tbuckley/cabot-search huggingface dataset:
Abstract 3412: Molecular and Cellular Characterization of Splice Site Mutations in <i>MYBPC3</i> -encoded Myosin Binding Protein C
Authors: Jeanne L Theis, J M Bos, Steve R Ommen, Michael J Ackerman
Journal: Circulation (2008)

Background: Mutations in MYBPC3 -encoded myosin binding protein C underlie the most common genotype in hypertrophic cardiomyopathy (HCM). Compared to most HCM-associated mutations which are primarily missense mutations, MYBPC3-HCM is often caused by insertions, deletions, nonsense mutations or mutations involving the canonical splice site. However, the effects of most mutations that prematurely truncate MYBPC3 are unknown. Access to cardiac specific mRNA and tissue has permitted a molecular and cellular elucidation of the consequences of two splice site mutations. Methods: Mutational analysis of MYBPC3 revealed 2 HCM-susceptibility mutations involving the splice donor sites of exons 7 and 30. Reverse transcription was performed on cDNA generated from RNA extracted from cardiac tissue obtained following surgical myectomy. Western blot analysis and immunohistochemistry (IHC) of the myofilaments were performed to further assess the impact of the splice-site mutations. Results: Both splice donor mutations produced abnormal RNA splicing of MYBPC3. The c.821+1 g&gt;a mutation in the splice donor site of exon 7 generated two alternatively-spliced mutant transcripts resulting in two frame-shifted, premature truncations (H257 fs/37 and H257 fs/15). The c.3330+2 t&gt;g mutation in exon 30’s splice donor site produced a single alternatively-spliced mutant transcript that translated into a frame-shifted premature truncation (V1063 fs/37). Expression levels of wild type myosin binding protein C were decreased in the myectomy specimen from the patient with the exon 7 splice donor site mutation. By IHC, the spatial organization of myosin binding protein C was disrupted severely in both patients. Conclusions: This study provides the first molecular and cellular characterization of HCM-causing mutations involving canonical splice-site motifs within the intron. Loss of function of the splice site resulted in exon skipping and generation of frame-shifted and prematurely truncated myosin binding protein C and disruption of the distribution and organization of myosin binding protein C in the heart tissue. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).
Abstract P148: Association between Chronic Kidney Disease, Blood Pressure, HbA1c, and Body Mass Index with Healthcare Resource Utilization and Costs in Type 2 Diabetes Mellitus Patients
Authors: Chien-Chia Chuang, Edward Lee, Erru Yang, Sabyasachi Ghosh, Alie Tawah, Shih-Yin Chen
Journal: Circulation (2014)

Background: Newer classes of oral anti-diabetic medications affect not only HbA1c but also weight and blood pressure (BP); however, the use and effects may be limited in patients with chronic kidney disease (CKD). To better understand the potential value of newer anti-diabetic medications, we assessed the individual and collective contribution of these co-existing conditions on healthcare resource utilization (HRU) and costs within a large US T2DM patient population. Methods: This study analyzed electronic health records from integrated delivery networks across the US between 2008 and 2012. Beginning at first evidence of T2DM diagnosis, adults with T2DM and medical and laboratory data observed were categorized by CKD, BP, HbA1c, and obesity status as observed in the 12-month post-index period.CKD stage 5 patients were excluded. HRU was assessed during the 12-month post-index period (i.e., physician office, outpatient, and emergency room [ER) visits and hospitalizations). Unit costs were assigned to HRU to estimate total medical costs. Regression models were performed to assess the association between clinical variables and HRU/costs. Results: The final study sample included 23,492 T2DM patients (mean age: 60.7 years; female: 52.2%). More advanced CKD and a higher systolic BP were associated with a higher risk of hospitalization/ER visits and more outpatient/physician visits. Higher HbA1c levels were associated with a higher risk of hospitalization/ER visits. The relationship between body mass index (BMI) and HRU varied. Compared to overweight patients, normal/underweight patients had significantly greater risk of being hospitalized and ER visits, while patients with obesity classes 1-3 had similar risk. CKD stage 1, 2, 3A, 3B, and 4 had total costs of 1.18, 1.17, 1.44, 1.54, and 1.80 times those of patients without CKD (all p&lt;0.01). Compared to patients with HbA1c &lt;7%, those with an HbA1c 7.5%-&lt;8%, 8%-&lt;9%, and ≥9% had 1.07, 1.17, and 1.24 times of total costs, respectively (all p&lt;0.05). Patients with systolic BP 130-&lt;140 and ≥140 mmHg had total costs 1.12 and 2.30 times those of patients with systolic BP&lt;130mmHg (both p&lt;0.01). Normal/underweight and obesity stage 1, 2, 3 patients showed a non-linear trend of having total costs of 1.13, 0.91, 0.92 and 1.07 times those of overweight patients, respectively (all p&lt;0.01). Conclusions: Among T2DM patients, t here is a positive relationship between CKD, BP, and HbA1c on HRU/costs. These findings highlight the importance of managing comorbid conditions in T2DM patients. Future studies should investigate reasons for the relationships we observed between BMI and HRU/costs.
Abstract 2028: A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro
Authors: Philipp Schlaermann, Thomas F. Meyer
Journal: Cancer Research (2014)

