shuying; Jones, Makoto; Garvin, Jennifer; Samore, Matthew H; Chapman, Wendy W; Gundlapalli, Adi V

    2009-01-01

    Background Natural Language Processing (NLP) systems can be used for specific Information Extraction (IE) tasks such as extracting phenotypic data from the electronic medical record (EMR). These data are useful for translational research and are often found only in free text clinical notes. A key required step for IE is the manual annotation of clinical corpora and the creation of a reference standard for (1) training and validation tasks and (2) to focus and clarify NLP system requirements. These tasks are time consuming, expensive, and require considerable effort on the part of human reviewers. Methods Using a set of clinical documents from the VA EMR for a particular use case of interest we identify specific challenges and present several opportunities for annotation tasks. We demonstrate specific methods using an open source annotation tool, a customized annotation schema, and a corpus of clinical documents for patients known to have a diagnosis of Inflammatory Bowel Disease (IBD). We report clinician annotator agreement at the document, concept, and concept attribute level. We estimate concept yield in terms of annotated concepts within specific note sections and document types. Results Annotator agreement at the document level for documents that contained concepts of interest for IBD using estimated Kappa statistic (95% CI) was very high at 0.87 (0.82, 0.93). At the concept level, F-measure ranged from 0.61 to 0.83. However, agreement varied greatly at the specific concept attribute level. For this particular use case (IBD), clinical documents producing the highest concept yield per document included GI clinic notes and primary care notes. Within the various types of notes, the highest concept yield was in sections representing patient assessment and history of presenting illness. Ancillary service documents and family history and plan note sections produced the lowest concept yield. Conclusions Challenges include defining and building appropriate annotation

  2. Developing a manually annotated clinical document corpus to identify phenotypic information for inflammatory bowel disease

    PubMed Central

    South, Brett R; Shen, Shuying; Jones, Makoto; Garvin, Jennifer; Samore, Matthew H; Chapman, Wendy W; Gundlapalli, Adi V

    2009-01-01

    Background Natural Language Processing (NLP) systems can be used for specific Information Extraction (IE) tasks such as extracting phenotypic data from the electronic medical record (EMR). These data are useful for translational research and are often found only in free text clinical notes. A key required step for IE is the manual annotation of clinical corpora and the creation of a reference standard for (1) training and validation tasks and (2) to focus and clarify NLP system requirements. These tasks are time consuming, expensive, and require considerable effort on the part of human reviewers. Methods Using a set of clinical documents from the VA EMR for a particular use case of interest we identify specific challenges and present several opportunities for annotation tasks. We demonstrate specific methods using an open source annotation tool, a customized annotation schema, and a corpus of clinical documents for patients known to have a diagnosis of Inflammatory Bowel Disease (IBD). We report clinician annotator agreement at the document, concept, and concept attribute level. We estimate concept yield in terms of annotated concepts within specific note sections and document types. Results Annotator agreement at the document level for documents that contained concepts of interest for IBD using estimated Kappa statistic (95% CI) was very high at 0.87 (0.82, 0.93). At the concept level, F-measure ranged from 0.61 to 0.83. However, agreement varied greatly at the specific concept attribute level. For this particular use case (IBD), clinical documents producing the highest concept yield per document included GI clinic notes and primary care notes. Within the various types of notes, the highest concept yield was in sections representing patient assessment and history of presenting illness. Ancillary service documents and family history and plan note sections produced the lowest concept yield. Conclusion Challenges include defining and building appropriate annotation

  3. Quantitative, Image-Based Phenotyping Methods Provide Insight into Spatial and Temporal Dimensions of Plant Disease1[OPEN

    PubMed Central

    Fentress, Sarah J.; Sher, Joel W.; Berry, Jeffrey C.; Pretz, Chelsea

    2016-01-01

    Plant disease symptoms exhibit complex spatial and temporal patterns that are challenging to quantify. Image-based phenotyping approaches enable multidimensional characterization of host-microbe interactions and are well suited to capture spatial and temporal data that are key to understanding disease progression. We applied image-based methods to investigate cassava bacterial blight, which is caused by the pathogen Xanthomonas axonopodis pv. manihotis (Xam). We generated Xam strains in which individual predicted type III effector (T3E) genes were mutated and applied multiple imaging approaches to investigate the role of these proteins in bacterial virulence. Specifically, we quantified bacterial populations, water-soaking disease symptoms, and pathogen spread from the site of inoculation over time for strains with mutations in avrBs2, xopX, and xopK as compared to wild-type Xam. ∆avrBs2 and ∆xopX both showed reduced growth in planta and delayed spread through the vasculature system of cassava. ∆avrBs2 exhibited reduced water-soaking symptoms at the site of inoculation. In contrast, ∆xopK exhibited enhanced induction of disease symptoms at the site of inoculation but reduced spread through the vasculature. Our results highlight the importance of adopting a multipronged approach to plant disease phenotyping to more fully understand the roles of T3Es in virulence. Finally, we demonstrate that the approaches used in this study can be extended to many host-microbe systems and increase the dimensions of phenotype that can be explored. PMID:27443602

  4. Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease.

    PubMed

    Suva, Larry J; Hartman, Eric; Dilley, Joshua D; Russell, Susan; Akel, Nisreen S; Skinner, Robert A; Hogue, William R; Budde, Ulrich; Varughese, Kottayil I; Kanaji, Taisuke; Ware, Jerry

    2008-02-01

    The platelet glycoprotein Ib-IX receptor binds surface-bound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass.

  5. Bicuspid Aortic Valve and Thoracic Aortic Aneurysm: Three Patient Populations, Two Disease Phenotypes, and One Shared Genotype

    PubMed Central

    Hinton, Robert B.

    2012-01-01

    Bicuspid aortic valve (BAV) and thoracic aortic aneurysm (TAA) are two discrete cardiovascular phenotypes characterized by latent progressive disease states. There is a clear association between BAV and TAA; however the nature and extent of this relationship is unclear. There are both distinct and overlapping developmental pathways that have been established to contribute to the formation of the aortic valve and the aortic root, and the mature anatomy of these different tissue types is intimately intertwined. Likewise, human genetics studies have established apparently separate and common contributions to these clinical phenotypes, suggesting complex inheritance and a shared genetic basis and translating 3 patient populations, namely, BAV, TAA, or both, into a common but diverse etiology. A better understanding of the BAV-TAA association will provide an opportunity to leverage molecular information to modify clinical care through more sophisticated diagnostic testing, improved counseling, and ultimately new pharmacologic therapies. PMID:22970404

  6. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

    PubMed

    Krause, Amanda; Mitchell, Claire; Essop, Fahmida; Tager, Susan; Temlett, James; Stevanin, Giovanni; Ross, Christopher; Rudnicki, Dobrila; Margolis, Russell

    2015-10-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.

  7. JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

    PubMed Central

    Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

    2015-01-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

  8. LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems.

    PubMed

    Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

    Characterizing a rare disease diagnosis for a given patient is often made through expert's networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine.

  9. LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems

    PubMed Central

    Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

    2015-01-01

    Characterizing a rare disease diagnosis for a given patient is often made through expert’s networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine. PMID:26958175

  10. Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation

    PubMed Central

    Gadd, Victoria L.; Patel, Preya J.; Jose, Sara; Horsfall, Leigh

    2016-01-01

    Background and Aims Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Methods Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. Results The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Conclusions Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which

  11. Maternal Genetic Mutations as Gestational and Early Life Influences in Producing Psychiatric Disease-Like Phenotypes in Mice

    PubMed Central

    Gleason, Georgia; Zupan, Bojana; Toth, Miklos

    2011-01-01

    Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate) genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g., maternal genetic variability and mutations). The focus of this review is “maternal genotype effects” that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin 1A receptor (5-HT1AR) and the fmr1 gene (encoding the fragile X mental retardation protein) in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Offspring of 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations. PMID:21629836

  12. Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome

    PubMed Central

    Okata, Shinichiro; Yuasa, Shinsuke; Suzuki, Tomoyuki; Ito, Shogo; Makita, Naomasa; Yoshida, Tetsu; Li, Min; Kurokawa, Junko; Seki, Tomohisa; Egashira, Toru; Aizawa, Yoshiyasu; Kodaira, Masaki; Motoda, Chikaaki; Yozu, Gakuto; Shimojima, Masaya; Hayashiji, Nozomi; Hashimoto, Hisayuki; Kuroda, Yusuke; Tanaka, Atsushi; Murata, Mitsushige; Aiba, Takeshi; Shimizu, Wataru; Horie, Minoru; Kamiya, Kaichiro; Furukawa, Tetsushi; Fukuda, Keiichi

    2016-01-01

    SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties. PMID:27677334

  13. Aggressive periodontitis: The unsolved mystery.

    PubMed

    Clark, Danielle; Febbraio, Maria; Levin, Liran

    2017-01-01

    Aggressive periodontal disease is an oral health mystery. Our current understanding of this disease is that specific bacteria invade the oral cavity and the host reacts with an inflammatory response leading to mass destruction of the alveolar bone. Aggressive periodontal disease is typically observed in a population under the age of 30 and occurs so rapidly that it is difficult to treat. Unfortunately, the consequence of this disease frequently involves tooth extractions. As a result, the aftermath is chewing disability and damage to self-esteem due to an altered self-image. Furthermore, patients are encumbered by frequent dental appointments which have an economic impact in regards to both personal financial strain and absent days in the workplace. Aggressive periodontal disease has a tremendous effect on patients' overall quality of life and needs to be investigated more extensively in order to develop methods for earlier definitive diagnosis and effective treatments. One of the mysteries of aggressive periodontal disease is the relatively nominal amount of plaque present on the tooth surface in relation to the large amount of bone loss. There seems to be a hidden factor that lies between the response by the patient's immune system and the bacterial threat that is present. A better mechanistic understanding of this disease is essential to provide meaningful care and better outcomes for patients.

  14. The Role of Alcohol Consumption in the Aetiology of Different Cardiovascular Disease Phenotypes: a CALIBER Study

    ClinicalTrials.gov

    2013-05-28

    Chronic Stable Angina; Unstable Angina; Coronary Heart Disease Not Otherwise Specified; Acute Myocardial Infarction; Heart Failure; Ventricular Arrhythmias; Cardiac Arrest; Abdominal Aortic Aneurysm; Peripheral Arterial Disease; Ischaemic Stroke; Subarachnoid Haemorrhagic Stroke; Intracerebral Haemorrhagic Stroke; Stroke Not Otherwise Specified; Sudden Cardiac Death; Unheralded Coronary Death; Mortality; Coronary Heart Disease (CHD); Cardiovascular Disease (CVD); Fatal Cardiovascular Disease (Fatal CVD); ST Elevation Myocardial Infarction (STEMI); Non-ST Elevation Myocardial Infarction (nSTEMI); Myocardial Infarction Not Otherwise Specified (MI NOS)

  15. Cleft Palate, Retrognathia and Congenital Heart Disease in Velo-Cardio-Facial Syndrome: A Phenotype Correlation Study

    PubMed Central

    Friedman, Marcia A.; Miletta, Nathanial; Roe, Cheryl; Wang, Dongliang; Morrow, Bernice E.; Kates, Wendy R.; Higgins, Anne Marie; Shprintzen, Robert J.

    2011-01-01

    Objective Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. Methods This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by chi square or Fisher exact test. Results For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Conclusions Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some

  16. GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

    PubMed

    Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

    2015-04-01

    Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching.

  17. Frailty phenotype and chronic kidney disease: a review of the literature.

    PubMed

    Musso, Carlos G; Jauregui, Jose R; Macías Núñez, Juan F

    2015-11-01

    Frailty is a construct originally coined by gerontologists to describe cumulative declines across multiple physiological systems that occur with aging and lead individuals to a state of diminished physiological reserve and increased vulnerability to stressors. Fried et al. provided a standardized definition for frailty, and they created the concept of frailty phenotype which incorporates disturbances across interrelated domains (shrinking, weakness, poor endurance and energy, slowness, and low physical activity level) to indentify old people who are at risk of disability, falls, institutionalization, hospitalization, and premature death. Some authors consider the presence of lean mass reduction (sarcopenia) as part of the frailty phenotype. The frailty status has been documented in 7 % of elderly population and 14 % of not requiring dialysis CKD adult patients. Sarcopenia increases progressively along with loss of renal function in CKD patients and is high in dialysis population. It has been documented that prevalence of frailty in hemodialysis adult patients is around 42 % (35 % in young and 50 % in elderly), having a 2.60-fold higher risk of mortality and 1.43-fold higher number of hospitalization, independent of age, comorbidity, and disability. The Clinical Frailty Scale is the simplest and clinically useful and validated tool for doing a frailty phenotype, while the diagnosis of sarcopenia is based on muscle mass assessment by body imaging techniques, bioimpedance analysis, and muscle strength evaluated with a handheld dynamometer. Frailty treatment can be based on different strategies, such as exercise, nutritional interventions, drugs, vitamins, and antioxidant agents. Finally, palliative care is a very important alternative for very frail and sick patients. In conclusion, since the diagnosis and treatment of frailty and sarcopenia is crucial in geriatrics and all CKD patients, it would be very important to incorporate these evaluations in pre

  18. COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype

    PubMed Central

    Packard, Thomas A.; Li, Quan Z.; Cosgrove, Gregory P.; Bowler, Russell P.

    2014-01-01

    The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly appreciated. In this study, we identified serum autoantibody reactivities associated with chronic bronchitis or emphysema, as well as systemic autoimmunity and associated lung disease. Using autoantigen array analysis, we demonstrated that COPD patients produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype. Patients with emphysema produced autoantibodies of higher titer and reactive to an increased number of array antigens. Strikingly, the autoantibody reactivities observed in emphysema were increased over those detected in rheumatoid arthritis patients, and included similar reactivities to those associated with lupus. These findings raise the possibility that autoantibody profiles may be used to determine COPD risk, as well as provide a diagnostic and prognostic tool. They shed light on the heterogeneity of autoantibody reactivities associated with COPD phenotype and could be of use in the personalization of medical treatment, including determining and monitoring therapeutic interventions. PMID:22941590

  19. Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic disease phenotype.

