tbuckley/cabot-search huggingface dataset:
1019. Immune System Regulation of Transgene Expression in the Brain 2: Differential Increase of mRNAs Encoding for Interferon-Regulated, Chemokine, and T-Cell Genes during Either Innate Acute or Chronic Systemic Adaptive Immune Responses to First Generation Adenoviral Vectors
Authors: Jeffrey M. Zirger, Carlos Barcia, Chunyan Liu, Mariana Puntel, Giovanni Sitia, Luca Guidotti, Ngan Mitchell, Iain Campbell, Maria G. Castro, Pedro R. Lowenstein
Journal: Molecular Therapy (2004)

Gene therapy approaches using first generation adenoviral (Ad) vectors have shown the ability to produce long-term transgene expression in the brain in animal models. The use of these first generation vectors is limited, however, by peripheral immunization that generates an anti-adenoviral immune response. This response is characterized by inflammation in the brain and the eventual elimination of the encoded transgene expression. The following study was designed to determine the cellular and molecular effectors involved in this immune response in mice. Both naive and immunized animals were injected with increasing doses of first generation Ad vectors carrying the gene for beta-galactosidase (b-gal) or thymidine kinase (TK). RNAse protection assays (RPAs) were performed on RNA extracted from homogenized brain tissue using probe sets to determine the expression of interferon (IFN) gene families, IFN-regulated genes, chemokines, as well as markers of T-cells (CD3, CD4 and CD8), and macrophages (F4/80). The results of this work indicate that the naive brain responds rapidly to the injection of Ad vectors by the induction of a variety of cellular effector mechanisms, including expression of the IFN-regulated genes, TGTP, OAS, and IRF-1, and the chemokines MCP-3, MIP-1b,MCP-1, IP-10, RANTES. A threshold level for injection of 1×107-1×108 infectious units has also been established for this response; below this dose no responses were detected. The time course experiments showed these responses to be transient, with most mRNAs returning to basal levels by day 14 post-injection into the brain. To study the mechanisms of the adaptive immune response, animals previously injected with RAd in the brain, were systemically immunized against adenovirus. In immunized animals there was an important increase in T-cell markers CD3, CD4, and CD8, while there was no increase of the monocyte marker F4/80. Expression of IFN-regulated genes was also increased. A different set of chemokines was elevated in the case of the adaptive immune response when compared to those seen in the early innate responses. These studies indicate that acute innate inflammatory responses in mice are dose dependent, transient, and mediated by an increase in interferon signaling and chemokine induction. The systemic immune response demonstrates a longer time course, and is mediated by CD4 and CD8 T-cells, and accompanied by an increase in interferon signaling, mainly due to interferons a and b, and possibly a smaller contribution of interferon g, and TNF.
133. Enhanced Expression of ABCA4 Stargardt Protein Mediated by Adenoviral Vectors in a Simulated Ocular Environment
Authors: Joshua N. Mallam, Mary Y. Hurwitz, Donna Palmer, Philip Ng, Richard L. Hurwitz
Journal: Molecular Therapy (2004)

Objective: Mutations in the ABCA4 gene have been associated with Stargardt disease and adult-onset macular degeneration. The ABCA4 protein is expressed exclusively in photoreceptor outer segments. The first-generation chimeric adenoviral vector AdV5/F35 can efficiently deliver reporter transgenes to the retina including photoreceptors in vivo. The objective of this study is to evaluate the feasibility of using the AdV5/F35 vector to express the large ABCA4 protein in a simulated ocular environment. Methods: As an initial step towards gene therapy for diseases caused by ABCA4 mutations, adenoviral vectors containing an ABCA4 transgene were constructed and characterized. HEK293 cells and WERI retinoblastoma cells were transduced with a first-generation chimeric adenoviral vector AdV5/F35 containing a transgene encoding ABCA4 (AdV5/F35-ABCA4) under the control of a CMV promoter. To examine the in vitro transduction efficiency in a simulated ocular environment, expression of ABCA4 in the presence or absence of vitreous (5%) or hyaluronic acid (0.5 mg/ml) was analyzed by Western blot analysis using anti-ABCA4 monoclonal antibody Rim3F4 (R. Molday). Results: AdV5/F35 can efficiently deliver the ABCA4 gene to either HEK293 cells or WERI retinoblastoma cells. Quantitative analysis of membrane proteins isolated from transduced cells indicates that ABCA4 protein expressed in the presence of vitreous or hyaluronic acid was approximately 6-fold greater than in the absence of vitreous or hyaluronic acid. The amount of ABCA4 protein expressed in these cell lines was at least as great as that expressed on native photoreceptor outer segments. Conclusions: The ocular environment is permissive for adenoviral transduction at least in part because of the presence of high concentrations of hyaluronic acid. These results demonstrate that the Ad5F35/ABCA4 vector is a suitable candidate for testing in a murine abcr(−/−) knock-out model of retinal rod/cone dysplasia.
MAIN BRANCH PULMONARY ARTERY THROMBOSIS WITH PULMONARY ABSCESS FORMATION: CASE REPORT
Authors: B C DOUST, J W RATHE
Journal: Annals of Internal Medicine (1958)