Abstract The significance of bacterial infections in the initiation of human cancers is increasingly being recognized. A well established example is Helicobacter pylori, a causative agent of gastric adenocarcinoma. Current research largely relies on the use of transformed human cell lines as in vitro models of these infections. Obviously, this concept is largely artificial and especially inappropriate when it comes to investigations on the mechanisms of cancerogenesis. A primary cell system would be preferable in order to approximate the in vivo situation, however, previous attempts to establish such models are hampered by the limited growth and reproducibility of normal human primary cell cultures. Here, we report on the establishment of specific long-term culture conditions that allow the formation of 3-dimensional human gastric organoids with epithelial domains that have the capacity to self-renew and can be maintained in culture indefinitely. Interestingly, these 3-dimensional structures can be transferred into 2-dimensional primary cell layers, which provide ideal conditions to study infections in vitro. We expect that our novel human gastric primary cell model will facilitate investigations on the mechanisms underlying infection and is suited to open up avenues of approach to investigations on the initial processes of cellular transformation from normal to a transformed cell stages including the tumor-promoting capacity of the gastric pathogen H. pylori. Citation Format: Philipp Schlaermann, Thomas F. Meyer. A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2028. doi:10.1158/1538-7445.AM2014-2028
Abstract 4383: Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma
Authors: Emmalena J. Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2014)

Abstract Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While these orphan malignancies are rare in the human, histiocytic diseases are relatively frequent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to malignant histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options in both humans and dogs. The overall goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases and identify better treatments. Our studies have focused on microRNAs (miRNAs), which are master regulators of gene expression and may have a significant role in tumorigenesis in histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, HS, and hemophagocytic HS. These samples were compared to normal canine histiocytes derived from peripheral blood or peritoneal fluid. Several miRNAs were identified to be upregulated in the disease samples and were selected for validation by qRT-PCR. From these results, two miRNA targets were selected for further evaluation. We are probing the significance of the upregulation of these miRNAs by inhibiting their function in canine HS cell lines using chemical miRNA inhibitors and sponge constructs designed to competitively bind the upregulated miRNAs, thus preventing them from acting on their targets. Our results to date indicate that inhibiting these miRNAs in the canine HS cell line, DH82, decreases growth rate by as much as 39%. Studies into other aspects of tumorigenicity potentially affected by the inhibition of these miRNAs are underway. Our preliminary data suggests these miRNAs themselves may be effective therapeutic targets for histiocytic diseases. Additionally, further analysis of the pathways regulated by these miRNAs may identify critical gene targets in HS tumorigenesis and thus increase our understanding of these malignancies and discover novel and effective therapies. Comparative studies have the potential to provide opportunities for advancement in these orphan malignancies, and in this case, improve clinical outcome in dogs and humans. Citation Format: Emmalena J. Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2014-4383
Abstract 13624: Perceived Health and Physical Activity among Patients treated with Ablation for Atrial Fibrillation or Atrial Flutter compared with a Healthy General Population - Results from a Nationwide Survey
Authors: Signe S Risom, Selina K Berg, Anne V Christensen, Ann-Dorthe Zwisler, Jesper H Svendsen, Lau C Thygesen
Journal: Circulation (2014)