    PubMed

    Lefevre, Gaelle M; Patel, Sanjeevkumar R; Kim, Doyeob; Tessarollo, Lino; Dressler, Gregory R

    2010-10-28

    Methylation of specific lysine residues in core histone proteins is essential for embryonic development and can impart active and inactive epigenetic marks on chromatin domains. The ubiquitous nuclear protein PTIP is encoded by the Paxip1 gene and is an essential component of a histone H3 lysine 4 (H3K4) methyltransferase complex conserved in metazoans. In order to determine if PTIP and its associated complexes are necessary for maintaining stable gene expression patterns in a terminally differentiated, non-dividing cell, we conditionally deleted PTIP in glomerular podocytes in mice. Renal development and function were not impaired in young mice. However, older animals progressively exhibited proteinuria and podocyte ultra structural defects similar to chronic glomerular disease. Loss of PTIP resulted in subtle changes in gene expression patterns prior to the onset of a renal disease phenotype. Chromatin immunoprecipitation showed a loss of PTIP binding and lower H3K4 methylation at the Ntrk3 (neurotrophic tyrosine kinase receptor, type 3) locus, whose expression was significantly reduced and whose function may be essential for podocyte foot process patterning. These data demonstrate that alterations or mutations in an epigenetic regulatory pathway can alter the phenotypes of differentiated cells and lead to a chronic disease state.

  20. Schistosome infection aggravates HCV-related liver disease and induces changes in the regulatory T-cell phenotype.

    PubMed

    Loffredo-Verde, E; Abdel-Aziz, I; Albrecht, J; El-Guindy, N; Yacob, M; Solieman, A; Protzer, U; Busch, D H; Layland, L E; Prazeres da Costa, C U

    2015-02-01

    Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-co-infected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios(pos) Treg were not elevated in Sm/HCV individuals, but frequencies of GrzB(+) Treg were significantly increased. Simultaneously, GrzB(+) CD8(+) T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co-infected individuals respond poorly to interferon therapy.

  1. Two Complex Cases of Hermansky-Pudlak Syndrome Highlight a Potential Biologic Explanation for an Associated Crohn’s Disease Phenotype

    PubMed Central

    Sakuraba, Atsushi; Rubin, David T.

    2017-01-01

    Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a lack of dense granules in platelets. HPS types 1 and 4 are associated with a granulomatous enterocolitis that is phenotypically indistinguishable from Crohn’s disease. We present two cases of HPS-associated Crohn’s disease phenotype in which the patients were refractory to standard medical management. The pathophysiology of HPS is mediated by single-gene defects that alter endosome trafficking, and we hypothesize that this mechanism leads to the observed association with a CD phenotype. PMID:28144619

  2. Sickle cell disease in Saudi Arabia: the phenotype in adults with the Arab-Indian haplotype is not benign.

    PubMed

    Alsultan, Abdulrahman; Alabdulaali, Mohammed K; Griffin, Paula J; Alsuliman, Ahmed M; Ghabbour, Hazem A; Sebastiani, Paola; Albuali, Waleed H; Al-Ali, Amein K; Chui, David H K; Steinberg, Martin H

    2014-02-01

    Sickle cell disease (SCD) in Saudi patients from the Eastern Province is associated with the Arab-Indian (AI) HBB (β-globin gene) haplotype. The phenotype of AI SCD in children was described as benign and was attributed to their high fetal haemoglobin (HbF). We conducted a hospital-based study to assess the pattern of SCD complications in adults. A total of 104 patients with average age of 27 years were enrolled. Ninety-six per cent of these patients reported history of painful crisis; 47% had at least one episode of acute chest syndrome, however, only 15% had two or more episodes; symptomatic osteonecrosis was reported in 18%; priapism in 17%; overt stroke in 6%; none had leg ulcers. The majority of patients had persistent splenomegaly and 66% had gallstones. Half of the patients co-inherited α-thalassaemia and about one-third had glucose-6-phosphate dehydrogenase deficiency. Higher HbF correlated with higher rate of splenic sequestration but not with other phenotypes. The phenotype of adult patients with AI SCD is not benign despite their relatively high HbF level. This is probably due to the continued decline in HbF level in adults and the heterocellular and variable distribution of HbF amongst F-cells.

  3. FRET-based calcium imaging: a tool for high-throughput/content phenotypic drug screening in Alzheimer disease.

    PubMed

    Honarnejad, Kamran; Kirsch, Achim K; Daschner, Alexander; Szybinska, Aleksandra; Kuznicki, Jacek; Herms, Jochen

    2013-12-01

    Perturbed intracellular store calcium homeostasis is suggested to play a major role in the pathophysiology of Alzheimer disease (AD). A number of mechanisms have been suggested to underlie the impairment of endoplasmic reticulum calcium homeostasis associated with familial AD-linked presenilin 1 mutations (FAD-PS1). Without aiming at specifically targeting any of those pathophysiological mechanisms in particular, we rather performed a high-throughput phenotypic screen to identify compounds that can reverse the exaggerated agonist-evoked endoplasmic reticulum calcium release phenotype in HEK293 cells expressing FAD-PS1. For that purpose, we developed a fully automated high-throughput calcium imaging assay using a fluorescence resonance energy transfer-based calcium indicator at single-cell resolution. This novel robust assay offers a number of advantages compared with the conventional calcium measurement screening technologies. The assay was employed in a large-scale screen with a library of diverse compounds comprising 20,000 low-molecular-weight molecules, which resulted in the identification of 52 primary hits and 4 lead structures. In a secondary assay, several hits were found to alter the amyloid β (Aβ) production. In view of the recent failure of AD drug candidates identified by target-based approaches, such a phenotypic drug discovery paradigm may present an attractive alternative for the identification of novel AD therapeutics.

  4. IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1.

    PubMed

    Gravel, Mathieu; Béland, Louis-Charles; Soucy, Geneviève; Abdelhamid, Essam; Rahimian, Reza; Gravel, Claude; Kriz, Jasna

    2016-01-20

    While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge. This microglial phenotype was associated with a 16-fold overexpression of anti-inflammatory cytokine IL-10 in baseline conditions followed by a 4.5-fold increase following LPS challenge. While infusion of IL-10R blocking antibody, initiated at day 60, caused a significant increase in markers of microglial activation and precipitated clinical onset of disease, a targeted overexpression of IL-10 in microglial cells, delivered via viral vectors expressed under CD11b promoter, significantly delayed disease onset and increased survival of SOD1(G93A) mice. We propose that the high IL-10 levels in resident microglia in early ALS represent a homeostatic and compensatory "adaptive immune escape" mechanism acting as a nonneuronal determinant of clinical onset of disease. Significance statement: We report here for the first time that changing the immune profile of brain microglia may significantly affect clinical onset and duration of disease in ALS models. We discovered that in presymptomatic disease microglial cells overexpress anti-inflammatory cytokine IL-10. Given that IL-10 is major homeostatic cytokine and its production becomes deregulated with aging, this may suggest that the capacity of microglia to adequately produce IL-10 may be compromised in ALS. We show

  5. Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.

    PubMed

    Machiela, Emily; Dues, Dylan J; Senchuk, Megan M; Van Raamsdonk, Jeremy M

    2016-12-01

    Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.

  6. A probable new syndrome with the storage disease phenotype caused by the VPS33A gene mutation.

    PubMed

    Dursun, Ali; Yalnizoglu, Dilek; Gerdan, Omer F; Yucel-Yilmaz, Didem; Sagiroglu, Mahmut S; Yuksel, Bayram; Gucer, Safak; Sivri, Serap; Ozgul, Riza K

    2017-01-01

    We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p. R498W missense mutation in the VPS33A gene might be responsible for this novel disease. Segregation analysis in family members and mutation prediction tools' results also supported the damaging effect of the missense mutation on the function of the Vps33a protein, which plays a role in the vesicular transport system. Electron microscopic studies of the cornea of the proband showed findings supportive of dysfunction in vesicular transport. The clinical phenotype and genetic studies support the suggestion that the siblings most probably have a novel disease very likely caused by a VPS33A gene defect.

  7. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    PubMed Central

    Trias, Emiliano; Díaz-Amarilla, Pablo; Olivera-Bravo, Silvia; Isasi, Eugenia; Drechsel, Derek A.; Lopez, Nathan; Bradford, C. Samuel; Ireton, Kyle E.; Beckman, Joseph S.; Barbeito, Luis

    2013-01-01

    Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 +AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 G93A rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100β expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 G93A rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS. PMID:24399933

  8. Achievement of disease control with donor-derived EB virus-specific cytotoxic T cells after allogeneic peripheral blood stem cell transplantation for aggressive NK-cell leukemia.

    PubMed

    Haji, Shojiro; Shiratsuchi, Motoaki; Matsushima, Takamitsu; Takamatsu, Akiko; Tsuda, Mariko; Tsukamoto, Yasuhiro; Tanaka, Emi; Ohno, Hirofumi; Fujioka, Eriko; Ishikawa, Yuriko; Imadome, Ken-Ichi; Ogawa, Yoshihiro

    2017-04-01

    Aggressive NK-cell leukemia (ANKL) is characterized by systemic infiltration of Epstein-Barr virus (EBV)-associated natural killer cells and poor prognosis. We report a case of ANKL in which EBV-specific cytotoxic T lymphocytes (CTLs) were induced. A 41-year-old male suffered from fever, pancytopenia, and hepatosplenomegaly. The number of abnormal large granular lymphocytes in the bone marrow was increased and the cells were positive for CD56 and EBV-encoded small nuclear RNAs. The patient was diagnosed with ANKL and achieved a complete response following intensive chemotherapy. He then underwent allogeneic peripheral blood stem cell transplantation from his sister. Conditioning therapy consisted of total body irradiation and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. On day 31, complete donor chimerism was achieved and no acute graft-versus-host disease developed. The ANKL relapsed on day 80, and cyclosporine was rapidly tapered and chemotherapy was started. During hematopoietic recovery, the number of atypical lymphocytes increased, but they were donor-derived EBV-specific CTLs. The patient achieved a partial response and EBV viral load decreased to normal range. Unfortunately, ANKL worsen again when the CTLs disappeared from his blood. This is the first case report of ANKL in which induced EBV-specific CTLs may have contributed to disease control.

  9. Multicolor Fluorescence Imaging as a Candidate for Disease Detection in Plant Phenotyping

    PubMed Central

    Pérez-Bueno, María L.; Pineda, Mónica; Cabeza, Francisco M.; Barón, Matilde

    2016-01-01

    The negative impact of conventional farming on environment and human health make improvements on farming management mandatory. Imaging techniques are implemented in remote sensing for monitoring crop fields and plant phenotyping programs. The increasingly large size and complexity of the data obtained by these techniques, makes the implementation of powerful mathematical tools necessary in order to identify informative parameters and to apply them in precision agriculture. Multicolor fluorescence imaging is a useful approach for the study of plant defense responses to stress factors at bench scale. However, it has not been fully applied to plant phenotyping. This work evaluates the possible application of multicolor fluorescence imaging in combination with thermography for the particular case of zucchini plants affected by soft-rot, caused by Dickeya dadantii. Several statistical models -based on logistic regression analysis (LRA) and artificial neural networks (ANN)- were obtained for the experimental system zucchini-D. dadantii, which classify new samples as “healthy” or “infected.” The LRA worked best in identifying high dose-infiltrated leaves (in infiltrated and non-infiltrated areas) whereas ANN offered a higher accuracy at identifying low dose-infiltrated areas. To assess the applicability of these results to cucurbits in a more general way, these models were validated for melon infected by the same pathogen, achieving accurate predictions for the infiltrated areas. The values of accuracy achieved are comparable to those found in the literature for classifiers identifying other infections based on data obtained by different techniques. Thus, MCFI in combination with thermography prove useful at providing data at lab scale that can be analyzed by machine learning. This approach could be scaled up to be applied in plant phenotyping. PMID:27994607

  10. Hypertriglyceridemic Waist Phenotype and Chronic Kidney Disease in a Chinese Population Aged 40 Years and Older

    PubMed Central

    Shao, Xiaofei; Liu, Xinyu; Guo, Jia; Zhang, Ying; Wang, Honglei; Wang, Xiaohong; Li, Bin; Deng, Kangping; Liu, Qin; Holthöfer, Harry; Zou, Hequn

    2014-01-01

    Objective To examine the relationship between the HW phenotype and risk for CKD in a community population aged 40 years and older. Methods A cross-sectional study was conducted in Zhuhai from June to October 2012. The participants were divided into three groups: Group 1, Waist circumference >90 cm in men or >85 cm in women and triglycerides ≥2 mmol/l; Group 3, Waist circumference ≤90 cm in men or ≤85 cm in women and triglycerides <2 mmol/l; Group 2, The remaining participants. The prevalence of the three subgroups and CKD were determined. The association between HW phenotype and CKD was then analyzed using SPSS (version 13.0). Results After adjusting for age and sex, Group 1 was associated with CKD (OR 3.08, 95% CI 2.01, 4.73, P<0.001), when compared with Group 3. Further adjustment for factors which were potential confounders and unlikely to be in the causal pathway between the HW phenotype and CKD, Group 1 was still significantly associated with CKD. The OR for CKD was 2.65 (95% CI 1.65, 4.26, P<0.001). When adjusted for diabetes and hypertension, the association of Group 1 and CKD was still significant (OR 2.09, 95% CI 1.26, 3.45, P = 0.004). Group 2 was associated with CKD (OR 1.81, 95% CI 1.29, 2.53, P = 0.001), when compared with Group 3. Further adjustment for factors which were potential confounders, Group 2 was still significantly associated with CKD. The OR for CKD was 1.75 (95% CI 1.22, 2.51, P = 0.002). When adjusted for diabetes and hypertension, the association between Group 2 and CKD still existed. The OR for CKD was 1.48 (95% CI 1.01, 2.16, P = 0.046). Conclusion Our results showed that HW phenotype was associated with CKD in the population aged 40 years and older. PMID:24663403

  11. Arylsulfatase a gene polymorphisms in relapsing remitting multiple sclerosis: genotype-phenotype correlation and estimation of disease progression.