Case Reports1 January 1958MAIN BRANCH PULMONARY ARTERY THROMBOSIS WITH PULMONARY ABSCESS FORMATION: CASE REPORTBREWSTER C. DOUST, M.D., JAMES W. RATHE, M.D.BREWSTER C. DOUST, M.D.Search for more papers by this author, JAMES W. RATHE, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-48-1-170 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAbscess formation in an area of infarction is an unusual complication of thrombosis of the pulmonary arteries. Ring and Bakke1 recently reported 21 cases of thrombosis of a main branch of the pulmonary artery, including seven cases with infarctions, only one of whom had an abscess. For this reason, reports of additional cases such as the one given here would appear to be of interest.CASE REPORTHistory:When first seen in 1944 the patient, a 49 year old white man, reported a cough of six months' duration and two weeks of pain in the right portion of his chest....Bibliography1. RingBakke AJR: Chronic massive pulmonary artery thrombosis, Ann. Int. Med. 43: 781-806, 1955. LinkGoogle Scholar2. KeatingBurkeyHellersteinFeil DRJNHKH: Chronic massive thrombosis of pulmonary arteries, Am. J. Roentgenol. 69: 208-220, 1953. Google Scholar3. BriggsCarlsonHouseworth GWHAJH: Superior vena cava obstruction with complete obstruction of the right main pulmonary artery, Am. Heart J. 48: 288-292, 1954. CrossrefMedlineGoogle Scholar4. Carroll D: Chronic obstruction of major pulmonary arteries, Am. J. Med. 9:175-185, 1950. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *Received for publication December 17, 1956.Requests for reprints should be addressed to Brewster C. Doust, M.D., Department of Internal Medicine, The Akron Clinic, 513 West Market Street, Akron 3, Ohio. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1958Volume 48, Issue 1Page: 170-174KeywordsAbscessesDyspneaEmphysemaFibrosisInfarctionPatient advocacyPolycythemiaPulmonary arteriesThoraxThrombosis ePublished: 1 December 2008 Issue Published: 1 January 1958 PDF downloadLoading ...
Large Artery Stiffness and Baroreflex Function
Authors: Bronwyn A. Kingwell, James D. Cameron, Anthony M. Dart
Journal: Circulation (2002)

We read with interest the recent article by Monahan et al 1 that examined the relationship between carotid arterial compliance and baroreflex sensitivity in the context of aging and fitness.The authors demonstrate that age-related carotid artery stiffening is associated with a smaller carotid diameter change in response to a given increase in systolic blood pressure.Thus, baroreceptor activation is attenuated and likely accounts for the lower cardiovagal baroreflex sensitivity reported in older individuals.Endurance-trained individuals are known to have large arteries that are more elastic than their sedentary counterparts, a phenomenon likely to reduce age-related impairment in baroreflex function in older athletes. 1,2 The findings of Monahan et al 1 are of particular relevance in disease states associated with large artery stiffening.We have previously explored the relationship between the cardiac baroreflex and large artery stiffness in hypertension individuals 2 who are known to have stiffer large vessels than normotensive individuals. 3 In this study, modeled changes in arterial circumference based on systemic arterial compliance measurements predicted the impaired gain and reduced bradycardic response to pressure elevation.Interestingly, although stiffer large vessels are predicted to impair the heart rate reduction to pressure elevation due to the nonlinear arterial pressure-volume relationship, we have shown that the effect on responsiveness to pressure reduction is less marked. 2 Thus, patients with stiff large vessels are likely to adequately respond to orthostatic stimuli, but impaired responses to a sudden pressure rise may contribute to long-term pressure elevation by upward baroreceptor resetting. 4 In addition to hypertension, this mechanism is likely relevant to all states of increased large artery stiffness, including diabetes and coronary disease.With recent studies highlighting large arterial stiffness as an independent predictor of cardiovascular mortality, 5 the impaired buffering of sudden pressure elevation should be considered an important contributing mechanism and aerobic exercise training a relevant preventive strategy.
New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet
Authors: Takahiro Ochiya, Yasushi Takahama, Shunji Nagahara, Yoshihiro Sumita, Akihiko Hisada, Hiroshi Itoh, Yutaka Nagai, Masaaki Terada
Journal: Nature Medicine (1999)
Abstract 379: TARBP1, a member of the SPOUT methyltransferase family, is involved in human carcinogenesis
Authors: Makoto Nakakido, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2014)