Introduction: Patients with atrial fibrillation (AF) or atrial flutter (AFL) report poor perceived health and avoidance behavior when suffering the arrhythmia. It is important to investigate if this perception and behavior changes after treatment with ablation, so that normality is regained. Objective: To describe patients’ perceived health and physical activity 6-12 months after ablation for AF or AFL and compare with an age- and sex- matched healthy general population. Methods: The nationwide cross-sectional survey was mailed to participants &gt;18 years old who had been hospitalized for ablation for AF or AFL from January to June 2011. The patients were identified in the Danish National Patient Register (n=714). The mailed questionnaire included Short Form 36 (SF-36) and a question about physical activity and was sent in Dec 2011 to eligible patients (n=627). The nationally representative Danish Health Interview Survey 2005 was used to sample an age- and sex-matched reference population. Differences in perceived health (SF-36) were tested with t-test and chi2-test was used to determine the differences in physical activity levels. Results: The questionnaire was answered by 462 patients (74%). We found in all domains on SF-36 significantly lower scores for patients treated for AF and AFL compared with the reference group (p=0.0001) (see Table 1). Physical activity levels were also significantly lower for the patients treated for AF and AFL (p&lt;0.0001). Conclusions: We found that patients treated for AF or AFL’s perceived health and physical activity levels were significantly impaired compared with a healthy general population. This is vital information for the health professional seeing the patients for follow-up after the ablation and rehabilitation should be considered.
Abstract 15568: Is the Association of Statin Use and Incident Diabetes Mellitus Still Significant in Primary Prevention Treatment When Accounting for Incident Cardiovascular Events?
Authors: Viet T Le, Raymond O McCubrey, Tami L Bair, Benjamin D Horne, Heidi T May, Stacey Knight, Joseph B Muhlestein, Jeffrey L Anderson
Journal: Circulation (2014)