    PubMed

    Baronica, Koraljka Bacić; Mlinac, Kristina; Ozretić, David; Vladić, Anton; Bognar, Svjetlana Kalanj

    2011-01-01

    Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS). This work presents usefulness of genotype-phenotype correlation in estimation of disease severity and progression. The presence of two most common mutations associated with ASA-PD was analyzed in 56 patients with diagnosis of relapsing-remitting multiple sclerosis, by polymerase chain reaction restriction fragment length polymorphism method. In MS patients confirmed as ASA-PD mutations carriers, arylsulfatase activity was determined in leukocyte homogenates by spectrophotometry. To determine whether there is a difference between disability level and/or disease progression in patients with or without mutations we have estimated disability level using Expanded disability status scale (EDSS) and disease progression using Multiple sclerosis severity score (MSSS). Correlation of genotypes and disease progression was statistically analyzed by Kruskal-Wallis test. Patients showing higher MSSS score and found to be carriers of both analyzed ASA-PD mutations were additionally examined using conventional magnetic resonance (MR) techniques. The presence of either one or both mutations was determined in 13 patients. Lower ASA activities were observed in all MS patients carrying the mutations. Nine of the mutations carriers had mild disability (EDSS=0-4.0), 1 had moderate disability (EDSS=4.5-5.5), and 3 had severe disability (EDSS > or = 6.0). On the other hand, only 3 MS patients who were mutation carriers showed MSSS values lower than 5.000 while in other MS patients-mutation carriers the MSSS values ranged from 5.267 to 9

  12. Genetics of aggressive behavior: An overview.

    PubMed

    Veroude, Kim; Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Bakker, Mireille J; Cormand, Bru; Faraone, Stephen V

    2016-01-01

    The Research Domain Criteria (RDoC) address three types of aggression: frustrative non-reward, defensive aggression and offensive/proactive aggression. This review sought to present the evidence for genetic underpinnings of aggression and to determine to what degree prior studies have examined phenotypes that fit into the RDoC framework. Although the constructs of defensive and offensive aggression have been widely used in the animal genetics literature, the human literature is mostly agnostic with regard to all the RDoC constructs. We know from twin studies that about half the variance in behavior may be explained by genetic risk factors. This is true for both dimensional, trait-like, measures of aggression and categorical definitions of psychopathology. The non-shared environment seems to have a moderate influence with the effects of shared environment being unclear. Human molecular genetic studies of aggression are in an early stage. The most promising candidates are in the dopaminergic and serotonergic systems along with hormonal regulators. Genome-wide association studies have not yet achieved genome-wide significance, but current samples are too small to detect variants having the small effects one would expect for a complex disorder. The strongest molecular evidence for a genetic basis for aggression comes from animal models comparing aggressive and non-aggressive strains or documenting the effects of gene knockouts. Although we have learned much from these prior studies, future studies should improve the measurement of aggression by using a systematic method of measurement such as that proposed by the RDoC initiative.

  13. Systems Medicine for Lung Diseases: Phenotypes and Precision Medicine in Cancer, Infection, and Allergy.

    PubMed

    Schmeck, Bernd; Bertrams, Wilhelm; Lai, Xin; Vera, Julio

    2016-01-01

    Lung diseases cause an enormous socioeconomic burden. Four of them are among the ten most important causes of deaths worldwide: Pneumonia has the highest death toll of all infectious diseases, lung cancer kills the most people of all malignant proliferative disorders, chronic obstructive pulmonary disease (COPD) ranks third in mortality among the chronic noncommunicable diseases, and tuberculosis is still one of the most important chronic infectious diseases. Despite all efforts, for example, by the World Health Organization and clinical and experimental researchers, these diseases are still highly prevalent and harmful. This is in part due to the specific organization of tissue homeostasis, architecture, and immunity of the lung. Recently, several consortia have formed and aim to bring together clinical and molecular data from big cohorts of patients with lung diseases with novel experimental setups, biostatistics, bioinformatics, and mathematical modeling. This "systems medicine" concept will help to match the different disease modalities with adequate therapeutic and possibly preventive strategies for individual patients in the sense of precision medicine.

  14. LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes.

    PubMed

    Hizawa, Nobuyuki

    2015-01-01

    In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors. The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD) continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines. COPD is a complex condition that has pulmonary and extrapulmonary manifestations. These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies. The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease. Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient's characteristics, together with his or her genotype, will be key to choosing the best treatment option. At present in Japan, fixed combinations of inhaled corticosteroids (ICSs) and LABAs are frequently prescribed in the earlier stages of COPD. However, ICSs increase the risk of pneumonia. Notably, 10%-30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids. Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that benefits from ICSs. In this review, I propose one plausible approach to position ICSs and LABAs/LAMAs in clinical practice, based on both

  15. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    PubMed

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  16. Novel Nomogram That Predicts Aggressive Disease and Treatment Failure Among African-American Men with Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment—postsurgery ( CAPRA -S) features following...grade disease and similar CAPRA -S scores. Results: With a median follow-up time of 27 months, the overall 7-year FFbF rate was 86% vs. 79% in CS and AA...0.35) or CAPRA -S score (P ¼ 0.28). In the subset analysis of patients with low-grade disease, AA race was associated with worse FFbF outcomes (P

  17. Successes and Challenges in Phenotype-Based Lead Discovery for Prion Diseases

    PubMed Central

    2015-01-01

    Creutzfeldt–Jakob disease (CJD) is a rare but invariably fatal neurodegenerative disease caused by misfolding of an endogenous protein into an alternative pathogenic conformation. The details of protein misfolding and aggregation are not well understood nor are the mechanism(s) by which the aggregated protein confers cellular toxicity. While there is as yet no clear consensus about how best to intervene therapeutically in CJD, prion infections can be propagated in cell culture and in experimental animals, affording both in vitro and in vivo models of disease. Here we review recent lead discovery efforts for CJD, with a focus on our own efforts to optimize 2-aminothiazole analogues for anti-prion potency in cells and for brain exposure in mice. The compounds that emerged from this effort were found to be efficacious in multiple animal models of prion disease even as they revealed new challenges for the field, including the emergence of resistant prion strains. PMID:24762293

  18. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients.

    PubMed

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2016-01-05

    Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

  19. Gene-environment interactions in the development of complex disease phenotypes.

    PubMed

    Ramos, Rosemarie G; Olden, Kenneth

    2008-03-01

    The lack of knowledge about the earliest events in disease development is due to the multi-factorial nature of disease risk. This information gap is the consequence of the lack of appreciation for the fact that most diseases arise from the complex interactions between genes and the environment as a function of the age or stage of development of the individual. Whether an environmental exposure causes illness or not is dependent on the efficiency of the so-called "environmental response machinery" (i.e., the complex of metabolic pathways that can modulate response to environmental perturbations) that one has inherited. Thus, elucidating the causes of most chronic diseases will require an understanding of both the genetic and environmental contribution to their etiology. Unfortunately, the exploration of the relationship between genes and the environment has been hampered in the past by the limited knowledge of the human genome, and by the inclination of scientists to study disease development using experimental models that consider exposure to a single environmental agent. Rarely in the past were interactions between multiple genes or between genes and environmental agents considered in studies of human disease etiology. The most critical issue is how to relate exposure-disease association studies to pathways and mechanisms. To understand how genes and environmental factors interact to perturb biological pathways to cause injury or disease, scientists will need tools with the capacity to monitor the global expression of thousands of genes, proteins and metabolites simultaneously. The generation of such data in multiple species can be used to identify conserved and functionally significant genes and pathways involved in gene-environment interactions. Ultimately, it is this knowledge that will be used to guide agencies such as the U.S. Department of Health and Human Services in decisions regarding biomedical research funding and policy.

  20. Influence of a nucleotide oligomerization domain 1 (NOD1) polymorphism and NOD2 mutant alleles on Crohn's disease phenotype

    PubMed Central

    Cantó, Elisabet; Ricart, Elena; Busquets, David; Monfort, David; García-Planella, Esther; González, Dolors; Balanzó, Joaquim; Rodríguez-Sánchez, José L; Vidal, Sílvia

    2007-01-01

    AIM: To examine genetic variation of nucleotide oligomerization domain 1 (NOD1) and NOD2, their respective influences on Crohn's disease phenotype and gene-gene interactions. METHODS: (ND1+32656*1) NOD1 polymorphism and SNP8, SNP12 and SNP13 of NOD2 were analyzed in 97 patients and 50 controls. NOD2 variants were determined by reaction restriction fragment length polymorphism analysis. NOD1 genotyping and NOD2 variant confirmation were performed by specific amplification and sequencing. RESULTS: The distribution of NOD1 polymorphism in patients was different from controls (P = 0.045) and not altered by existence of NOD2 mutations. In this cohort, 30.92% patients and 6% controls carried at least one NOD2 variant (P < 0.001) with R702W being the most frequent variant. Presence of at least one NOD2 mutation was inversely associated with colon involvement (9.09% with colon vs 36.4% with ileal or ileocolonic involvement, P = 0.04) and indicative of risk of penetrating disease (52.63% with penetrating vs 25.64% with non-penetrating or stricturing behavior, P = 0.02). L1007finsC and double NOD2 mutation conferred the highest risk for severity of disease (26.3% with penetrating disease vs 3.8% with non-penetrating or stricturing behavior presented L1007finsC, P = 0.01 and 21.0% with penetrating disease vs 2.5% with non-penentrating or stricturing behavior carried double NOD2 mutation, P = 0.007). Exclusion of patients with NOD2 mutations from phenotype/NOD1-genotype analysis revealed higher prevalence of *1*1 genotype in groups of younger age at onset and colonic location. CONCLUSION: This study suggests population differences in the inheritance of risk NOD1 polymorphism and NOD2 mutations. Although no interaction between NOD1-NOD2 was noticed, a relationship between disease location and Nod-like receptor molecules was established. PMID:17907287

  1. Phenotypic, genetic, and single nucleotide polymorphism marker associations between calf diseases and subsequent performance and disease occurrences of first-lactation German Holstein cows.

    PubMed

    Mahmoud, M; Yin, T; Brügemann, K; König, S

    2017-03-01

    A total of 31,396 females born from 2010 to 2013 in 43 large-scale Holstein-Friesian herds were phenotyped for calf and cow disease traits using a veterinarian diagnosis key. Calf diseases were general disease status (cGDS), calf diarrhea (cDIA), and calf respiratory disease (cRD) recorded from birth to 2 mo of age. Incidences were 0.48 for cGDS, 0.28 for cRD, and 0.21 for cDIA. Cow disease trait recording focused on the early period directly after calving in first parity, including the interval from 10 d before calving to 200 d in lactation. For cows, at least one entry for the respective disease implied a score = 1 (sick); otherwise, score = 0 (healthy). Corresponding cow diseases were first-lactation general disease status (flGDS), first-lactation diarrhea (flDIA), and first-lactation respiratory disease (flRD). Additional cow disease categories included mastitis (flMAST), claw disorders (flCLAW), female fertility disorders (flFF), and metabolic disorders (flMET). A further cow trait category considered first-lactation test-day production traits from official test-days 1 and 2 after calving. The genotype data set included 41,256 single nucleotide polymorphisms (SNP) from 9,388 females with phenotypes. Linear and generalized linear mixed models with a logit link-function were applied to Gaussian and categorical cow traits, respectively, considering the calf disease as a fixed effect. Most of the calf diseases were not significantly associated with the occurrence of any cow disease. By trend, increasing risks for the occurrence of cow diseases were observed for healthy calves, indicating mechanisms of disease resistance with aging. Also by trend, occurrence of calf diseases was associated with decreasing milk, protein, and fat yields. Univariate linear and threshold animal models were used to estimate heritabilities and breeding values (EBV) for all calf and cow traits. Heritabilities for cGDS and cRD were 0.06 and 0.07 for cDIA. Genetic correlations among all

  2. Genetically Closely Related but Phenotypically Divergent Trichoderma Species Cause Green Mold Disease in Oyster Mushroom Farms Worldwide▿ †

    PubMed Central

    Komoń-Zelazowska, Monika; Bissett, John; Zafari, Doustmorad; Hatvani, Lóránt; Manczinger, László; Woo, Sheri; Lorito, Matteo; Kredics, László; Kubicek, Christian P.; Druzhinina, Irina S.

    2007-01-01

    The worldwide commercial production of the oyster mushroom Pleurotus ostreatus is currently threatened by massive attacks of green mold disease. Using an integrated approach to species recognition comprising analyses of morphological and physiological characters and application of the genealogical concordance of multiple phylogenetic markers (internal transcribed spacer 1 [ITS1] and ITS2 sequences; partial sequences of tef1 and chi18-5), we determined that the causal agents of this disease were two genetically closely related, but phenotypically strongly different, species of Trichoderma, which have been recently described as Trichoderma pleurotum and Trichoderma pleuroticola. They belong to the Harzianum clade of Hypocrea/Trichoderma which also includes Trichoderma aggressivum, the causative agent of green mold disease of Agaricus. Both species have been found on cultivated Pleurotus and its substratum in Europe, Iran, and South Korea, but T. pleuroticola has also been isolated from soil and wood in Canada, the United States, Europe, Iran, and New Zealand. T. pleuroticola displays pachybasium-like morphological characteristics typical of its neighbors in the Harzianum clade, whereas T. pleurotum is characterized by a gliocladium-like conidiophore morphology which is uncharacteristic of the Harzianum clade. Phenotype MicroArrays revealed the generally impaired growth of T. pleurotum on numerous carbon sources readily assimilated by T. pleuroticola and T. aggressivum. In contrast, the Phenotype MicroArray profile of T. pleuroticola is very similar to that of T. aggressivum, which is suggestive of a close genetic relationship. In vitro confrontation reactions with Agaricus bisporus revealed that the antagonistic potential of the two new species against this mushroom is perhaps equal to T. aggressivum. The P. ostreatus confrontation assays showed that T. pleuroticola has the highest affinity to overgrow mushroom mycelium among the green mold species. We conclude that

  3. CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves' disease and modulates clinical phenotype of disease.

    PubMed

    Pawlak-Adamska, Edyta; Frydecka, Irena; Bolanowski, Marek; Tomkiewicz, Anna; Jonkisz, Anna; Karabon, Lidia; Partyka, Anna; Nowak, Oskar; Szalinski, Marek; Daroszewski, Jacek

