tbuckley/cabot-search huggingface dataset:
TRIM5α Variations Influence Transduction Efficiency With Lentiviral Vectors in Both Human and Rhesus CD34+ Cells In Vitro and In Vivo
Authors: Molly E Evans, Chutima Kumkhaek, Matthew M Hsieh, Robert E Donahue, John F Tisdale, Naoya Uchida
Journal: Molecular Therapy (2013)

Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5α (TRIM5α) plays an important role for restriction of retroviral infection. In this study, we examined whether TRIM5α could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34+ cell culture. Evaluation of TRIM5α genotypes (Mamu-1, -2, -3, -4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34+ cells showed a significant correlation between TRIM5α Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5α coding polymorphisms were not known, we evaluated TRIM5α expression levels in human CD34+ cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5α expression levels. In summary, transduction efficiency in both rhesus and human CD34+ cells was influenced by TRIM5α variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34+ cells. Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5α (TRIM5α) plays an important role for restriction of retroviral infection. In this study, we examined whether TRIM5α could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34+ cell culture. Evaluation of TRIM5α genotypes (Mamu-1, -2, -3, -4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34+ cells showed a significant correlation between TRIM5α Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5α coding polymorphisms were not known, we evaluated TRIM5α expression levels in human CD34+ cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5α expression levels. In summary, transduction efficiency in both rhesus and human CD34+ cells was influenced by TRIM5α variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34+ cells.
Prosciuto Consumption in Roseto, Pa
Authors: Stewart Wolf
Journal: JAMA (1964)

<h3>To the Editor:—</h3> These points are well taken. Our findings that the community is generally obese and that relatively large quantities of calories and animal fat are consumed was given an unwarranted interpretation by some in the lay press. I note that Drs. Ritota and Cooper do not have any quarrel with our findings, but point out that prosciuto is a delicacy eaten only on special occasions. This is correct. As we stated, however, it is a great favorite that was often served to us in the meals we ate with various of the hospitable Roseto families.
Abstract 4527: Pharmacodynamic and pathway analysis of three presumed inhibitors of poly (ADP-ribose) polymerase: ABT-888, AZD2281, and BSI201
Authors: Jiuping Ji, Maxwell P. Lee, Mitsutaka Kadota, Yiping Zhang, Ralph E. Parchment, Joseph E. Tomaszewski, James H. Doroshow
Journal: Cancer Research (2011)

Abstract Poly (ADP-ribose) (PAR) polymerases (PARP1 and PARP2) are activated in response to DNA single-strand breaks and are pivotal to the base excision repair pathway for homologous recombination-defective cells or for the chemotherapy-damaged genome. ABT-888, AZD2281, and BSI201 are three presumed PARP inhibitors currently being evaluated in phase 1-3 clinical trials; each has demonstrated therapeutic activity either as a single agent for patients with BRCA-deficient malignancies or in combination with DNA-damaging chemotherapeutic agents. To compare the pharmacodynamics of these agents, we employed the BRCA1-defective breast cancer cell line MX-1 as a model. By monitoring γH2AX foci formation with a validated slide-based immunofluorescence assay, we found that γH2AX foci increased in a dose- and time-dependent fashion during treatment with each of the three drugs. However, utilizing our validated quantitative chemiluminescence ELISA for PAR (Clin. Cancer Res. 14: 6877, 2008), we unexpectedly found that PARP1/2 inhibition was dose and time dependent only for tumor cells treated with ABT-888 or AZD2281, but not BSI201. This observation was confirmed using ex vivo treatment of PBMCs from human whole blood. To investigate the mechanism of action of these drugs further, we used next-generation sequencing to identify genes that were induced or suppressed by exposure to these drugs. We found that a 4-hour exposure of MX-1 cells to a clinically achievable concentration of either ABT-888 or BSI201 produced expression changes in dramatically different sets of genes. Gene ontology and pathway analyses indicated that BSI201 specifically suppressed genes in the telomere pathway, suggesting PARP5/6 as potential targets and a different mechanism of γH2AX foci formation, whereas ABT-888 induced genes in the chromosome organization network, consistent with PARP1/2 as primary targets. These experiments strongly suggest that the major therapeutic mechanism of action of BSI201, unlike ABT-888 and AZD2281, is not mediated by inhibition of PARP1 or PARP2. Funded, in part, by NCI Contract No. HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4527. doi:10.1158/1538-7445.AM2011-4527
High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice
Authors: T. Kitahara, Y. Takeishi, M. Harada, T. Niizeki, S. Suzuki, T. Sasaki, M. Ishino, O. Bilim, O. Nakajima, I. Kubota
Journal: Cardiovascular Research (2008)