Abstract It has recently been recognized that protein methylation plays a critical role in many biological processes, and its deregulation has been observed in various kinds of diseases, including cancer. To date, a number of protein methyltransferases have already been reported to be associated with human carcinogenesis. Although many protein methyltransferases belong to the SET-domain containing protein family or the protein arginine methyltransferase (PRMT) family, a series of other methyltransferase families have also been discovered by bioinformatics-based approaches. On the contrary, physiological functions of these methyltransferases, especially, the significance in human disease like cancer, still remains unknown. In this study, we demonstrated that expression levels of TARBP1 (TAR RNA-Binding Protein 1), a member of the SPOUT methyltransferase family, are significantly up-regulated in many types of cancer tissues compared to corresponding non-tumor tissues. In addition, knockdown of TARBP1 resulted in the suppression of cancer cell growth, indicating that TARBP1 seems to regulate the proliferation of cancer cells. Since expression levels of TARBP1 in normal tissues are significantly low, TARBP1 may be a good new target for anti-cancer therapy. Citation Format: Makoto Nakakido, Yusuke Nakamura, Ryuji Hamamoto. TARBP1, a member of the SPOUT methyltransferase family, is involved in human carcinogenesis. [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 379. doi:10.1158/1538-7445.AM2014-379
Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302
Authors: Fred Saad, Neal Shore, Hendrik Van Poppel, Dana E. Rathkopf, Matthew R. Smith, Johann S. de Bono, Christopher J. Logothetis, Paul de Souza, Karim Fizazi, Peter F.A. Mulders, Paul Mainwaring, John D. Hainsworth, Tomasz M. Beer, Scott North, Yves Fradet, Thomas A. Griffin, Peter De Porre, Anil Londhe, Thian Kheoh, Eric J. Small, Howard I. Scher, Arturo Molina, Charles J. Ryan
Journal: European Urology (2015)
Detection of Anaplastic Lymphoma Kinase (ALK) and Nucleolar Protein Nucleophosmin (NPM)-ALK Proteins in Normal and Neoplastic Cells With the Monoclonal Antibody ALK1
Authors: Karen Pulford, Laurence Lamant, Stephan W. Morris, Lisa H. Butler, Katrina M. Wood, David Stroud, Georges Delsol, David Y. Mason
Journal: Blood (1997)
Abstract 13347: Injectable Collagen-based Hydrogel Matrix Modulates Micro-RNA Expression and Prevents Cardiac Deterioration Post-myocardial Infarction
Authors: Nick J Blackburn, Brian McNeill, Helene Chiarella-Redfern, Tanja Sofrenovic, Drew Kuraitis, Ali Ahmadi, Marc Ruel, Katey J Rayner, Erik J Suuronen
Journal: Circulation (2014)