    2017-01-01

    Graves' disease, an autoimmune disease with heterogeneous symptoms including Graves' orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves' disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves' disease patients. CTLA-4c.49A>G, CTLA-4g.319C>T, and CT60 were genotyped by PCR-RFLP; Jo31 and CD28c.17+3C>T by minisequencing; CTLA-4g.*642AT(8_33) and ICOSc.1554+4GT(8_15)-PCR and fluorescence-based technique. CD28c.17+3T>C(rs3116496)T/CTLA-4g.319C>T(rs5742909)C/CTLA-4c.49A>G(rs231775)G/CTLA-4g.*642AT(8_33)(AT16-21)/CT60(rs3087243)G/Jo31(rs11571302)G/ICOSc.1554+4GT(8_15)(m) and TCA(AT<16)GT(m) haplotypes increased risk of Graves' disease, especially in males, as well as overall Graves' orbitopathy development with severe outcome. TCG(AT16-21)GG(l) haplotype increased risk of Graves' disease and reduced the chance of successful medical treatment. Although this haplotype was mainly observed in patients without signs of Graves' orbitopathy, if Graves' orbitopathy developed it favored a Graves' orbitopathy outcome. Haplotype TCA(AT>21)GT(m) increased Graves' disease risk in women and, in all patients, was linked to Graves' disease without Graves' orbitopathy. TCG(AT<16)GG(m) haplotype was predominantly observed in patients without Graves' orbitopathy, whereas TCA(AT16-21)GG(m) was absent in those patients. TCA(AT16-21)GG(m) occurred in patients with a mild Graves' orbitopathy outcome. The marker CTLA-4g.*642AT(8_33) was the only independent Graves' disease risk factor, whereas CT60 was an independent factor for disease progression. Sporadic Graves' disease was related to presence of CTLA-4c.49A>G[A] and

  4. Isolated Ro52 Antibodies as Immunological Marker of a Mild Phenotype of Undifferentiated Connective Tissue Diseases

    PubMed Central

    Navarro-Gonzálvez, José Antonio; Rodríguez-Lozano, Beatriz

    2017-01-01

    The term undifferentiated connective tissue disease (UCTD) is used to describe undiagnosed patients that do not fulfill classification criteria for definite connective tissue disease (Systemic Lupus, Systemic Sclerosis, Sjögren Syndrome, and Dermatomyositis/Polymyositis). It is important to find serological markers as predictors of the evolution or severity of these diseases. The objective of this retrospective study was to investigate if there was a milder subgroup of UCTD with a special clinical profile consisting only in the presence of anti-Ro52 autoantibodies. Immunological and clinical records of 62 patients attending the hospital during 30 months were studied. Results showed a target population formed by mostly women, aged between 40 and 80 years at the moment of the study, with a registered age of onset between 40 and 60 years. Speckled pattern was the most frequent pattern found by indirect immunofluorescence. Given the obtained results and keeping in mind possible limitations because of sample size, isolated positive anti-Ro52 autoantibodies seem to lead to a benign effect in terms of evolution of the disease. As a future objective, the follow-up of these patients should be necessary to investigate new clinical symptoms, serological markers, or development of a definite connective tissue disease over time. PMID:28210273

  5. Genetic features of Huntington disease in Cuban population: implications for phenotype, epidemiology and predictive testing.

    PubMed

    Vázquez-Mojena, Yaimeé; Laguna-Salvia, Leonides; Laffita-Mesa, José M; González-Zaldívar, Yanetza; Almaguer-Mederos, Luis E; Rodríguez-Labrada, Roberto; Almaguer-Gotay, Dennis; Zayas-Feria, Pedro; Velázquez-Pérez, Luis

    2013-12-15

    Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease. Sixty-two patients with chorea belonging to 16 unrelated families carried a pathological CAG expansion in the HTT gene, ranging from 39 to 67 repeats. Eighty-three percent of them come from the eastern region of the country. A significant inverse correlation between age at onset and expanded CAG repeats was seen. Intermediate alleles in affected individuals and controls represented 4.8% and 3.97% respectively, which have been a putative source of de novo mutation. This study represents the largest molecular characterization of Huntington disease in the Cuban population. These results may have significant implications for an understanding of the disease, its diagnosis and prognosis in Cuban patients, giving health professionals the tools to implement confirmatory genetic testing, pre-symptomatic testing and clinical trials in this population.

  6. Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies.

    PubMed

    Bousquet, Jean; Jorgensen, Christian; Dauzat, Michel; Cesario, Alfredo; Camuzat, Thierry; Bourret, Rodolphe; Best, Nicolas; Anto, Josep M; Abecassis, Frederic; Aubas, Pierre; Avignon, Antoine; Badin, Melanie; Bedbrook, Anna; Blain, Hubert; Bourdin, Arnaud; Bringer, Jacques; Camu, William; Cayla, Guilhaume; Costa, David J; Courtet, Philippe; Cristol, Jean-Paul; Demoly, Pascal; de la Coussaye, Jean-Emmanuel; Fesler, Pierre; Gouzi, Fares; Gris, Jean-Christophe; Guillot, Bernard; Hayot, Maurice; Jeandel, Claude; Jonquet, Olivier; Journot, Laurent; Lehmann, Sylvain; Mathieu, Gwenaelle; Morel, Jacques; Ninot, Gregory; Pelissier, Jacques; Picot, Marie-Christine; Radier-Pontal, Francoise; Robine, Jean-Marie; Rodier, Michel; Roubille, Francois; Sultan, Ariane; Wojtusciszyn, Anne; Auffray, Charles; Balling, Rudi; Barbara, Cristina; Cambon-Thomsen, Anne; Chavannes, Niels H; Chuchalin, Alexander; Crooks, George; Dedeu, Antoni; Fabbri, Leonardo M; Garcia-Aymerich, Judith; Hajjam, Jawad; Melo Gomes, Elisabete; Palkonen, Susana; Piette, Francois; Pison, Christophe; Price, David; Samolinski, Boleslaw; Schunemann, Holger J; Sterk, Peter J; Yiallouros, Panayiotis; Roca, Josep; Van de Perre, Philippe; Mercier, Jacques

    2014-01-01

    Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

  7. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    PubMed

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

  8. Right ventricular nitric oxide signaling in an ovine model of congenital heart disease: a preserved fetal phenotype.

    PubMed

    Kameny, Rebecca Johnson; He, Youping; Morris, Catherine; Sun, Christine; Johengen, Michael; Gong, Wenhui; Raff, Gary W; Datar, Sanjeev A; Oishi, Peter E; Fineman, Jeffrey R

    2015-07-01

    We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4-wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs.

  9. Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

    PubMed

    Chen, Junmei; Hinckley, Jesse D; Haberichter, Sandra; Jacobi, Paula; Montgomery, Robert; Flood, Veronica H; Wong, Randall; Interlandi, Gianluca; Chung, Dominic W; López, José A; Di Paola, Jorge

    2015-07-09

    Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.

  10. Molecular phylogeny of the psittacid herpesviruses causing Pacheco's disease: correlation of genotype with phenotypic expression.

    PubMed

    Tomaszewski, Elizabeth K; Kaleta, Erhard F; Phalen, David N

    2003-10-01

    Fragments of 419 bp of the UL16 open reading frame from 73 psittacid herpesviruses (PsHVs) from the United States and Europe were sequenced. All viruses caused Pacheco's disease, and serotypes of the European isolates were known. A phylogenetic tree derived from these sequences demonstrated that the PsHVs that cause Pacheco's disease comprised four major genotypes, with each genotype including between two and four variants. With the exception of two viruses, the serotypes of the virus isolates could be predicted by the genotypes. Genotypes 1 and 4 corresponded to serotype 1 isolates, genotype 2 corresponded to serotype 2 isolates, and genotype 3 corresponded to serotype 3 isolates. The single serotype 4 virus mapped to genotype 4. DNA from a virus with a unique serotype could not be amplified with primers that amplified DNA from all other PsHVs, and its classification remains unknown. Viruses representing all four genotypes were found in both the United States and Europe, and it was therefore predicted that serotypes 1, 2, and 3 were present in the United States. Serotype 4 was represented by a single European isolate that could not be genetically distinguished from serotype 1 viruses; therefore, the presence of serotype 4 in the United States could not be predicted. Viruses of genotype 4 were found to be the most commonly associated with Pacheco's disease in macaws and conures and were least likely to be isolated in chicken embryo fibroblasts in the United States. All four genotypes caused deaths in Amazon parrots, but genotype 4 was associated with Pacheco's disease only in Amazons in Europe. Genotypes 2, 3, and 4, but not 1, were found in African grey parrots. Although parrots from the Pacific distribution represent a relatively small percentage of the total number of birds with Pacheco's disease, all four genotypes were found to cause disease in these species.

  11. Regulatory T Cells Phenotype in Different Clinical Forms of Chagas' Disease

    PubMed Central

    Teixeira-Carvalho, Andréa; Renato Zuquim Antas, Paulo; Assis Silva Gomes, Juliana; Sathler-Avelar, Renato; Otávio Costa Rocha, Manoel; Elói-Santos, Silvana Maria; Pinho, Rosa Teixeira; Correa-Oliveira, Rodrigo; Martins-Filho, Olindo Assis

    2011-01-01

    CD25High CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND) clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25HighCD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25High CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology during parasite

  12. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease.

    PubMed

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-04-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance.

  13. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    PubMed Central

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  14. Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren's Contracture

    PubMed Central

    2012-01-01

    Background Dupuytren's contracture (DC) is a fibroproliferative disorder characterized by the progressive development of a scar-like collagen-rich cord that affects the palmar fascia of the hand and leads to digital flexion contractures. DC is most commonly treated by surgical resection of the diseased tissue, but has a high reported recurrence rate ranging from 27% to 80%. We sought to determine if the transcriptomic profiles of fibroblasts derived from DC-affected palmar fascia, adjacent phenotypically normal palmar fascia, and non-DC palmar fascial tissues might provide mechanistic clues to understanding the puzzle of disease predisposition and recurrence in DC. Methods To achieve this, total RNA was obtained from fibroblasts derived from primary DC-affected palmar fascia, patient-matched unaffected palmar fascia, and palmar fascia from non-DC patients undergoing carpal tunnel release (6 patients in each group). These cells were grown on a type-1 collagen substrate (to better mimic their in vivo environments). Microarray analyses were subsequently performed using Illumina BeadChip arrays to compare the transcriptomic profiles of these three cell populations. Data were analyzed using Significance Analysis of Microarrays (SAM v3.02), hierarchical clustering, concordance mapping and Venn diagram. Results We found that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected fascia of DC patients exhibited a much greater overlap than fibroblasts derived from the palmar fascia of patients undergoing carpal tunnel release. Quantitative real time RT-PCR confirmed the differential expression of select genes validating the microarray data analyses. These data are consistent with the hypothesis that predisposition and recurrence in DC may stem, at least in part, from intrinsic similarities in the basal gene expression of diseased and phenotypically unaffected palmar fascia fibroblasts. These data also demonstrate that a collagen

  15. Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.

    PubMed

    Gray-Edwards, Heather L; Brunson, Brandon L; Holland, Merrilee; Hespel, Adrien-Maxence; Bradbury, Allison M; McCurdy, Victoria J; Beadlescomb, Patricia M; Randle, Ashley N; Salibi, Nouha; Denney, Thomas S; Beyers, Ronald J; Johnson, Aime K; Voyles, Meredith L; Montgomery, Ronald D; Wilson, Diane U; Hudson, Judith A; Cox, Nancy R; Baker, Henry J; Sena-Esteves, Miguel; Martin, Douglas R

    2015-01-01

    Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.

  16. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response

    PubMed Central

    Dekker, Nick; van Dussen, Laura; Hollak, Carla E. M.; Overkleeft, Herman; Scheij, Saskia; Ghauharali, Karen; van Breemen, Mariëlle J.; Ferraz, Maria J.; Groener, Johanna E. M.; Maas, Mario; Wijburg, Frits A.; Speijer, Dave; Tylki-Szymanska, Anna; Mistry, Pramod K.; Boot, Rolf G.

    2011-01-01

    Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7nM, range 15.6-1035.2nM; normal (n = 28): median 1.3nM, range 0.8-2.7nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease. PMID:21868580

  17. Multi-omic profiles of human non-alcoholic fatty liver disease tissue highlight heterogenic phenotypes

    PubMed Central

    Wruck, Wasco; Kashofer, Karl; Rehman, Samrina; Daskalaki, Andriani; Berg, Daniela; Gralka, Ewa; Jozefczuk, Justyna; Drews, Katharina; Pandey, Vikash; Regenbrecht, Christian; Wierling, Christoph; Turano, Paola; Korf, Ulrike; Zatloukal, Kurt; Lehrach, Hans; Westerhoff, Hans V.; Adjaye, James

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states. PMID:26646939

  18. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.

    PubMed

    Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A; Li, Wei; Leoni, Valerio; Schon, Eric A; Dantzer, Françoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

    2014-06-03

    Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans.

  19. Molecular immunity to mycobacteria: knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases

    PubMed Central

    Qu, Hui-Qi; Fisher-Hoch, Susan P.; McCormick, Joseph B.

    2011-01-01

    Summary Understanding molecular immunity against mycobacterial infection is critical for the development of effective strategies to control tuberculosis (TB), which is a major health issue in the developing world. Host immunogenetic studies represent an indispensable approach to understand the molecular mechanisms against mycobacterial infection. A superb paradigm is the identification of rare mutations causing Mendelian susceptibility to mycobacterial diseases (MSMD). Mutations in the interferon-gamma (IFN-γ) receptor genes are highly specific (although not exclusive) for mycobacterial infection. Only dominant negative mutations of STAT1 have specific susceptibility to mycobacterial infection. Mutations in the interleukin-12 (IL-12) signaling genes have phenotypes with non-specificity. Current studies highlight a complex molecular network in antimycobacterial immunity, centered on IFN-γ signaling. PMID:21330176

  20. Complete Phenotypic Recovery of an Alzheimer's Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor

    PubMed Central

    Scherzer-Attali, Roni; Pellarin, Riccardo; Convertino, Marino; Frydman-Marom, Anat; Egoz-Matia, Nirit; Peled, Sivan; Levy-Sakin, Michal; Shalev, Deborah E.; Caflisch, Amedeo; Gazit, Ehud; Segal, Daniel

    2010-01-01

    The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated β-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Aβ oligomerization and fibrillization, as well as the cytotoxic effect of Aβ oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Aβ while immuno-staining of the 3rd instar larval brains showed a significant reduction in Aβ accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Aβ. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease. PMID:20559435

  1. The neurobiology of aggression and violence.

    PubMed

    Rosell, Daniel R; Siever, Larry J

    2015-06-01

    Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.