High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac function after myocardial infarction (MI), we generated transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) using alpha-myosin heavy chain promoter.The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1-overexpressing hearts. The size of MI was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodelling and dysfunction after MI were prevented in HMGB1-Tg mice compared with Wt mice. Furthermore, the survival rate after MI of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formation after MI was enhanced in HMGB1-Tg mice.We report the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac function, and improves survival after MI. These results may provide a novel therapeutic approach for left ventricular dysfunction after MI.
Varicella and Herpes Zoster
Authors: Donald Kaye
Journal: JAMA (1964)

<h3>To the Editor:—</h3> Dr. Ross is correct. All evidence indicates that the identical viral agent causes both herpes zoster and varicella, and the editorial did not intend to imply a different etiology for each syndrome. However, the syndrome of herpes zoster is not identical to that of varicella, and it is proper to state that in some patients with herpes zoster a "clinical syndrome develops which closely resembles varicella." We would qualify Dr. Ross's statement, "It is well known that administration of steroids to patients who have chickenpox may result in death." All the evidence concerning adrenocorticosteroids in varicella indicates that more severe manifestations may be observed when varicella occurs in patients who have been receiving these drugs. It is not clear if steroids have a deleterious effect when administered to patients who already have varicella.
728-6 Identification of Significant Left-to-Right Intracardiac Shunts by Velocity-Encoded, Phase-Difference, Cine Magnetic Resonance Imaging: A Comparison with Oximetry and Indocyanine Green Dye
Authors: W. Gregory Hundley, Richard A. Lange, Hong F. Lee, Charles Landau, John E. Willard, Dennis Pfeiffer, Ronald M. Peshock
Journal: Journal of the American College of Cardiology (1995)
Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene
Authors: Lei Yuan, Vesna Nikolova-Krstevski, Yumei Zhan, Maiko Kondo, Manoj Bhasin, Laya Varghese, Kiichiro Yano, Chris V. Carman, William C. Aird, Peter Oettgen
Journal: Circulation Research (2009)

ERG (Ets-related gene) is an ETS transcription factor that has recently been shown to regulate a number of endothelial cell (EC)-restricted genes including VE-cadherin, von Willebrand factor, endoglin, and intercellular adhesion molecule-2. Our preliminary data demonstrate that unlike other ETS factors, ERG exhibits a highly EC-restricted pattern of expression in cultured primary cells and several adult mouse tissues including the heart, lung, and brain. In response to inflammatory stimuli, such as tumor necrosis factor-alpha, we observed a marked reduction of ERG expression in ECs. To further define the role of ERG in the regulation of normal EC function, we used RNA interference to knock down ERG. Microarray analysis of RNA derived from ERG small interfering RNA- or tumor necrosis factor-alpha-treated human umbilical vein (HUV)ECs revealed significant overlap (P<0.01) in the genes that are up- or downregulated. Of particular interest to us was a significant change in expression of interleukin (IL)-8 at both protein and RNA levels. Exposure of ECs to tumor necrosis factor-alpha is known to be associated with increased neutrophil attachment. We observed that knockdown of ERG in HUVECs is similarly associated with increased neutrophil attachment compared to control small interfering RNA-treated cells. This enhanced adhesion could be blocked with IL-8 neutralizing or IL-8 receptor blocking antibodies. ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. Direct binding of ERG to the IL-8 promoter in ECs was confirmed by chromatin immunoprecipitation. In summary, our findings support a role for ERG in promoting antiinflammatory effects in ECs through repression of inflammatory genes such as IL-8.
TCT-358 Reproducibility Of The Carpet View System: A Novel Technical Solution For Display And Off Line Analysis Of OCT Images
Authors: Laura Gatto, Alex Gabriele, Valeria Marco, Giulia Paoletti, Luca Di Vito, fausto Castriota, Enrico Romagnoli, fabrizio imola, vito ramazzotti, maria teresa mallus, Andrea Ricciardi, Francesco Prati
Journal: Journal of the American College of Cardiology (2014)
Dialysis for psoriasis.
Authors: J Halevy, S Halevy, E Feuerman, J B Rosenfeld
Journal: BMJ (1979)