Background: Injectable hydrogel biomaterials have emerged as promising therapies for treating myocardial infarction (MI). We developed a collagen type I based injectable hydrogel matrix that can prevent the deterioration of cardiac function when delivered soon post-MI and found that the effects may be mediated through a microRNA (miRNA) mechanism. Methods/Results: C57BL/6J mice underwent LAD ligation to induce MI. Mice then received myocardial injections of PBS or matrix delivered at 3hours post-MI. Analyses were performed at 2 days, 1 and 3 months post-treatment. At one month post-treatment, mice that received the matrix had superior left ventricular ejection fraction (LVEF; 45.1±2.3%) compared to the PBS group (29.6±2.4%; p&lt; 0.001). LVEF was maintained in matrix-treated mice at 3 months (42.9±3.8%). Matrix treatment was also associated with reduced infarct sizes and improved ventricular volumes. Matrix-treated mice had more angiogenesis, mitigated apoptosis and reduced inflammation in the infarcted myocardium at both 2 and 28 days post-treatment. To better understand the mechanisms, we performed miRNA microarrays on infarct and peri-infarct tissue. Matrix treatment resulted in 120 miRNAs with differential expression within +/- 0.3 log2 fold change. In particular, we found matrix treatment down-regulated miR-92a ( p&lt; 0.0005), an anti-angiogenic miRNA. Integrins α5 (Itgα5) and αV (ItgαV), involved in angiogenesis and cell-matrix interactions, were identified as putative miR-92a targets and pursued further in vitro using circulating angiogenic cells (CACs). CACs cultured on the matrix had increased Itgα5 and ItgαV expression after 4 days (12.4-fold and 13.9-fold, respectively vs. fibronectin; p&lt; 0.01). When applied in an in vitro angiogenesis assay, the number of CACs that incorporated into capillary-like structures was greater (by 4.2-fold) for cells derived from matrix culture ( p &lt;0.005). Conclusion: We demonstrate pronounced benefits associated with our hydrogel matrix when delivered at 3h post-MI. The matrix effects may be mediated, at least in part, through its ability to regulate miR-92a and integrin-mechanisms. Overall, the matrix may provide a promising therapeutic approach for protecting the myocardium post-MI.
Abstract 3430: Recurrent somatic mutations of nitric oxide synthase <i>NOS3</i>, netrin receptor <i>UNC5C</i> and DNA repair genes in muscle-invasive bladder carcinoma
Authors: Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Miran Jang, Magdeline Montoya, Cory Ganshert, Tomoaki Fujioka, Gary Steinberg, Peter O'Donnell, Yusuke Nakamura
Journal: Cancer Research (2014)

Abstract Bladder cancer is the fourth most common cancer type in males and approximately 72,500 individuals were diagnosed in the United States in 2012. Patients with superficial (low-grade papillary) tumors generally have a good prognosis with a 5-year survival rate exceeding 90%, but those with muscle-invasive or locally advanced disease at surgical resection have a significant risk of recurrence with 5-year survival rates of 30-60%. The systemic chemotherapy options for bladder cancer are very limited, and no new drugs have been approved in the United States for metastatic bladder cancer in over 20 years. Although a number of newer, molecularly targeting drugs have been developed and approved for multiple cancer types in the last two decades, no such drug has been developed for the treatment of bladder cancer. This is likely due, in part, to the relatively limited molecular understanding of invasive bladder cancers and lack of knowledge about potential genetic drivers of invasive forms of the disease. Hence, it is of priority to discover novel genetic pathways involved in the carcinogenesis of muscle-invasive bladder cancer for the assessment of risk stratification and for the development of novel drugs. We analyzed exomes of 43 muscle-invasive bladder carcinomas and identified two novel significantly mutated genes, NOS3 (18.6%) and UNC5C (16.3%), in addition to previously reported frequently mutated genes like TP53 (37.2%) and KDM6A (18.6%). Both NOS3 and UNC5C are known to be involved in the apoptotic pathways, with NOS3 encoding for endothelial nitric oxide synthase (eNOS), and UNC5C for netrin receptor, a member of the dependence receptor family. When we correlated the mutational profiles with clinicopathological outcomes by stratifying patients according to disease recurrence status and observing for specific clustering of genetic mutations, we found that somatic mutations in six DNA repair genes (ATM, ERCC2, FANCD2, RAD51AP1, PALB2, BRCA2) were significantly associated with enhanced recurrence-free survival (hazard ratio of 0.091 with 95% CI of 0.018 to 0.45; P=0.0034) even after adjustment for pathologic TN staging, suggestive of their mutations as favorable prognostic events in bladder cancer. Citation Format: Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Miran Jang, Magdeline Montoya, Cory Ganshert, Tomoaki Fujioka, Gary Steinberg, Peter O'Donnell, Yusuke Nakamura. Recurrent somatic mutations of nitric oxide synthase NOS3, netrin receptor UNC5C and DNA repair genes in muscle-invasive bladder carcinoma. [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 3430. doi:10.1158/1538-7445.AM2014-3430
How best to organise acute hospital services?
Authors: B. Harrison, D. Ralphs, V. Patterson, R. T Taylor, B. McCloskey
Journal: BMJ (2001)