  2. Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype

    PubMed Central

    Paloneva, Juha; Manninen, Tuula; Christman, Grant; Hovanes, Karine; Mandelin, Jami; Adolfsson, Rolf; Bianchin, Marino; Bird, Thomas; Miranda, Roxana; Salmaggi, Andrea; Tranebjærg, Lisbeth; Konttinen, Yrjö; Peltonen, Leena

    2002-01-01

    Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as “Nasu-Hakola disease,” is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. PMID:12080485

  3. Correlation of conventional and conformational anti-desmoglein antibodies with phenotypes and disease activities in patients with pemphigus vulgaris.

    PubMed

    Li, Zhiliang; Zhang, Jiechen; Xu, Haoxiang; Jin, Peiying; Feng, Suying; Wang, Baoxi

    2015-04-01

    Pemphigus is an autoimmune disease characterised by anti-desmoglein (Dsg) antibodies in the serum of patients. The disease can be divided into pemphigus foliaceus and pemphigus vulgaris. Anti-Dsg1 antibody is generally related to pemphigus with cutaneous lesion, and the anti-Dsg3 antibody is related to pemphigus with mucosa lesion. Twenty-nine patients with pemphigus vulgaris were selected in the clinical study. The severity of the cutaneous and mucosa lesions of these patients was evaluated using Pemphigus disease area index (PDAI). Conventional and conformational anti-Dsg index values were determined using enzyme-linked immunosorbent assay (ELISA) and ethylenediaminetetraacetic acid-treated ELISA. The relationship between clinical phenotypes and immunological profiles was analysed. In the correlation analysis, both the conventional and conformational anti-Dsg1 ELISA index values were correlated with the total and cutaneous PDAIs. In addition, conformational anti-Dsg3 ELISA index values exhibited a positive correlation with cutaneous PDAI in both types of pemphigus vulgaris, whereas no correlation was observed for the conventional anti-Dsg3 ELISA index values.

  4. Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy

    PubMed Central

    Bauer, Thomas R.; Hai, Mehreen; Tuschong, Laura M.; Burkholder, Tanya H.; Gu, Yu-chen; Sokolic, Robert A.; Ferguson, Cole; Dunbar, Cynthia E.; Hickstein, Dennis D.

    2006-01-01

    Canine leukocyte adhesion deficiency (CLAD) represents the canine counter-part of the human disease leukocyte adhesion deficiency (LAD). Defects in the leukocyte integrin CD18 adhesion molecule in both CLAD and LAD lead to recurrent, life-threatening bacterial infections. We evaluated ex vivo retroviral-mediated gene therapy in CLAD using 2 nonmyeloablative conditioning regimens—200 cGy total body irradiation (TBI) or 10 mg/kg busulfan—with or without posttransplantation immunosuppression. In 6 of 11 treated CLAD dogs, therapeutic levels of CD18+ leukocytes were achieved. Conditioning with either TBI or busulfan allowed long-term engraftment, and immunosuppression was not required for efficacy. The percentage of CD18+ leukocytes in the peripheral blood progressively increased over 6 to 8 months after infusion to levels ranging from 1.26% to 8.37% at 1-year follow-up in the 6 dogs. These levels resulted in reversal or moderation of the severe CLAD phenotype. Linear amplification–mediated polymerase chain reaction assays indicated polyclonality of insertion sites. These results describe ex vivo hematopoietic stem cell gene transfer in a disease-specific, large animal model using 2 clinically applicable conditioning regimens, and they provide support for the use of nonmyeloablative conditioning regimens in preclinical protocols of retroviral-mediated gene transfer for nonmalignant hematopoietic diseases such as LAD. PMID:16868255

  5. Disease Phenotypes in a Mouse Model of RNA Toxicity Are Independent of Protein Kinase Cα and Protein Kinase Cβ

    PubMed Central

    Kim, Yun K.; Yadava, Ramesh S.; Mandal, Mahua; Mahadevan, Karunasai; Yu, Qing; Leitges, Michael; Mahadevan, Mani S.

    2016-01-01

    Myotonic dystrophy type 1(DM1) is the prototype for diseases caused by RNA toxicity. RNAs from the mutant allele contain an expanded (CUG)n tract within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The toxic RNAs affect the function of RNA binding proteins leading to sequestration of muscleblind-like (MBNL) proteins and increased levels of CELF1 (CUGBP, Elav-like family member 1). The mechanism for increased CELF1 is not very clear. One favored proposition is hyper-phosphorylation of CELF1 by Protein Kinase C alpha (PKCα) leading to increased CELF1 stability. However, most of the evidence supporting a role for PKC-α relies on pharmacological inhibition of PKC. To further investigate the role of PKCs in the pathogenesis of RNA toxicity, we generated transgenic mice with RNA toxicity that lacked both the PKCα and PKCβ isoforms. We find that these mice show similar disease progression as mice wildtype for the PKC isoforms. Additionally, the expression of CELF1 is also not affected by deficiency of PKCα and PKCβ in these RNA toxicity mice. These data suggest that disease phenotypes of these RNA toxicity mice are independent of PKCα and PKCβ. PMID:27657532

  6. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

    PubMed Central

    Eng, C. M.; Ashley, G. A.; Burgert, T. S.; Enriquez, A. L.; D'Souza, M.; Desnick, R. J.

    1997-01-01

    BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the alpha-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and their family members. The seven alpha-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. RESULTS: Two patients with the mild cardiac phenotype had missense mutations, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T-->C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively. CONCLUSIONS: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy. Images FIG. 2 PMID:9100224

  7. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease

    PubMed Central

    Sánchez-Danés, Adriana; Richaud-Patin, Yvonne; Carballo-Carbajal, Iria; Jiménez-Delgado, Senda; Caig, Carles; Mora, Sergio; Di Guglielmo, Claudia; Ezquerra, Mario; Patel, Bindiben; Giralt, Albert; Canals, Josep M; Memo, Maurizio; Alberch, Jordi; López-Barneo, José; Vila, Miquel; Cuervo, Ana Maria; Tolosa, Eduard; Consiglio, Antonella; Raya, Angel

    2012-01-01

    Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type. PMID:22407749

  8. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    SciTech Connect

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A.; Lewis, R.A.; MacCluer, J.W.; Schwartz, P.J.; Locati, E.H.; Tzivoni, D.

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  9. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease

    PubMed Central

    Veyradier, Agnès; Boisseau, Pierre; Fressinaud, Edith; Caron, Claudine; Ternisien, Catherine; Giraud, Mathilde; Zawadzki, Christophe; Trossaert, Marc; Itzhar-Baïkian, Nathalie; Dreyfus, Marie; d’Oiron, Roseline; Borel-Derlon, Annie; Susen, Sophie; Bezieau, Stéphane; Denis, Cécile V.; Goudemand, Jenny

    2016-01-01

    Abstract von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which

  10. Alcohol and Aggression.

    ERIC Educational Resources Information Center

    Gustafson, Roland

    1994-01-01

    Reviews the acute effects of alcohol on aggressive responding. From experimental studies that use human subjects, it is concluded that a moderate dose of alcohol does not increase aggression if subjects are unprovoked. Under provocative situations, aggression is increased as a function of alcohol intoxication, provided that subjects are restricted…

  11. Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes.

    PubMed

    Hoffman, Eric A; Lynch, David A; Barr, R Graham; van Beek, Edwin J R; Parraga, Grace

    2016-03-01

    Pulmonary x-ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient-relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well-summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD.

  12. FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

    PubMed

    Mak, Victor C Y; Wong, Oscar G W; Siu, Michelle K Y; Wong, Esther S Y; Ng, Wai-Yan; Wong, Richard W C; Chan, Ka-Kui; Ngan, Hextan Y S; Cheung, Annie N Y

    2015-07-01

    Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.

  13. Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

    PubMed Central

    Szilagyi, Andrew; Leighton, Henry; Burstein, Barry; Xue, Xiaoqing

    2014-01-01

    Countries with high lactase nonpersistence (LNP) or low lactase persistence (LP) populations have lower rates of some “western” diseases, mimicking the effects of sunshine and latitude. Inflammatory bowel disease (IBD), ie, Crohn’s disease and ulcerative colitis, is putatively also influenced by sunshine. Recent availability of worldwide IBD rates and lactase distributions allows more extensive comparisons. The aim of this study was to evaluate the extent to which modern day lactase distributions interact with latitude, sunshine exposure, and IBD rates. National IBD rates, national distributions of LP/LNP, and population-weighted average national annual ultraviolet B exposure were obtained, estimated, or calculated from the literature. Negative binomial analysis was used to assess the relationship between the three parameters and IBD rates. Analyses for 55 countries were grouped in three geographic domains, ie, global, Europe, and non-Europe. In Europe, both latitude and ultraviolet B exposure correlate well with LP/LNP and IBD. In non-Europe, latitude and ultraviolet B exposure correlate weakly with LP/LNP, but the latter retains a more robust correlation with IBD. In univariate analysis, latitude, ultraviolet B exposure, and LP/LNP all had significant relationships with IBD. Multivariate analysis showed that lactase distributions provided the best model of fit for IBD. The model of IBD reveals the evolutionary effects of the human lactase divide, and suggests that latitude, ultraviolet B exposure, and LP/LNP mimic each other because LP/LNP follows latitudinal directions toward the equator. However, on a large scale, lactase patterns also follow lateral polarity. The effects of LP/LNP in disease are likely to involve complex interactions. PMID:24971037

  14. Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model.

    PubMed

    Szilagyi, Andrew; Leighton, Henry; Burstein, Barry; Xue, Xiaoqing

    2014-01-01

    Countries with high lactase nonpersistence (LNP) or low lactase persistence (LP) populations have lower rates of some "western" diseases, mimicking the effects of sunshine and latitude. Inflammatory bowel disease (IBD), ie, Crohn's disease and ulcerative colitis, is putatively also influenced by sunshine. Recent availability of worldwide IBD rates and lactase distributions allows more extensive comparisons. The aim of this study was to evaluate the extent to which modern day lactase distributions interact with latitude, sunshine exposure, and IBD rates. National IBD rates, national distributions of LP/LNP, and population-weighted average national annual ultraviolet B exposure were obtained, estimated, or calculated from the literature. Negative binomial analysis was used to assess the relationship between the three parameters and IBD rates. Analyses for 55 countries were grouped in three geographic domains, ie, global, Europe, and non-Europe. In Europe, both latitude and ultraviolet B exposure correlate well with LP/LNP and IBD. In non-Europe, latitude and ultraviolet B exposure correlate weakly with LP/LNP, but the latter retains a more robust correlation with IBD. In univariate analysis, latitude, ultraviolet B exposure, and LP/LNP all had significant relationships with IBD. Multivariate analysis showed that lactase distributions provided the best model of fit for IBD. The model of IBD reveals the evolutionary effects of the human lactase divide, and suggests that latitude, ultraviolet B exposure, and LP/LNP mimic each other because LP/LNP follows latitudinal directions toward the equator. However, on a large scale, lactase patterns also follow lateral polarity. The effects of LP/LNP in disease are likely to involve complex interactions.

  15. Phenotypic characterization of CD8+ T cell populations in HIV disease and in anti-HIV immunity.

    PubMed

    Watret, K C; Whitelaw, J A; Froebel, K S; Bird, A G

    1993-04-01

    The CD8+ T cell population is believed to play an important role in the control of viral infection, both for suppression of viral replication and for cytotoxic activity against viral infected cells. Elevated numbers of CD8+ T cells have been demonstrated in HIV infection, and CD8+ cytotoxic T cell (CTL) activity is associated with the early, asymptomatic stage of disease. We investigated the phenotypic characteristics of the CD8 population, in whole blood, in HIV disease and determined the predominant CD8+ subpopulation involved in anti-HIV CTL activity. We found that CD8+ T cells co-expressing markers of activation (HLA-DR), memory (CD45RO, CD29), and cytotoxic activity (S6F1) were significantly elevated in the early stages of disease, while the numbers of naive (CD45RA) cells remained unchanged. Progression to AIDS resulted in an overall loss of absolute CD8+ T cells, though the percentages of CD8+ HLA-DR+ and CD8+ S6F1+ remained elevated. In contrast to patients in the late stages of disease, anti-HIVgag CTL activity, following in vitro stimulation, was present in most HIV+ asymptomatic subjects and was associated with an expansion of CD8+ HLA-DR+ and CD8+ CD45RO+ cells. The absence of CTL activity was associated with a reduced ability of these populations to expand in vitro and with a significant loss of peripheral CD4+ T cells, independent of clinical stage. We suggest that CD8+ expressing HLA-DR+ CD45RO+ and S6F1+ play an important role in anti-HIV cytotoxicity.

  16. VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease.

    PubMed

    An, Wei; Mohapatra, Bhopal C; Zutshi, Neha; Bielecki, Timothy A; Goez, Benjamin T; Luan, Haitao; Iseka, Fany; Mushtaq, Insha; Storck, Matthew D; Band, Vimla; Band, Hamid

    2016-09-13

    CBL and CBL-B ubiquitin ligases play key roles in hematopoietic stem cell homeostasis and their aberrations are linked to leukemogenesis. Mutations of CBL, often genetically-inherited, are particularly common in Juvenile Myelomonocytic Leukemia (JMML), a disease that manifests early in children. JMML is fatal unless corrected by bone marrow transplant, which is effective in only half of the recipients, stressing the need for animal models that recapitulate the key clinical features of this disease. However, mouse models established so far only develop hematological malignancy in adult animals. Here, using VAV1-Cre-induced conditional CBL/CBL-B double knockout (DKO) in mice, we established an animal model that exhibits a neonatal myeloproliferative disease (MPD). VAV1-Cre induced DKO mice developed a strong hematological phenotype at postnatal day 10, including severe leukocytosis and hepatomegaly, bone marrow cell hypersensitivity to cytokines including GM-CSF, and rapidly-progressive disease and invariable lethality. Interestingly, leukemic stem cells were most highly enriched in neonatal liver rather than bone marrow, which, along with the spleen and thymus, were hypo-cellular. Nonetheless, transplantation assays showed that both DKO bone marrow and liver cells can initiate leukemic disease in the recipient mice with seeding of both spleen and bone marrow. Together, our results support the usefulness of the new hematopoietic-specific CBL/CBL-B double KO animal model to study JMML-related pathogenesis and to further understand the function of CBL family proteins in regulating fetal and neonatal hematopoiesis. To our knowledge, this is the first mouse model that exhibits neonatal MPD in infancy, by day 10 of postnatal life.