antigenic concentrations of plasma anti- proteases, as protease-antiprotease complexes with no functional activity are still detected immunochemically.Of particular relevance to the above mentioned article were the observa- tions of Teger-Nilsson,7 who found that functional antiplasmin activities in patients with acute venous thrombosis were normal on the day of diagnosis and that elevated activities were found three and four days after the diagnosis.Another point to be considered is the possible role of platelet antiproteases released during thrombus formation.Platelets contain inhibitors of fibrinolysis,8 which would certainly hinder thrombus resolution.We would like to suggest that chromogenic substrate assays for the estimation of functional antiprotease activities should be included in any protocol for studies on the various plasma protease systems.These assays, which are simple and rapid to perform, give a better indication of the inhibitor status than immunochemical determinations.
Physiology of the Heart and Circulation
Authors: J. Buetikofer
Journal: JAMA (1987)

Every physician should have a basic understanding of cardiovascular physiology. Robert C. Little provides a concise review of the basic physiological principles governing the heart and circulation in<i>Physiology of the Heart and Circulation</i>. The softcover textbook is an outgrowth of material used in lectures to medical and graduate students in physiology. The book is divided into three sections which discuss basic physiological principles, dynamics and energetics of the heart, and the structure and function of the vascular system. The movement of fluids and dissolved solutes in the body, as well as the importance of ions in maintaining cell-membrane potentials, are simply explained and provide the basis for understanding the ionic mechanisms responsible for cardiac depolarization and repolarization. Concisely reviewed and illustrated are current theories regarding the ultrastructure of ion channels and gates and the importance of calcium in the contractile response of cardiac muscle. The fundamentals of electrocardiography (including
474. Deletion of All Membranous Genes of Recombinant Sendai Virus Results in the Dramatic Reduction of Toxicity for Pulmonary Gene Transfer in Neonatal Mice
Authors: Sakura Tanaka, Yoshikazu Yonemitsu, Mamoru Hasegawa, Tomoaki Taguchi, Katsuo Sueishi
Journal: Molecular Therapy (2006)