Background: Statins are first line therapy for hyperlipidemia and the preferred treatment for primary and secondary prevention of cardiovascular disease (CVD). Meta-analyses of prior statin studies suggest an association of statin use with incident diabetes (DM). It is unknown whether incident co-morbid disease plays a role in this observed increase in incident DM amongst statin users. We examined the risk of incident DM using a competing risk of time to first event model. Method: Patients from an integrated health care system were included if they were &gt; 45 years of age, had no prior history of either CVD or DM and who were started on a statin medication for primary prevention. Patients were followed from January 2002 to November 2012 and assessed at 1, 5, and 10 years (n=14736, 10305, and 2541 respectively) for the association of continuous statin use and incident DM or CV event (MI, CVA, AF, CHF, or coronary revascularization). Time until first event was examined using a competing risks statistical model, where the outcome was incident DM a first CV event, or neither. Risk estimates were adjusted using propensity scores of sex, age, hypertension, hyperlipidemia, renal failure, or tobacco use. Results: Patients averaged 55±6 years and were 56% male. Though not statistically significant, 1 -yr follow-up of statin use trended toward an association with incident DM (HR=1.68, 95% CI (0.978, 2.89), p=0.06). 5-yr follow-up of statin use was significantly associated with incident DM (HR=1.48, 95% CI (1.11, 1.97), p =0.008). 10-yr follow-up of statin use was not significantly associated with incident DM (HR=1.01, 95% CI (0.687, 1.47), p =0.97). Conclusion: Using a competing risks model, an association between continuous statin use at 5-years and incident DM was observed, with a trend toward an association at 1-year. Although continuous statin treatment through 5 years was associated with risk of DM , these results do not reveal whether that risk outweighs the expected benefit of statin therapy for primary prevention.
Abstract 2738: Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma
Authors: Hesham M. Hassan, Michelle L. Varney, rakesh K. Singh, Bhavana J. Dave
Journal: Cancer Research (2014)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). TP73 gene is a member of the p53 tumor suppressor gene family, which is critical in the regulation of cell cycle and apoptosis. TP73 is located in distal 1p36 chromosomal region that is commonly disrupted in DLBCL. TP73 gene function is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic by antagonizing both TAp73 and p53). Up-regulated expression of -Np73 isoforms has been reported in activated and germinal center B- cells as compared to very low levels in memory B- cells and follicular mantle cells, suggesting temporal expression of -Np73 isoforms during specific B- cell developmental stages. In the present study we have investigated the biological relevance of p73 isoforms in DLBCL. The DLBCL cell line DHL-16 was transfected with TAp73 encoded mammalian expression vector. The ‘control cells’ comprised of DHL-16 cells transfected with control vector. To evaluate growth differences under basal conditions as well as with serum deprivation, phenotypic comparison was performed between the two cell lines. Further, to evaluate the response to chemotherapy and to determine the differences in transcriptional targets, the p73 transfected and control cells were studied for the expression of p73 transcriptional targets PUMA, BIM, and GRAMD4. TAp73-transfected cells were more sensitive to serum deprivation and chemotherapy and showed an increased expression of the pro-apoptotic p73 transcriptional targets compared to control cells. We transfected DHL-16 cells with a truncated p73 isoform functionally similar to ΔNp73. These ΔNp73-transfected cells were resistant to serum deprivation and chemotherapy and showed a reduction in the expression of the pro-apoptotic p73 transcriptional targets PUMA, BIM, and GRAMD4 compared to control-vector transfected cells. Together, our data demonstrate that modulation of p73 isoform expression can alter the behavior of DLBCL and highlights p73 as a potential new therapeutic target in DLBCL. Note: This abstract was not presented at the meeting. Citation Format: Hesham M. Hassan, Michelle L. Varney, rakesh K. Singh, Bhavana J. Dave. Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2738. doi:10.1158/1538-7445.AM2014-2738
Platelet MAO activity and the dexamethasone suppression test in depressed patients
Authors: A F Schatzberg, P J Orsulak, A J Rothschild, M S Salomon, J Lerbinger, P P Kizuka, J O Cole, J J Schildkraut
Journal: American Journal of Psychiatry (1983)

Platelet monoamine oxidase (MAO) activity and postdexamethasone cortisol levels were determined in 26 depressed patients. The incidence of cortisol nonsuppression and the mean postdexamethasone cortisol levels were significantly higher in patients with high MAO activity than in those with low MAO activity.
Activating <i>BRAF</i> mutations in eruptive melanocytic naevi
Authors: A. Sekulic, M.B. Colgan, M.D.P. Davis, D.J. DiCaudo, M.R. Pittelkow
Journal: British Journal of Dermatology (2010)

Eruptive melanocytic naevi (EMN) are melanocytic proliferations developing rapidly on previously unaffected skin in association with various clinical scenarios, most commonly systemic immunosuppression. However, the exact mechanism leading to development of EMN is not understood. In particular, it is not known whether EMN harbour the BRAF mutations which occur frequently in melanoma and most common naevi.To evaluate whether activating BRAF mutations may play a role in genesis of EMN.Genomic DNA was isolated from 20 EMN from a patient treated with 6-mercaptopurine (6-MP). Primary BRAF genotyping was performed by allelespecific polymerase chain reaction, followed by validation using direct sequencing.The BRAF V600E mutation was identified in 85% of EMN examined.Our results implicate mutational activation of the BRAF–MAPK pathway as a factor in development of EMN in the setting of 6-MP treatment. The mechanism leading to development of EMN in this, and potentially other patients, may relate to synergistic mutagenic effects of thioguanines and ultraviolet (UV) A. Together with the documented importance of BRAF mutations in melanoma development and maintenance, these findings highlight the importance of UVA protection, especially in patients treated with thiopurines such as 6-MP.
Alterations in the Characteristics of Sugar Uptake by Mouse Cells Transformed by Murine Sarcoma Viruses&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Masakazu Hatanaka, Robert J. Huebner, Raymond V. Gilden
Journal: JNCI Journal of the National Cancer Institute (1969)