  17. VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease

    PubMed Central

    An, Wei; Mohapatra, Bhopal C.; Zutshi, Neha; Bielecki, Timothy A.; Goez, Benjamin T.; Luan, Haitao; Iseka, Fany; Mushtaq, Insha; Storck, Matthew D.; Band, Vimla; Band, Hamid

    2016-01-01

    CBL and CBL-B ubiquitin ligases play key roles in hematopoietic stem cell homeostasis and their aberrations are linked to leukemogenesis. Mutations of CBL, often genetically-inherited, are particularly common in Juvenile Myelomonocytic Leukemia (JMML), a disease that manifests early in children. JMML is fatal unless corrected by bone marrow transplant, which is effective in only half of the recipients, stressing the need for animal models that recapitulate the key clinical features of this disease. However, mouse models established so far only develop hematological malignancy in adult animals. Here, using VAV1-Cre-induced conditional CBL/CBL-B double knockout (DKO) in mice, we established an animal model that exhibits a neonatal myeloproliferative disease (MPD). VAV1-Cre induced DKO mice developed a strong hematological phenotype at postnatal day 10, including severe leukocytosis and hepatomegaly, bone marrow cell hypersensitivity to cytokines including GM-CSF, and rapidly-progressive disease and invariable lethality. Interestingly, leukemic stem cells were most highly enriched in neonatal liver rather than bone marrow, which, along with the spleen and thymus, were hypo-cellular. Nonetheless, transplantation assays showed that both DKO bone marrow and liver cells can initiate leukemic disease in the recipient mice with seeding of both spleen and bone marrow. Together, our results support the usefulness of the new hematopoietic-specific CBL/CBL-B double KO animal model to study JMML-related pathogenesis and to further understand the function of CBL family proteins in regulating fetal and neonatal hematopoiesis. To our knowledge, this is the first mouse model that exhibits neonatal MPD in infancy, by day 10 of postnatal life. PMID:27449297

  18. Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

    PubMed

    Cook, J R; Carta, L; Galatioto, J; Ramirez, F

    2015-01-01

    Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor β (TGFβ) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFβ pathway. While TGFβ antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFβ signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

  19. Phenotypical and genotypical characterization of Shewanella putrefaciens strains isolated from diseased freshwater fish.

    PubMed

    Pękala, A; Kozińska, A; Paździor, E; Głowacka, H

    2015-03-01

    Between 2007 and 2012, a variety of disease outbreaks most often characterized by skin disorders were observed among different species of freshwater fish in Poland. In most cases, the clinical signs included focally necrotized gills, necrotic skin lesions or ulcers. Internally, haemorrhages, oedematous kidney and abnormal spleen enlargement were generally noted. The disorders were accompanied by increased mortality. Most of the problems concerned cultured common carp Cyprinus carpio L. and rainbow trout Oncorhynchus mykiss (Walbaum). Fish have been examined from a number of these farms, and additionally, the wild and ornamental fish with similar clinical signs of diseases were also tested. Bacteria were isolated consistently from lesions and internal organs. They had characteristic orange-pigmented colonies which grew in pure culture or constituted 55-95% of total bacterial flora. One hundred and eighteen isolates were collected and biochemically identified as Shewanella putrefaciens group, and this was confirmed by sequencing. Challenge tests confirmed the pathogenicity of these bacteria. This is the first report characterizing and describing S. putrefaciens as a pathogen of different species of freshwater fish in Europe.

  20. Hearing regulates Drosophila aggression.

    PubMed

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

    2017-02-21

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

  1. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes

    PubMed Central

    Raja, Waseem K.; Mungenast, Alison E.; Lin, Yuan-Ta; Ko, Tak; Abdurrob, Fatema; Seo, Jinsoo; Tsai, Li-Huei

    2016-01-01

    The dismal success rate of clinical trials for Alzheimer’s disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD. PMID:27622770

  2. A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice

    PubMed Central

    Shukla, Varsha; Zheng, Ya-Li; Mishra, Santosh K.; Amin, Niranjana D.; Steiner, Joseph; Grant, Philip; Kesavapany, Sashi; Pant, Harish C.

    2013-01-01

    Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70–80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.—Shukla, V., Zheng, Y.-L., Mishra, S. K., Amin, N. D., Steiner, J., Grant, P., Kesavapany, S., Pant, H. C. A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. PMID:23038754

  3. Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration.

    PubMed

    Saini, Janmeet S; Corneo, Barbara; Miller, Justine D; Kiehl, Thomas R; Wang, Qingjie; Boles, Nathan C; Blenkinsop, Timothy A; Stern, Jeffrey H; Temple, Sally

    2017-01-21

    Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human-induced pluripotent stem cells (hiPSCs) from patients with diagnosed AMD, including two donors with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from the AMD donors show significantly increased complement and inflammatory factors, which are most exaggerated in the ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discover that nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins and inflammatory and complement factors while upregulating nucleosome, ribosome, and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.

  4. Analysis of thiopurine S-methyltransferase phenotype-genotype in a Tunisian population with Crohn's disease.

    PubMed

    Ben Salah, Lynda; Belkhiria el Haj Amor, Mouna; Chbili, Chahra; Khlifi, Saida; Fathallah, Neila; Bougmiza, Iheb; Ben Jazia, Elhem; Houdret, Nicole; Ben Salem, Chaker; Saguem, Saad

    2013-12-01

    This study was conducted to investigate the thiopurine S-methyltransferase TPMT activity distribution and gene mutations in Tunisian population with positive diagnostic for Crohn's disease. TPMT activity was measured in Tunisian population (n = 88) by a high performance liquid chromatography assay. Polymerase chain reaction-based methods were used to determine the frequency of TPMT mutant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C. TPMT activity was normally distributed, ranging from 4.58 to 35.27 nmol/(h ml) RBC with a mean of 18.67 ± 7.10 nmol/(h ml) RBC. Seven TPMT*3A heterozygotes and one TPMT*3C homozygote were found in 88 patients, with allele frequencies of 0.039 and 1.13, respectively. TPMT*3A and the TPMT*3C, which cause the largest decrease in enzyme activity, were both variant alleles detected in the Tunisian population.

  5. Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

    PubMed

    Pellagatti, Andrea; Boultwood, Jacqueline

    2017-01-01

    Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

  6. Evidence of selection on phenotypic plasticity and cost of plasticity in response to host-feeding sources in the major Chagas disease vector Triatoma infestans.

    PubMed

    Nattero, Julieta; Leonhard, Gustavo; Gürtler, Ricardo E; Crocco, Liliana B

    2015-12-01

    Phenotypic plasticity is the ability of a genotype to display alternative phenotypes in different environments. Understanding how plasticity evolves and the factors that favor and constrain its evolution have attracted great interest. We investigated whether selection on phenotypic plasticity and costs of plasticity affect head and wing morphology in response to host-feeding sources in the major Chagas disease vector Triatoma infestans. Full-sib families were assigned to blood-feeding on either live pigeons or guinea pigs throughout their lives. We measured diet-induced phenotypic plasticity on wing and head size and shape; characterized selection on phenotypic plasticity for female and male fecundity rates, and evaluated costs of plasticity. Wing size and shape variables exhibited significant differences in phenotypic plasticity associated with host-feeding source in female and male bugs. Evidence of selection on phenotypic plasticity was detected in head size and shape for guinea pig-fed females. A lower female fecundity rate was detected in more plastic families for traits that showed selection on plasticity. These results provide insights into the morphological phenotypic plasticity of T. infestans, documenting fitness advantages of head size and shape for females fed on guinea pigs. This vector species showed measurable benefits of responding plastically to environmental variation rather than adopting a fixed development plan. The presence of cost of plasticity suggests constraints on the evolution of plasticity. Our study indicates that females fed on guinea pigs (and perhaps on other suitable mammalian hosts) have greater chances of evolving under selection on phenotypic plasticity subject to some constraints.

  7. Genomic screening for dissection of a complex disease: The multiple sclerosis phenotype

    SciTech Connect

    Haines, J.L.; Bazyk, A.; Gusella, J.F.

    1994-09-01

    Application of positional cloning to diseases with a complex etiology is fraught with problems. These include undefined modes of inheritance, heterogeneity, and epistasis. Although microsatellite markers now make genotyping the genome a straightforward task, no single analytical method is available to efficiently and accurately use these data for a complex disease. We have developed a multi-stage genomic screening strategy which uses a combination of non-parametric approaches (Affected Pedigree Member (APM) linkage analysis and robust sib pair analysis (SP)), and the parametric lod score approach (using four different genetic models). To warrant follow-up, a marker must have two or more of: a nominal P value of 0.05 or less on the non-parametric tests, or a lod score greater than 1.0 for any model. Two adjacent markers each fulfilling one criterion are also considered for follow-up. These criteria were determined both by simulation studies and our empirical experience in screening a large number of other disorders. We applied this approach to multiple sclerosis (MS), a complex neurological disorder with a strong but ill-defined genetic component. Analysis of the first 91 markers from our screen of 55 multiplex families found 5 markers which met the SP criteria, 13 markers which met the APM criteria, and 8 markers which met the lod score criteria. Five regions (on chromosomes 2, 4, 7, 14, and 19) met our overall criteria. However, no single method identified all of these regions, suggesting that each method is sensitive to various (unknown) influences. The chromosome 14 results were not supported by follow-up typing and analysis of markers in that region, but the chromosome 19 results remain well supported. Updated screening results will be presented.

  8. The Role of Dopamine Replacement on the Behavioural Phenotype of Parkinson’s Disease

    PubMed Central

    Alobaidi, Hajar; Pall, Hardev

    2013-01-01

    Objectives: The pharmacotherapy of Parkinson’s disease (PD) is often challenging as clinicians have to find a favourable balance between the efficacy on motor symptoms and side effect profiles of different dopaminergic medications. We aimed to assess the available evidence on the role of dopamine agonist monotherapy as an alternative to Levodopa in the treatment of motor symptoms of PD, along with the role of dopamine antagonists in the treatment of PD-related psychosis. Methods: We performed a systematic literature review using the databases MEDLINE, EMBASE, PsycINFO and the Cochrane Library Central register of controlled trials. Two searches were performed, ‘Search 1’ extracting trials on dopamine agonists, and ‘Search 2’ on atypical antipsychotics. Eligible studies were Double-blind Randomised Controlled Trials (RCTs) using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Brief Psychiatric Rating Scale (BPRS) as outcome measures for Search 1 and 2, respectively. Results: 16 relevant RCTs were extracted from the search results. Overall, dopamine agonists were shown to significantly improve UPDRS scores, with a mean percentage improvement of 14.4% compared to −1.9% in the control arm (P value < 0.05)However, their side effect profile illustrated they were associated with twice the incidence of psychotic symptoms in comparison to the controls. The results on the efficacy of atypical antipsychotics for the treatment of PD-related psychosis were not significant. Conclusions: This evidence-based review confirmed that dopamine agonists can be an effective and safe treatment as monotherapy in PD, however psychotic symptoms remain a significant side effect. Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy. PMID:22713412

  9. Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction

    PubMed Central

    Esposito, Federica; Guaschino, Clara; Sorosina, Melissa; Clarelli, Ferdinando; Ferre', Laura; Mascia, Elisabetta; Santoro, Silvia; Pagnesi, Matteo; Radaelli, Marta; Colombo, Bruno; Moiola, Lucia; Rodegher, Mariaemma; Stupka, Elia; Martinelli, Vittorio; Comi, Giancarlo

    2015-01-01

    Objective: To investigate the role of known multiple sclerosis (MS)-associated genetic variants in MS familial aggregation, clinical expression, and accuracy of disease prediction in sporadic and familial cases. Methods: A total of 1,443 consecutive patients were screened for MS and familial autoimmune history in a hospital-based Italian cohort. Among them, 461 sporadic and 93 familial probands were genotyped for 107 MS-associated polymorphisms. Their effect sizes were combined to calculate the weighted genetic risk score (wGRS). Results: Family history of MS was reported by 17.2% of probands, and 33.8% reported a familial autoimmune disorder, with autoimmune thyroiditis and psoriasis being the most frequent. No difference in wGRS was observed between sporadic and familial MS cases. In contrast, a lower wGRS was observed in probands with greater familial aggregation (>1 first-degree relative or >2 relatives with MS) (p = 0.03). Also, female probands of familial cases with greater familial aggregation had a lower wGRS than sporadic cases (p = 0.0009) and male probands of familial cases (p = 0.04). An inverse correlation between wGRS and age at onset was observed (p = 0.05). The predictive performance of the genetic model including all known MS variants was modest but greater in sporadic vs familial cases (area under the curve = 0.63 and 0.57). Conclusions: Additional variants outside the known MS-associated loci, rare variants, and/or environmental factors may explain disease occurrence within families; in females, hormonal and epigenetic factors probably have a predominant role in explaining familial aggregation. The inclusion of these additional factors in future versions of aggregated genetic measures could improve their predictive ability. PMID:26185776

  10. Creutzfeldt–Jakob Disease Phenotype and Course: Our Experience from a Tertiary Center

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Philip, Mariamma; Gadad, Veeranna

    2016-01-01

    Introduction: Prion diseases are protein conformation disorders and neither caused by viroid or virus but is a transmissible particle labeled a prion by Pruisner. Normal prion protein becomes infectious by a different folding, but the triggers are not known. Based on the characteristic brain pathology, they are grouped under spongiform encephalopathy affecting both man and animals. Estimated prevalence is one per million. Creutzfeldt–Jakob disease (CJD) registry from National Institute and Neurosciences (NIMHANS), Bengaluru, reported 69 cases in 30 years. Patient and Methods: Patients seen by our team from December 2011 to October 2015 who satisfied criteria for probable CJD were evaluated for clinical, electrophysiological, radiological, and demographic factors. None of them underwent histopathological examination of brain tissue or tonsils. Cerebrospinal fluid protein 14-3-3 was not done. All of them were followed up by telephonic inquiry for the course of the illness. All of them received symptomatic medications with anticonvulsants, flupirtine 200 mg orally daily, and other symptomatic medications. Results: Sporadic CJD is the most common form seen in India and is probably under reported. males seem to be more affected, and the mean duration for the bed bound state is 12 months. Drugs were only effective for a very brief period in controlling myoclonus and behavior. Discussion: Sporadic CJD is one of the most common and rapidly fatal forms of dementia in India. Cortical ribboning and periodic complexes are the most common laboratory findings. Familial CJD is a very rare occurrence and variant CJD is probably not prevalent. Conclusion: All patients with rapidly progressive dementia should be handled with biohazard precautions unless proved otherwise. Role of alcohol and smoking in the transformation of PrPc to PrPsc needs to be evaluated. PMID:27833227

  11. Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo.