Background and Aim: We previously demonstrated the dramatically high efficiency of recombinant Sendai virus (SeV) for pulmonary gene transfer, 1,000-100,000 fold over that via adenoviruses, and suggested that its possible application for gene therapy of cystic fibrosis (CF) (Yonemitsu Y et al. Nature Biotechnol 2000). As widely known, however, experimental inoculation of SeV exhibits inflammatory and immune responses in rodent lung, frequently resulted in the death of animals. For future directions of pulmonary gene therapy for monogenic diseases, including CF, neonatal gene transfer is ideal, because the lung disease may be in reversible. We recently developed a new and advanced design of SeVs for clinical application, namely F-deficient SeV (SeV/dF), temperature-sensitive SeV/dF (tsSeV/dF), and SeV deleted with all membranous genes (SeV/dFdMdHN). Here we characterized these new constructs for pulmonary gene transfer in neonatal mice, especially referring to toxicity. Method and Results: Recombinant SeVs expressing GFP (2.5 × 106 pfu in 10μl PBS /neonate or 2.5 × 107 pfu in 100μl PBS /adult) was placed into the nasal cavity and the solution was sniffed into the lungs of neonate (day 0) or adult (8 weeks old, female) of ICR (CD-1) mice. The efficiency of gene transfer and the level of gene expression were also monitored using same amount of SeVs expressing luciferase. The peak of gene expression in lung of neonatal mice was at 48 h and decreased gradually, and then almost disappeared at 14 days after infection in all constructs, similar to the finding found in adult mice. Increase of the body weight of neonates transfected with tsSeV/dF or SeV/dFdMdHN, however, was significantly larger than those of animals transfected with wild-SeV or SeV/dF, and the effect was dramatic in use of SeV/dFdMdHN. Mortality rate was dramatically diminished in the mice translated SeV/dFdMdHN (survival rate=100%, n=43) compared with wild-SeV (25%, n=36) or tsSeV/dF (75%, n=44). Assessments of immunological parameters are now underway. Discussion and Conclusion: Our current study revealed that deletion of all membranous genes of recombinant SeV dramatically reduced the toxicity for pulmonary gene transfer in neonatal mice. In conclusion, the potential of pulmonary gene thansfer using SeV/dFdMdHN warrants for further intervention to develop more efficient therapy of neonatal lung diseases including cystic fibrosis.
House of Lords rules against government’s restriction on foreign doctors
Authors: Clare Dyer
Journal: BMJ (2008)

A report from the Association of American Medical Colleges suggests that all 129 member medical schools should prohibit pharmaceutical and devices manufacturers from providing gifts, food, and travel to doctors, faculty members, and students.The report will be considered at the association's meeting in June.The association set up a task force to examine industry funding and to guide the association, medical schools, and teaching hospitals in developing policies and procedures about gifts and funding from industry.The report said that medical schools and teaching hospitals had become increasingly dependent on industry support for their core educational missions."This reliance raises concerns because such support, including gifts, can influence the objectivity and integrity of academic teaching, learning, and practice, thereby calling into question the commitment of academia and industry together to promote the public's interest by fostering the most cost-effective, evidencebased medical care possible."The report called on academic medical centers "to accelerate their adoption of policies that better manage, and when necessary, prohibit, academic-industry interactions that can inherently create conflicts of interest and undermine standards of professionalism."It concluded, "Industry should voluntarily discontinue those practices that compromise professionalism as well as public trust."The New York Times noted that medical schools, with their prominent professors and impressionable trainees, were particularly attractive targets for marketing (28 April; www.nytimes.com/
PREOPERATIVE CORONARY ANGIOGRAPHY WITH MULTIDETECTOR CT IS A SAFE ALTERNATIVE TO INVASIVE CATHETERIZATION IN PATIENTS UNDERGOING MITRAL VALVE REPAIR
Authors: Javier G. Castillo, Gonzalo Pizarro, Leticia Fernandez-Friera, Valentin Fuster, David H. Adams, Mario J. Garcia, Javier Sanz
Journal: Journal of the American College of Cardiology (2010)
Hemodialysis And Diabetic Nephropathy
Authors: Eugene Schupak
Journal: JAMA (1973)

<h3>To The Editor.—</h3> The prognosis for patients with diabetes mellitus dependent on hemodialysis is indeed grim if other centers confirm the 22% oneyear survival statistics given by Ghavamian et al.<sup>1</sup>Fortunately, other centers have had somewhat more success in dealing with these patients. Knepshield et al<sup>2</sup>recently summarized the experience among the Georgetown and Peter Bent Brigham diabetic dialysis populations. They had 29 patients with 347 patient-months of dialysis experience with an overall survival of 76%. We have had 40 diabetic patients with 589 patient-months of dialysis. One patient recently died after 53 months of dialysis and another is alive and well after 45 months. Seventeen of the patients were blind. Eleven deaths occurred during the first year of dialysis, eg, a one-year survival rate of 72%. Beyond the first year, the patients generally are clinically stable and there have been only four deaths. Of the deaths, five
Replacement of Left Ventricular Myocardium
Authors: HAROLD A. COLLINS, ISABELLA S. COLLINS
Journal: Circulation (1968)