Mouse-embryo tissue cultures infected with and transformed by murine sarcoma viruses (MSV) showed significant increases in the rate of uptake of glucose, mannose, and galactose. This uptake was characterized by a Km value approximately tenfold lower than that of uninfected mouse cells, cells infected with murine leukemia viruses, or SV40-transformed 3T3 cells. By contrast, and perhaps surprisingly, 3-0-methylglucose uptake was characterized by a Km value significantly higher for the sarcoma virus-infected cells. The data suggest virus-specific membrane alterations that may be useful in assigning a viral etiology to spontaneous sarcomas in mice.
High frequency of deletional α‐thalassemia in β‐thalassemia trait: Implications for genetic counseling
Authors: I. Panigrahi, P.H. Ahmed Rafeeq, V.P. Choudhry, R. Saxena
Journal: American Journal of Hematology (2004)

Abstract Thalassemias are a group of genetic hemolytic disorders with varying phenotypes. In this study, the frequency of α globin gene deletions was studied in the β‐thalassemia trait, the mildest form of the disorder. Eleven out of 33 (33%) individuals were positive for α −3.7 kb deletions. None of the subjects was positive for the Southeast Asian deletion. Such a high frequency for α deletions has not been reported earlier in thalassemia minor. Hematological parameters are compared, and implications of this finding for genetic counseling are discussed. Am. J. Hematol. 76:297–299, 2004. © 2004 Wiley‐Liss, Inc.
A LONG-TERM STUDY OF THE NATURAL HISTORY OF ESSENTIAL HYPERTENSION
Authors: K A EVELYN
Journal: Annals of Internal Medicine (1950)

Article1 September 1950A LONG-TERM STUDY OF THE NATURAL HISTORY OF ESSENTIAL HYPERTENSIONKENNETH A. EVELYN, M.D., F.A.C.P.KENNETH A. EVELYN, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-33-3-629 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptIt is indeed an honor to be given the opportunity to address this distinguished audience as one of the former Research Fellows of the College who have been asked by your President to report on the way in which their work has been influenced by the advantages derived from the tenure of a Research Fellowship of the American College of Physicians.My Fellowship year, which had been postponed from 1940 to 1946 because of war service with the Royal Canadian Air Force, proved to be an ideal transition period from military to civilian research, and provided me with an excellent...Bibliography1. DuffMore GLRH: Methods of preparation and examination of neoprene casts of the renal arterial tree, J. Tech. Methods 24: 1, 1944. Google Scholar2. Evelyn KA: The state of the arterioles in essential hypertension, Am. J. M. Sc. 214: 312, 1947. CrossrefMedlineGoogle Scholar3. Ayman D: Arterial hypertension, New York, Oxford University Press, 1948. Google Scholar4. EvelynAlexanderCooper KAFSR: Effect of sympathectomy on blood pressure in hypertension, J. A. M. A. 140: 592, 1949. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *Read at the Thirty-first Annual Session of the American College of Physicians, Boston, Mass., April 21, 1950.†Research Fellow of the American College of Physicians for 1946. Present appointment, Associate Professor of Medicine and Director of the Research Institute of Biophysics, McGill University, Montreal. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byLabile (Borderline) Hypertension—New Aspects of a Common DisorderA Method of Grading and Recording*The life history of one hundred patients with hypertensive vascular disease 1 September 1950Volume 33, Issue 3Page: 629-635KeywordsArmed forcesFellowshipsHypertension ePublished: 1 December 2008 Issue Published: 1 September 1950 PDF downloadLoading ...