    PubMed

    O'Brien, Robert; DeGiacomo, Francesco; Holcomb, Jennifer; Bonner, Akilah; Ring, Karen L; Zhang, Ningzhe; Zafar, Khan; Weiss, Andreas; Lager, Brenda; Schilling, Birgit; Gibson, Bradford W; Chen, Sylvia; Kwak, Seung; Ellerby, Lisa M

    2015-07-31

    The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken β-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552-Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148).

  12. Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo*

    PubMed Central

    O'Brien, Robert; DeGiacomo, Francesco; Holcomb, Jennifer; Bonner, Akilah; Ring, Karen L.; Zhang, Ningzhe; Zafar, Khan; Weiss, Andreas; Lager, Brenda; Schilling, Birgit; Gibson, Bradford W.; Chen, Sylvia; Kwak, Seung; Ellerby, Lisa M.

    2015-01-01

    The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken β-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552-Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148). PMID:26025364

  13. TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn's disease.

    PubMed

    Grillo, Alessia Rosaria; Scarpa, Melania; D'Incà, Renata; Brun, Paola; Scarpa, Marco; Porzionato, Andrea; De Caro, Raffaele; Martines, Diego; Buda, Andrea; Angriman, Imerio; Palù, Giorgio; Sturniolo, Giacomo Carlo; Castagliuolo, Ignazio

    2015-09-15

    Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) signaling can mediate inflammatory responses as well as tissue remodeling. Intestinal mucosal myofibroblast (IMF) activation drives gut fibrosis in Crohn's disease (CD); however, the molecular pathways involved are largely unknown. Thus we investigated the yet-unknown expression and function of TAK1 in human CD-associated fibrosis. Ileal surgical specimens, ileal biopsies, and IMF isolated from controls and CD patients were analyzed for TAK1 and its active phosphorylated form (pTAK1) by Western blotting, immunohistochemistry, and real-time quantitative PCR. TAK1 pharmacological inhibition and silencing were used to assess its role in collagen and inflammatory cytokine synthesis in IMF. TAK1 and pTAK1 levels increased in ileum specimens from CD patients compared with controls and correlated to tissue fibrosis. Similarly, TAK1 mRNA in ileal biopsies of CD patients correlated with fibrogenic marker expression but not inflammatory cytokines. CD-derived IMF showed higher TAK1 and pTAK1 expression associated with increased collagen1(α)1 mRNA levels compared with control IMF. TGF-β1 promoted pTAK1 nuclear translocation and collagen synthesis. TAK1 inhibition or silencing significantly reduced TGF-β1-stimulated collagen production and normalized the profibrogenic phenotype of CD-derived IMF. Taken together, these data suggest that TAK1 activation and nuclear translocation induce and maintain a fibrogenic phenotype in the IMF. Thus the TAK1 signaling pathway may represent a suitable target to design new, antifibrotic therapies.

  14. [Aggressive and prosocial behavior in childhood psychopathology].

    PubMed

    Vida, Péter; Halász, József; Gádoros, Júlia

    2013-01-01

    Aggressive/attacking and helpful/emphatic/prosocial behaviors are extremely important in human relationships. Both high levels of aggression and deficits of prosociality play important role in the development and conservation of mental disorders. We review the measurement options and clinical importance of aggressive and prosocial behavior. The typical developmental pathways and the genetic and environmental background of these behaviors are presented. The clinical tools used in the measurement of aggression and prosociality are summarized in the present paper, with specific attention on questionnaires applied in Hungarian practice. The connections between diagnostic categories (conduct disorder, oppositional-defiant disorder, attention deficit and hyperactive disorder, autism spectrum disorders) and the two behaviors are evaluated. In the end, we present those additional research projects that explore the cognitive-emotional background of aggressive or prosocial behavior with clinical relevance either in the diagnosis or in the treatment of child psychiatric diseases.

  15. Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype.

    PubMed

    Lankisch, Tim O; Moebius, Ulrike; Wehmeier, Michael; Behrens, Georg; Manns, Michael P; Schmidt, Reinhold E; Strassburg, Christian P

    2006-11-01

    Gilbert's disease leads to intermittent non-hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV-treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (-66C) and UGT1A7 (-57G) promoter variants, and UGT1A7(129K/131K). ATV treatment increased median bilirubin levels from 10 to 41 micromol/L (P = .001) with hyperbilirubinemia exceeding 43 micromol/L in 37%. Hyperbilirubinemia over 43 micromol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3-66C, UGT1A7-57G, and UGT1A7(129K/131K), although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 micromol/L) to 41% to 46.1% (43 to >85 micromol/L), and 100% (>85 micromol/L). All six patients with hyperbilirubinemia greater than 85 micromol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion, the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy.

  16. Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels.

    PubMed

    Rué, Laura; Bañez-Coronel, Mónica; Creus-Muncunill, Jordi; Giralt, Albert; Alcalá-Vida, Rafael; Mentxaka, Gartze; Kagerbauer, Birgit; Zomeño-Abellán, M Teresa; Aranda, Zeus; Venturi, Veronica; Pérez-Navarro, Esther; Estivill, Xavier; Martí, Eulàlia

    2016-11-01

    Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.

  17. Callosal microstructural abnormalities in Alzheimer's disease and alcoholism: same phenotype, different mechanisms.

    PubMed

    Pitel, Anne-Lise; Chanraud, Sandra; Sullivan, Edith V; Pfefferbaum, Adolf

    2010-10-30

    Magnetic resonance (MRI) and diffusion tensor imaging (DTI) data were acquired in 13 Alzheimer's disease (AD) patients, 15 elderly alcoholics, and 32 elderly controls. Midsagittal area, length, dorsoventral height, fractional anisotropy (FA), and mean diffusivity (MD) of the total corpus callosum and volume of the lateral ventricles were measured; area, FA, and MD were also determined for the callosal genu, body, and splenium. On DTI, both patient groups had lower FA and higher MD than controls in all callosal regions. On MRI, both patient groups had smaller genu than controls; additional size deficits were present in the alcoholism group's callosal body and the AD group's splenium. The callosal arch was higher in the AD but not the alcoholic group compared with controls. The two patient groups had larger ventricles than controls, and the AD group had larger ventricles than the alcoholic group. Callosal area correlated with its height, and callosal FA and MD correlated with ventricular volume in AD, whereas callosal area correlated only with FA in alcoholics. In AD, the disruption of the callosal integrity, which was associated with distorted callosal shape, was related to ventricular dilation, which has been shown in twin studies to be under a multitude of genetic, polygenetic, and environmental influences. Conversely, in alcoholism, disruption of callosal microstructural integrity was related to shrinkage of the corpus callosum itself.

  18. Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

    PubMed Central

    Rué, Laura; Bañez-Coronel, Mónica; Creus-Muncunill, Jordi; Giralt, Albert; Alcalá-Vida, Rafael; Mentxaka, Gartze; Kagerbauer, Birgit; Aranda, Zeus; Venturi, Veronica; Pérez-Navarro, Esther; Estivill, Xavier

    2016-01-01

    Huntington’s disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid–modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders. PMID:27721240

  19. Phenomics Research on Coronary Heart Disease Based on Human Phenotype Ontology

    PubMed Central

    Shi, Qi; Gao, Kuo; Zhao, Huihui; Wang, Juan; Zhai, Xing; Chen, Jianxin; Wang, Wei

    2014-01-01

    The characteristics of holistic, dynamics, complexity, and spatial and temporal features enable “Omics” and theories of TCM to interlink with each other. HPO, namely, “characterization,” can be understood as a sorting and generalization of the manifestations shown by people with diseases on the basis of the phenomics. Syndrome is the overall “manifestation” of human body pathological and physiological changes expressed by four diagnostic methods' information. The four diagnostic methods' data could be the most objective and direct manifestations of human body under morbid conditions. In this aspect, it is consistent with the connation of “characterization.” Meanwhile, the four diagnostic methods' data also equip us with features of characterization in HPO. In our study, we compared 107 pieces of four diagnostic methods' information with the “characterization database” to further analyze data of four diagnostic methods' characterization in accordance with the common characteristics of four diagnostic methods' information and characterization and integrated 107 pieces of four diagnostic methods' data to relevant items in HPO and finished the expansion of characterization information in HPO. PMID:25610858

  20. Phenotyping the effect of diet on non-alcoholic fatty liver disease.

    PubMed

    de Wit, Nicole J W; Afman, Lydia A; Mensink, Marco; Müller, Michael

    2012-12-01

    Non-alcoholic fatty liver disease (NAFLD) is associated with the growing incidence of metabolic syndrome. Diet is an important contributor to the pathogenesis of NAFLD. In this review, we focused on recent publications reporting on the effect of macro- and micronutrients on development and progression of NAFLD. In general, saturated fat and fructose seem to stimulate hepatic lipid accumulation and progression into NASH, whereas unsaturated fat, choline, antioxidants, and high-protein diets rich in isoflavones seem to have a more preventive effect. Knowledge of the underlying mechanisms by which diet affects NAFLD is expanding, not in the least due to innovative techniques, such as genomics tools that provide detailed comprehensive information on a large high-throughput scale. Although most nutrients seem to interfere with the balance between hepatic de novo lipogenesis (endogenous synthesis of fatty acids) and lipid oxidation (burning fat for energy), there are also indications that diet can trigger or prevent hepatic lipid accumulation by influencing the interaction between liver, gut, and adipose tissue. This review now gives a current detailed overview of diet-mediated mechanisms underlying NAFLD development and progression and summarizes recent results of genomics (transcriptomics, proteomics and metabolomics) studies that contribute to improved staging, monitoring and understanding of NAFLD pathophysiology.

  1. Differential Effects of Delayed Aging on Phenotype and Striatal Pathology in a Murine Model of Huntington Disease

    PubMed Central

    Tallaksen-Greene, Sara J.; Sadagurski, Marianna; Zeng, Li; Mauch, Roseanne; Perkins, Matthew; Banduseela, Varuna C.; Lieberman, Andrew P.; Miller, Richard A.; Paulson, Henry L.

    2014-01-01

    The common neurodegenerative syndromes exhibit age-related incidence, and many Mendelian neurodegenerative diseases exhibit age-related penetrance. Mutations slowing aging retard age related pathologies. To assess whether delayed aging retards the effects of a mutant allele causing a Huntington's disease (HD)-like syndrome, we generated compound mutant mice, placing a dominant HD knock-in polyglutamine allele onto the slow-aging Snell dwarf genotype. The Snell genotype did not affect mutant huntingtin protein expression. Bigenic and control mice were evaluated prospectively from 10 to 100 weeks of age. Adult HD knock-in allele mice lost weight progressively with weight loss blunted significantly in male bigenic HD knock-in/Snell dwarf mice. Impaired balance beam performance developed significantly more slowly in bigenic HD knock-in/Snell dwarf mice. Striatal dopamine receptor expression was diminished significantly and similarly in all HD-like mice, regardless of the Snell genotype. Striatal neuronal intranuclear inclusion burden was similar between HD knock-in mice with and without the Snell genotype, whereas nigral neuropil aggregates were diminished in bigenic HD knock-in/Snell dwarf mice. Compared with control mice, Snell dwarf mice exhibited differences in regional benzodiazepine and cannabinoid receptor binding site expression. These results indicate that delaying aging delayed behavioral decline with little effect on the development of striatal pathology in this model of HD but may have altered synaptic pathology. These results indicate that mutations prolonging lifespan in mice delay onset of significant phenotypic features of this model and also demonstrate dissociation between striatal pathology and a commonly used behavioral measure of disease burden in HD models. PMID:25411494

  2. Mild Left Ventricular Hypertrophy Unravels a Novel Nonsense Mutation of the GLA Gene Associated with the Classical Phenotype of Fabry Disease.

    PubMed

    Azevedo, Olga; Gago, Miguel; Miltenberger-Miltenyi, Gabriel; Gaspar, Paulo; Sousa, Nuno; Cunha, Damião

    2017-02-03

    We report on the clinical, biochemical, and genetic findings of a large family with the classical phenotype of Fabry disease due to the novel nonsense mutation c.607G>T (p.E203X) of the GLA gene, which occurs in the active site of the α-galactosidase A enzyme. This report highlights that (i) Fabry disease diagnosis should be considered in all cases of unexplained left ventricular hypertrophy (LVH), even in its milder forms; (ii) a complete evaluation of patients with unexplained LVH is important to find diagnostic red flags of treatable causes of LVH, such as Fabry disease; (iii) cascade family screening is paramount to the earlier diagnosis and treatment of other affected family members; and (iv) the Fabry disease phenotype is highly variable in heterozygote females, even within the same family.

  3. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    ERIC Educational Resources Information Center

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  4. Orthodontic Management in Aggressive Periodontitis.

    PubMed

    Gyawali, Rajesh; Bhattarai, Bhagabat

    2017-01-01

    Aggressive periodontitis is a type of periodontitis with early onset and rapid progression and mostly affecting young adults who occupy a large percentage of orthodontic patients. The role of the orthodontist is important in screening the disease, making a provisional diagnosis, and referring it to a periodontist for immediate treatment. The orthodontist should be aware of the disease not only before starting the appliance therapy, but also during and after the active mechanotherapy. The orthodontic treatment plan, biomechanics, and appliance system may need to be modified to deal with the teeth having reduced periodontal support. With proper force application and oral hygiene maintenance, orthodontic tooth movement is possible without any deleterious effect in the tooth with reduced bone support. With proper motivation and interdisciplinary approach, orthodontic treatment is possible in patients with controlled aggressive periodontitis.