Medical Council is flawed as he assumes that Worcestershire Health Authority has power in managing its responsibility for a successful public health immunisation campaign. 1It is precisely because the authority is impotent as a public statutory public body that it asked the GMC to intervene.The continuing debate about measles, mumps, and rubella vaccine dents the confidence of many public and professional people, not least because of the assumption that there is no smoke without fire.Majeed's third reference indicates his anxiety despite his initial position statement on the safety of the vaccine.Patients and the media take heed of these different emphases.Maintaining a high level of vaccination cover against diseases that are seen rarely or not at all poses serious difficulties.Majeed's role as an educationalist-a position of power and responsibility-could provide a forum where these difficulties are debated.The role of medical journals and the media should not be ignored in that debate.Their keenness for headlines containing bad news, however misguided or ill informed, while
Abstract 11486: Velocity of the Heart Vector Through the QRS Complex Predicts Sudden Cardiac Death in Cardiovascular Disease-Free Adults
Authors: Larisa G Tereshchenko, Charles A Henrikson, Elsayed Soliman, Muammar Kabir, Sunil Agarwal, Nona Sotoodehnia, David S Siscovick, Dan Arking, Scott Solomon, Wendy Post, Josef Coresh, Mark E Josephson
Journal: Circulation (2014)

Introduction: The majority of sudden cardiac deaths (SCDs) occur due to ventricular arrhythmia as the first manifestation of the coronary heart disease (CHD) in the general population. Hypothesis: We hypothesized that velocity of heart vector movement through the QRS is associated with SCD. Methods: A community dwelling cohort was studied. We excluded participants with paced rhythm, atrial fibrillation, prevalent CHD, heart failure, and QRS duration ≥120 ms; remaining participants (n = 13, 368, mean age 53.9±5.7ms; 56.5% female; 73.2% white) were analyzed. Baseline resting 12-lead ECG was transformed into orthogonal XYZ; filtered (40-49Hz) QRS loop length was measured. Velocity was calculated as the distance traveled by filtered heart vector over each 10ms of QRS length, divided by time. Results: During a median follow up of 14 years, 183 participants had SCD. Averaged baseline conduction velocity (9.3±3.9 vs. 7.7±3.6 μV/ms; P=0.0001) and conduction over 110-119ms of QRS (2.6±1.3 vs. 2.1±0.9; P&lt;0.0001) was faster in those who had SCD than those without. In unadjusted Cox regression velocity at 110-119ms (continuous variable HR 1.42; 95% CI 1.29-1.57) and velocity at 100-109ms (HR1.14; 95%CI 1.07-1.21) were associated with SCD (Figure 1). After adjustment for age, sex, CHD risk factors (total cholesterol, triglycerides, high density lipoprotein, current smoking, diabetes, body mass index, leisure activity index, systolic blood pressure, use of antihypertensive drugs), QT-prolonging drugs, ECG characteristics (heart rate, QRS duration, QTc, QRS-T angle, sex-specific Cornell product), and stratified by race and study center, 110-119ms velocity (HR 1.21; 95%CI 1.08-1.36) and 100-109ms velocity (HR 1.09; 95%CI 1.02-1.16) remained significant predictors of SCD. Conclusions: Increased velocity of the heart vector movement through terminal 20 ms of filtered QRS loop is an independently associated with SCD in community-dwelling cohort of CHD-free adults.
Russian Report: Alcoholism and rising mortality in the Russian Federation
Authors: M. Ryan
Journal: BMJ (1995)

In the Russian Federation today the high incidence of alcoholism and drunkenness helps to account for rising death rates, more particularly among the male population. During the mid-1980s a significant reduction in deaths from alcohol related diseases was achieved by state action in curtailing the supply of alcohol. However, official data disclose a pattern of sharply increased consumption per head since 1987, with high proof drinks--especially vodka--now forming a larger share in the total. In current economic conditions the effects of a traditional macho drinking culture are exacerbated by a reduction of state control over the quality of alcohol available for purchase. A substantial increase has occurred in deaths from most principal causes, with a disproportionate increase in deaths from non-natural causes, including deaths caused predominantly by alcohol. Average expectation of life at birth has fallen especially sharply for men; by 1993 it had slumped to 59.0 years--that is, to below the age at which a pension starts to be paid.