The feasibility of resection and prosthetic replacement of left ventricular myocardium as a therapeutic adjuvant in myocardial infarction was assessed in a series of 72 dogs. Intracardiac pressures and cardiac output were measured in each dog several days preoperatively. During temporary cardiopulmonary bypass a large segment of the anterolateral wall of the left ventricle was excised. The defect was closed with either Teflon felt, woven Teflon cloth, or a pedicled diaphragmatic flap. Cardiac outputs and intracardiac pressures were measured immediately before and for several hours after myocardial replacement. Survivors were evaluated for periods up to three years by cardiac catheterization at appropriate intervals and pathological observation. Forty-four dogs survived longer than 24 hours. The immediate hemodynamic consequences of myocardial replacement were a diminished systemic arterial pressure and a low, fixed cardiac output. The arterial pressure and cardiac output gradually increased over a period of weeks, occasionally attaining preoperative levels. Left ventricular end-diastolic pressures were always within normal limits. The most common cause of death in the first two postoperative weeks was graft detachment. Observations of healing characteristics revealed Teflon felt to be the most satisfactory prosthesis. The diaphragmatic flap frequently necrosed, and woven Teflon produced intraventricular thrombus and incomplete healing. This study demonstrated the feasibility of resection and prosthetic replacement of large segments of left ventricular myocardium. Complications of the procedure were related to a temporarily diminished cardiac output and inadequate healing of the prosthesis to myocardium.
Effect of disruption of Akt-1 of lin-c-kit+ stem cells on myocardial performance in infarcted heart
Authors: A. Tseng, J. Stabila, B. McGonnigal, N. Yano, M.-J. Yang, Y.-T. Tseng, P. A. Davol, L. G. Lum, J. F. Padbury, T. C. Zhao
Journal: Cardiovascular Research (2010)

We have demonstrated an important role of bone marrow-derived stem cells in preservation of myocardial function. We investigated whether Akt-1 of lin(-)c-kit(+) stem cells preserves ventricular function following myocardial infarction (MI).Isolated lin(-)c-kit(+) cells were conjugated with anti-c-kit heteroconjugated to anti-vascular cell adhesion molecule to facilitate the attachment of stem cells into damaged tissues. Female severe combined immunodeficient mice were used as recipients. MI was created by ligation of the left descending artery. After 48 h, animals were divided into four groups: (i) sham (n = 5): animals underwent thoracotomy without MI; (ii) MI (n = 5): animals underwent MI and received medium; (iii) MI + wild-type (Wt) stem cells (n = 6): MI animals received 5 x 10(5) Wt lin(-)c-kit(+) stem cells; (iv) MI + Akt-1(-/-) stem cells (n = 6): MI animals received 5 x 10(5) Akt-1(-/-) lin(-)c-kit(+) stem cells. Two weeks later, left ventricular function was measured in the Langendorff mode. The peripheral administration of Wt armed stem cells into MI animals restored ventricular function, which was absent in animals receiving Akt-1(-/-) cells. Real-time PCR indicates a decrease in SRY3, a Y chromosome marker in hearts receiving Akt-1(-/-) cells. An increase in angiogenic response was demonstrated in hearts receiving Wt stem cells but not Akt-1(-/-) stem cells.Our results demonstrate that the peripheral administration of Wt lin(-)c-kit(+) stem cells restores ventricular function and promotes angiogenic response following MI. These benefits were abrogated in MI mice receiving Akt-1(-/-) stem cells, suggesting the pivotal role of Akt-1 in mediating stem cells to protect MI hearts.