  5. Orthodontic Management in Aggressive Periodontitis

    PubMed Central

    Bhattarai, Bhagabat

    2017-01-01

    Aggressive periodontitis is a type of periodontitis with early onset and rapid progression and mostly affecting young adults who occupy a large percentage of orthodontic patients. The role of the orthodontist is important in screening the disease, making a provisional diagnosis, and referring it to a periodontist for immediate treatment. The orthodontist should be aware of the disease not only before starting the appliance therapy, but also during and after the active mechanotherapy. The orthodontic treatment plan, biomechanics, and appliance system may need to be modified to deal with the teeth having reduced periodontal support. With proper force application and oral hygiene maintenance, orthodontic tooth movement is possible without any deleterious effect in the tooth with reduced bone support. With proper motivation and interdisciplinary approach, orthodontic treatment is possible in patients with controlled aggressive periodontitis. PMID:28299350

  6. Computed tomography phenotypes in severe, early-onset chronic obstructive pulmonary disease.

    PubMed

    Hersh, Craig P; Jacobson, Francine L; Gill, Ritu; Silverman, Edwin K

    2007-12-01

    Subjects with severe chronic obstructive pulmonary disease (COPD) may have marked differences in emphysema severity on chest computed tomography (CT) scans. Although many patients with severe COPD will have chest CTs performed during their clinical care, chest CTs have not been widely included in epidemiologic and genetic studies of COPD. We sought to determine whether chest CT scans performed for clinical indications can provide useful data in an epidemiologic study of COPD and to determine whether chest CT scans can be used to define subtypes of severe, early-onset COPD. Clinical chest CT scans on 91 probands in the Boston Early-Onset COPD Study were retrospectively reviewed by 2 pulmonologists and 1 to 2 chest radiologists, using a semi-quantitative emphysema severity score, ranging from 0-24. 88 of 91 chest CT scans were suitable for emphysema analysis. There was a wide range of emphysema severity, from mild to severe (1.3-23.7). Emphysema-predominant subjects (upper 3 quartiles of emphysema scores) had more severe airflow obstruction than airway-predominant subjects (lowest quartile of emphysema scores): FEV(1) 17.4% vs. 22.4% predicted, p=0.009. A higher percentage of airway-predominant subjects had a positive bronchodilator response (28.6% vs. 6.7%, p=0.009). Airway-predominant subjects also had a higher frequency of physician-diagnosed asthma (p=0.04) and a trend towards higher serum immunoglobulin E levels (p=0.09). Analysis of siblings of early-onset COPD probands suggested a genetic contribution to the subgroups. Using clinical chest CT scans, we were able to identify an airway-predominant subgroup with asthma-like features among subjects with severe, early-onset COPD.

  7. Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

    PubMed Central

    Doerfler, Phillip A.; Todd, Adrian G.; Clément, Nathalie; Falk, Darin J.; Nayak, Sushrusha; Herzog, Roland W.; Byrne, Barry J.

    2016-01-01

    Pompe disease is a progressive neuromuscular disorder caused by lysosomal accumulation of glycogen from a deficiency in acid alpha-glucosidase (GAA). Replacement of the missing enzyme is available by repeated protein infusions; however, efficacy is limited by immune response and inability to restore enzymatic function in the central nervous system. An alternative therapeutic option is adeno-associated virus (AAV)-mediated gene therapy, which results in widespread gene transfer and prolonged transgene expression. Both enzyme replacement therapy (ERT) and gene therapy can elicit anti-GAA immune reactions that dampen their effectiveness and pose life-threatening risks to patient safety. To modulate the immune responses related to gene therapy, we show that a human codon-optimized GAA (coGAA) driven by a liver-specific promoter (LSP) using AAV9 is capable of promoting immune tolerance in a Gaa−/− mouse model. Copackaging AAV9-LSP-coGAA with the tissue-restricted desmin promoter (AAV9-DES-coGAA) demonstrates the necessary cell autonomous expression in cardiac muscle, skeletal muscle, peripheral nerve, and the spinal cord. Simultaneous high-level expression in liver led to the expansion of GAA-specific regulatory T-cells (Tregs) and induction of immune tolerance. Transfer of Tregs into naïve recipients prevented pathogenic allergic reactions after repeated ERT challenges. Copackaged AAV9 also attenuated preexisting humoral and cellular immune responses, which enhanced the biochemical correction. Our data present a therapeutic design in which simultaneous administration of two copackaged AAV constructs may provide therapeutic benefit and resolve immune reactions in the treatment of multisystem disorders. PMID:26603344

  8. Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

    PubMed Central

    Barbarin, Alice; Cayssials, Emilie; Jacomet, Florence; Nunez, Nicolas Gonzalo; Basbous, Sara; Lefèvre, Lucie; Abdallah, Myriam; Piccirilli, Nathalie; Morin, Benjamin; Lavoue, Vincent; Catros, Véronique; Piaggio, Eliane; Herbelin, André; Gombert, Jean-Marc

    2017-01-01

    Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T

  9. Laboratory diagnosis of legionnaires' disease due to Legionella pneumophila serogroup 1: comparison of phenotypic and genotypic methods.

    PubMed

    Lindsay, Diane S J; Abraham, William H; Findlay, William; Christie, Peter; Johnston, Fiona; Edwards, Giles F S

    2004-03-01

    Laboratory results of 67 cases of legionnaires' disease caused by Legionella pneumophila serogroup (Sg) 1 spanning a 6-year period were analysed by both phenotypic and genotypic methods. The methods compared were urinary antigen enzyme immunoassay (EIA), an immunofluorescent antibody (IFA) test, direct fluorescent antibody (DFA), culture and a 5S rRNA PCR with Southern blotting confirmation. Urine was available in 53 cases, of which 35 (66%) were positive, with an antigen peak observed at 5-10 days after onset of disease symptoms. The IFA test was positive in 62 (92.5%) cases, with 56 (90.3%) cases producing a greater than fourfold rise in titre and 6 (9.7%) giving presumptive high titres of > or =1:128. There were two antibody peaks, one at 10-15 days and another at >25 days after onset. In 23 cases where samples were available, DFA and culture were respectively positive in 5 (22%) and 10 (48%) cases. There was a peak in culture-positives 5-10 days after onset of disease. A Legionella-specific 5S rRNA PCR on patient serum was positive in 54 (80.5%) cases, with a peak in PCR positivity at 6-10 days after disease onset. In 22 of the 67 cases, the full panel of diagnostic methods was available for comparison. The relative sensitivity and specificity of the urinary antigen EIA and the serum PCR was 100%. The IFA gave relative sensitivity and specificity values of 93.8 and 95%. DFA and culture, although 100% specific, produced only low sensitivities, of 19 and 42.8%, respectively. This study has shown that urinary antigen and serum PCR are valuable tests in the acute phase of disease, with excellent sensitivity and specificity values. At present, the Legionella species causing infection requires to be verified by IFA serology and/or culture, but this could become unnecessary as new antigen and L. pneumophila Sg 1-specific PCR tests become available.

  10. Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease

    PubMed Central

    2017-01-01

    Background Bax inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc) expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD) model. Methods We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. Results The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes

  11. A Phylogenetic and Phenotypic Analysis of Salmonella enterica Serovar Weltevreden, an Emerging Agent of Diarrheal Disease in Tropical Regions

    PubMed Central

    Makendi, Carine; Page, Andrew J.; Wren, Brendan W.; Le Thi Phuong, Tu; Clare, Simon; Hale, Christine; Goulding, David; Klemm, Elizabeth J.; Pickard, Derek; Okoro, Chinyere; Hunt, Martin; Thompson, Corinne N.; Phu Huong Lan, Nguyen; Tran Do Hoang, Nhu; Thwaites, Guy E.; Le Hello, Simon; Brisabois, Anne; Weill, François-Xavier; Baker, Stephen; Dougan, Gordon

    2016-01-01

    Salmonella enterica serovar Weltevreden (S. Weltevreden) is an emerging cause of diarrheal and invasive disease in humans residing in tropical regions. Despite the regional and international emergence of this Salmonella serovar, relatively little is known about its genetic diversity, genomics or virulence potential in model systems. Here we used whole genome sequencing and bioinformatics analyses to define the phylogenetic structure of a diverse global selection of S. Weltevreden. Phylogenetic analysis of more than 100 isolates demonstrated that the population of S. Weltevreden can be segregated into two main phylogenetic clusters, one associated predominantly with continental Southeast Asia and the other more internationally dispersed. Subcluster analysis suggested the local evolution of S. Weltevreden within specific geographical regions. Four of the isolates were sequenced using long read sequencing to produce high quality reference genomes. Phenotypic analysis in Hep-2 cells and in a murine infection model indicated that S. Weltevreden were significantly attenuated in these models compared to the classical S. Typhimurium reference strain SL1344. Our work outlines novel insights into this important emerging pathogen and provides a baseline understanding for future research studies. PMID:26867150

  12. Neuroprotective effect of taurine in 3-nitropropionic acid-induced experimental animal model of Huntington's disease phenotype.

    PubMed

    Tadros, Mariane G; Khalifa, Amani E; Abdel-Naim, Ashraf B; Arafa, Hossam M M

    2005-11-01

    An experimental animal model of Huntington's disease (HD) phenotype was induced using the mycotoxin 3-nitropropionic acid (3-NP) and was well characterized behaviorally, neurochemically, morphometrically and histologically. Administration of 3-NP caused a reduction in prepulse inhibition (PPI) of acoustic startle response, locomotor hyper- and/or hypoactivity, bilateral striatal lesions, brain oxidative stress, and decreased striatal gamma-aminobutyric acid (GABA) levels. Taurine is a semi-essential beta-amino acid that was demonstrated to have both antioxidant and GABA-A agonistic activity. In this study, treatment with taurine (200 mg/kg daily for 3 days) prior to 3-NP administration reversed both reduced PPI response and locomotor hypoactivity caused by 3-NP injection. Taurine pretreatment also caused about 2-fold increase in GABA concentration compared to 3-NP-treated animals. In addition, taurine demonstrated antioxidant activity against oxidative stress induced by 3-NP administration as evidenced by the reduced striatal malondialdehyde (MDA) and elevated striatal glutathione (GSH) levels. Histochemical examination of striatal tissue showed that prior administration of taurine ahead of 3-NP challenge significantly increased succinate dehydrogenase (SDH) activity compared to 3-NP-treated animals. Histopathological examination further affirmed the neuroprotective effect of taurine in 3-NP-induced HD in rats. Taken together, one may conclude that taurine has neuroprotective role in the current HD paradigm due, at least partly, to its indirect antioxidant effect and GABA agonistic action.

  13. CAG repeat lengths ≥335 attenuate the phenotype in the R6/2 Huntington’s disease transgenic mouse

    PubMed Central

    Dragatsis, I.; Goldowitz, D.; Del Mar, N.; Deng, Y.P.; Meade, C.A.; Liu, Li; Sun, Z.; Dietrich, P.; Yue, J.; Reiner, A.

    2015-01-01

    With spontaneous elongation of the CAG repeat in the R6/2 transgene to ≥335, resulting in a transgene protein too large for passive entry into nuclei via the nuclear pore, we observed an abrupt increase in lifespan to >20 weeks, compared to the 12 weeks common in R6/2 mice with 150 repeats. In the ≥335 CAG mice, large ubiquitinated aggregates of mutant protein were common in neuronal dendrites and perikaryal cytoplasm, but intranuclear aggregates were small and infrequent. Message and protein for the ≥335 CAG transgene were reduced to one-third that in 150 CAG R6/2 mice. Neurological and neurochemical abnormalities were delayed in onset and less severe than in 150 CAG R6/2 mice. These findings suggest that polyQ length and pathogenicity in Huntington’s disease may not be linearly related, and pathogenicity may be less severe with extreme repeats. Both diminished mutant protein and reduced nuclear entry may contribute to phenotype attenuation. PMID:19027857

  14. Phenotypic differences of CD4(+) T cells in response to red blood cell immunization in transfused sickle cell disease patients.

    PubMed

    Vingert, Benoît; Tamagne, Marie; Habibi, Anoosha; Pakdaman, Sadaf; Ripa, Julie; Elayeb, Rahma; Galacteros, Frédéric; Bierling, Philippe; Ansart-Pirenne, Hélène; Bartolucci, Pablo; Noizat-Pirenne, France

    2015-06-01

    Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50-70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4(+) T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4(+) T-cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4(+) T-cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4(+) T cells were associated with the nonresponder status, whereas spontaneous expression of IL-10 by CD4(+) T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb(k) . These findings implicate CD4(+) T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders.

  15. miR-196a Ameliorates Cytotoxicity and Cellular Phenotype in Transgenic Huntington’s Disease Monkey Neural Cells

    PubMed Central

    Carter, Richard L.; Prucha, Melinda S.; Yang, Jinjing; Parnpai, Rangsun; Chan, Anthony W. S.

    2016-01-01

    Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics. PMID:27631085

  16. Metabolic phenotyping of the diseased rat heart using 13C-substrates and ex vivo perfusion in the working mode.

    PubMed

    Vincent, Geneviève; Khairallah, Maya; Bouchard, Bertrand; Des Rosiers, Christine

    2003-01-01

    alliance between ex vivo semi-recirculating working perfused rat hearts with 13C-substrates and mass isotopomer analysis by GCMS, can provide an unprecedented insight into the metabolic phenotype of normal and diseased rat hearts. The clinical relevance of metabolic alterations herein documented in the SHR heart is suggested by its resemblance to those reported in cardiac patients. Taken altogether, our results raise the possibility that the increased citrate release of diseased hearts results from an imbalance between citrate synthesis and utilization rates, which becomes more apparent underconditions of substrate abundance.

  17. CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation in 612 Patients with Inflammatory Bowel Disease

    PubMed Central

    Lesage, Suzanne; Zouali, Habib; Cézard, Jean-Pierre; Colombel, Jean-Frédéric; Belaiche, Jacques; Almer, Sven; Tysk, Curt; O’Morain, Colm; Gassull, Miquel; Binder, Vibeke; Finkel, Yigael; Modigliani, Robert; Gower-Rousseau, Corinne; Macry, Jeanne; Merlin, Françoise; Chamaillard, Mathias; Jannot, Anne-Sophie; Thomas, Gilles; Hugot, Jean-Pierre

    2002-01-01

    CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel