tbuckley/cabot-search huggingface dataset:
692. A Novel AAV Vector for the Treatment of Cystic Fibrosis Airway Disease
Authors: Maria Limberis, Guangping Gao, Daniel J. Weiner, Lili Wang, Peter Bell, James M. Wilson
Journal: Molecular Therapy (2004)

Cystic fibrosis (CF) is one of the most common life-threatening autosomal recessive disorders affecting the Caucasian population. The malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in both severe chronic lung disease, which currently accounts for more than 95% of the morbidity and mortality of CF patients, and manageable pancreatic disease. Up to date CFTR gene transfer to the lung for the treatment of CF airway disease has been limited by poor vector performance combined with the significant barriers that the airway epithelium poses to effective gene transfer. Recently, our group isolated a novel AAV family (AAV9). In an attempt to evaluate its tropism and transfection efficiency we tested the AAV2 genome packaged in the AAV9 capsid (AAV2/9) and compared it to AAV2/5 in various airway model systems. A 50 ml single dose of 1 × 1011 genome copies (gc) of AAV2/9 expressing either the nuclear targeted b-galactosidase (nLacZ) gene or the green fluorescence protein (GFP) gene under the transcriptional control of the chicken b-actin promoter was instilled intranasally into nude and also C57Bl/6 mice. Twenty-one days later, the lung and nose were processed for gene expression. In control animals transduced with AAV2/9-GFP no LacZ positive cells were seen. AAV2/9-nLacZ successfully transduced mainly airways, whereas AAV2/5-nLacZ transduced mainly alveoli and few airways. Across the nasal airway epithelium both AAV2/5 and AAV2/9 transduced ciliated and non-ciliated epithelial cells. We are currently evaluating epithelial cell specific promoters to improve targeting to the airway cells in vivo. Based on the in vivo findings we next tested the gene transfer efficiency of AAV2/9 to human airway epithelial cells. Airway epithelial cells were isolated from human trachea and bronchi and grown at air-liquid-interface (ALI) on collagen coated membrane supports. Once the cells polarized and differentiated they were transduced with AAV2/9 or AAV2/5 expressing GFP from the apical as well as the basolateral side. Both AAV2/5 and AAV2/9 were successful at transducing epithelial cells from the basolateral surface. However, when applied onto the apical surface AAV2/9 resulted in a 10-fold increase in the number of transduced cells compared to AAV2/5. Currently, we are assessing the gene transfer performance of AAV2/9 in the lungs and nasal airways of nonhuman primates. We have demonstrated that AAV2/9 can efficiently transduce the airways of murine lung and well-differentiated human airway epithelial cells grown at ALI. These encouraging results have prompted the evaluation of AAV2/9 in nonhuman primates as well as the evaluation of AAV2/9-CFTR gene transfer to the nasal airway epithelium of cystic fibrosis knockout mice in an attempt to evaluate physiological correction of the CF defect. This novel family of AAV vectors shows great promise for the treatment of CF airway disease.
Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis
Authors: Bindya Jacob, Motomi Osato, Namiko Yamashita, Chelsia Wang, Yoshiaki Ito
Journal: Clinical Cancer Research (2007)

C3  The RUNX1/AML1 gene encodes a transcription factor which is critical for the generation and maintenance of hematopoietic stem cells and is the most frequently targeted gene in human leukemia. Loss of function of RUNX1 predisposes cells to leukemia, and with the acquisition of cooperating genetic alterations, the cells become fully leukemogenic. Conditional deletion of Runx1 in adult mice results in an increase of hematopoietic stem/progenitor cells which serves as the target cell pool for leukemia. However, Runx1-/- mice do not develop spontaneous leukemia, probably due to the phenomenon called exhaustion. Bone marrow transplantation experiments showed that Runx1-/- stem cell maintenance was compromised, resulting in decreasing contribution of Runx1-/- stem cells to blood cell production. The development of leukemia from stem cells harboring property of exhaustion may therefore require accumulation of additional genetic alterations that prevent exhaustion. We employed insertional retroviral mutagenesis on conditional Runx1 knockout mice and identified Evi5 as an additional genetic alteration that prevents the stem cell exhaustion caused by Runx1 deficiency in the development of leukemia.
Abstract 3144: Prevalence Of Insulin Resistance Among Non-diabetic Chronic Heart Failure Patients And Its Relation To Disease Severity
Authors: Chim C Lang, Matlooba A ALZadjali, Valerie Godfrey, AnnaMaria Choy, Faisel Khan, Allan D Struthers
Journal: Circulation (2007)

Body: Background Purpose- There is increasing evidence of a reciprocal interrelationship between chronic heart failure (CHF) and insulin resistance (IR) such that IR may be pathophysiologically linked to the evolution of the disease in CHF. However, the prevalence of IR in the CHF population has not been fully defined. The purpose of this study was to establish the prevalence of IR among non-diabetic CHF patients and to assess its relation to disease severity. Methods- The homeostatic model of insulin resistance (HOMA-IR) was assessed in a cohort of 129 CHF patients; mean age (69.2±10.4 yrs) [range 30 –90 yrs], males 76%, CHF of ischemic etiology 82.2% and BMI (27.4±4.4kg/m2). All were on regular CHF medication. Patients underwent cardiopulmonary exercise testing and peripheral endothelial function testing by reactive hyperemia peripheral arterial tonometry (RH-PAT). Results- Prevalence of IR as defined by Fasting Insulin Resistance Index &gt;2.7 was 61% in CHF and was significantly higher than in the 23 subjects who were coronary artery disease controls without HF(P&lt;0.05). The degree of IR was not related to the etiology of CHF. There was a significant correlation between IR and serum triglyceride (r = 0.333, P&lt;0.01), HDL cholesterol (r = − 0.275, p&lt;0.05), impaired fasting glucose (r = 0.358, P&lt;0.01) and central obesity (r = 0.232, p&lt;0.01). The degree of IR was related to the exercise capacity and peak oxygen consumption (VO 2 ). Mean of IR increased significantly with worsening functional NYHA Classes I, II, III and IV [2.1, 2.9, 4.8, 8.9], (r = 0.437, p&lt;0.01). The IR patients had a significantly lower exercise duration (340 ±168.3 vs. 601 ±265.9 s, p&lt; 0.01) and peak VO 2 (6.4 ± 2.3 vs. 14.5 ±1.7 ml/kg per min, p&lt; 0.05). Exercise peak cardiac output determined by the inert gas re-breathing method was lower in patients with IR (5.2 ±1.2 vs. 9.2 ± 0.89 l/min, p&lt;0.05). Endothelial function as measured by RH-PAT decreased significantly in patients with IR compared to the patients with normal insulin sensitivity (1.64 ± 0.36 vs. 2.0 ± 0.53, p&lt;0.05I). Conclusion - These findings suggest that IR is highly prevalent among CHF patients and is associated with decreased exercise effort and capacity in patients with CHF. Targeting IR might represent a new strategy in the treatment of CHF.
Abstract 13067: Cyclophilin A is an Inflammatory Mediator That Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Patrizia Nigro, Kimio Satoh, Michael R O'Dell, Nwe Nwe Soe, Zhaoqiang Cui, Amy Mohan, Jun-ichi Abe, Jeffrey Alexis, Janet D Sparks, Bradford C Berk
Journal: Circulation (2010)
Effects of Nifedipine and Nitroglycerin on Left Ventricular Systolic Dysfunction and Impaired Diastolic Filling After Exercise-Induced Ischemia in Humans11This study was supported by a grant from the American Heart Association, Kentucky Affiliate, Louisville, Kentucky.
Authors: MARCUS F STODDARD, STEVEN G WAGNER, SOHAIL IKRAM, RITA A LONGAKER, CHARLES R PRINCE
Journal: Journal of the American College of Cardiology (1996)
CLINICAL USE OF NEW TYPES OF MODIFIED PROTAMINE ZINC INSULIN
Authors: Renato Sanz Del Fierro, Elmer L. Sevringhaus
Journal: Annals of Internal Medicine (1945)

Article1 May 1945CLINICAL USE OF NEW TYPES OF MODIFIED PROTAMINE ZINC INSULINRENATO SANZ DEL FIERRO, M.D., ELMER L. SEVRINGHAUS, M.D., F.A.C.P.RENATO SANZ DEL FIERRO, M.D.Search for more papers by this author, ELMER L. SEVRINGHAUS, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-22-5-667 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe report by MacBryde and Roberts1 concerning the clinical use of a new type of modified protamine zinc insulin in the treatment of diabetic patients with excellent results moved us to use it in clinical trial in a small number of selected cases.It is well known that for the great majority of diabetics, crystalline zinc insulin if divided in proper doses, or commercial protamine zinc insulin (PZI) with convenient shifts of carbohydrate allotments in the diet, will suffice. There are, however, a certain number of patients that cannot be controlled by this means, especially when they require large doses...Bibliography1. MACBRYDEROBERTS CMHK: Modified protamine zinc insulin: an improvement on standard protamine zinc insulin, Jr. Am. Med. Assoc., 1943, cxxii, 1225-1231. CrossrefGoogle Scholar2. PECK FB: Approximate insulin content of extemporaneous mixtures of insulin and protamine zinc insulin, Ann. Int. Med., 1943, xviii, 177. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Madison, Wisconsin*Received for publication September 14, 1944.From the Wisconsin General Hospital, Madison.†Pan-American Fellow in Endocrinology, 1943-44. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Internal Secretion of the Pancreas 1 May 1945Volume 22, Issue 5Page: 667-670KeywordsCarbohydratesClinical trial reportingDietEndocrinologyGlobinsInsulinPatientsProtaminesResearch laboratoriesZinc ePublished: 1 December 2008 Issue Published: 1 May 1945 PDF downloadLoading ...
542. DNA Shuffling Generates Novel HIV-1 Envelope Variants That Can Induce Broadly Neutralizing Antibodies in Rabbits
Authors: Douglas E. Brough, Mark Praetorius, Chi Hsu, Kim Baker, Hinrick Staecker
Journal: Molecular Therapy (2004)

Top of pageAbstract
Gene delivery to the inner ear has the potential to treat hearing loss and balance disorders. A number of studies have shown that adenovirus vectors can transduce sensory and non-sensensory cells within the inner ear. In addition, the expression of growth factors and regulatory genes has been shown to have biological effects. As more candidate therapeutic genes are being discovered, further understanding of the mechanisms involved in adenoviral vector transduction of the inner ear is needed. Multiply deficient and targeted adenovirus vectors have the potential to enhance safety and efficacy of a gene delivery candidate to treat hearing and balance disorders. The advantages that multiply deficient adenoviral vectors deleted of E1A, E1B, E3 and E4 for gene delivery to the inner ear have been shown and the ability of these vectors with modified capsids to specifically transduce the inner ear will be discussed.
Abstract 16528: Predictive and Protective Value of High Density Lipoprotein-Cholesterol for Cardiovascular Events in Patients With Acute Myocardial Infarction Who had Percutaneous Coronary Intervention and Statin Treatment
Authors: Jin Sup Park, Kwang Soo Cha, Donghun Shin, Dae Sung Lee, Hye Won Lee, Jun-Hyok Oh, Jung Hyun Choi, Han Cheol Lee, Taek Jong Hong
Journal: Circulation (2014)

Introduction: Low level of high density lipoprotein-cholesterol (HDL-C) has been identified as a residual risk of cardiovascular events after lowering low density lipoprotein-cholesterol (LDL-C) in patients with stable coronary artery disease. Further, high HDL-C level is proven to have a protective effect for cardiovascular events in primary prevention studies. Hypothesis: We assessed the hypothesis that we evaluated whether the HDL-C level may have predictive and protective value in patients with acute myocardial infarction (MI) who had percutaneous coronary intervention (PCI) and statin treatment. Methods: A total of 15,938 patients who had PCI and statin treatment were selected from the Korean Myocardial Infarction registry. According to the ATP III criteria, baseline HDL-C level was used to identify patients with low HDL-C (<40 mg/dL, Group A), normal HDL-C (≥40 to < 60 mg/dL, Group B), or high HDL-C (≥60 mg/dL, Group C). Major adverse cardiac events (MACE) at one-year, the primary endpoint, were com...
PAIN—THE PATIENT'S COMPLAINT
Authors: Cullen Ward Irish
Journal: Annals of Internal Medicine (1935)

Article1 June 1935PAIN—THE PATIENT'S COMPLAINTCULLEN WARD IRISH, M.D.CULLEN WARD IRISH, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-8-12-1659 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptPain is defined in Dorland's Medical Dictionary as "distress or suffering." The derivation of the word is from the Greek appellation for penalty. Hence, in Webster's Dictionary, the first definition is given as "punishment, penalty, or fine," and its common usage as "an affection or feeling due to derangement of functions, disease or bodily injury," second, and "distressing uneasiness of mind; grief" is placed fourth.With consideration of the wider uses of the word "pain," practically all bodily and mental ills present attributes which may be included under this designation. Pain is the most frequent complaint offered by the patient...Bibliography HOWE EG: Motives and mechanisms of the mind, Lancet, Ltd., 1931, London. Google Scholar LIBMAN E: Observations on individual sensitiveness to pain, Jr. Am. Med. Assoc., 1934, cii, 335-341. CrossrefGoogle Scholar POTTENGER FM: Clinical aspects of abdominal pain, Jr. Am. Med. Assoc., 1934, cii, 341-344. CrossrefGoogle Scholar CARNETT JB: Pain and tenderness of abdominal wall, Jr. Am. Med. Assoc., 1934, cii, 345-348. CrossrefGoogle Scholar HALLMACKAY GWRP: Posttraumatic neuroses, Jr. Am. Med. Assoc., 1934, cii, 510-513. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Los Angeles, California*Read at a meeting of the Physician's and Surgeon's Fellowship Section of the Los Angeles County Medical Society April 11, 1934. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 June 1935Volume 8, Issue 12Page: 1659-1666KeywordsEmotionsFellowships Issue Published: 1 June 1935 PDF downloadLoading ...
A Comparison of Activators of Proteolytic Enzymes and Peptidases in Normal Rat Livers and Hepatomas
Authors: Paul C. Zamecnik, Mary L. Stephenson
Journal: Cancer Research (1949)

Summary  The cathepsin-activating ability of ultrafiltrates prepared from hepatomas has been found to be considerably less than that of various types of control livers. Since sulfhydryl groups are the most common cathepsin activators found in tissues, we have looked for a possible correlation of the above finding with the glutathione concentrations of the hepatomas. The hepatoma ultrafiltrates had both the lowest glutathione concentrations and the least cathepsin-activating power. The fetal livers, however, had a low glutathione concentration but the greatest cathepsin-activating ability. It is evident, therefore, that the cathepsin may be activated by more than one tissue component.  Glutathione appears (in the normal liver, in the regenerating liver, and in the hepatoma) to be a major cathepsin-activating agent and to be particularly low in the hepatoma. It is thus possible that the increased growth rate of this type of hepatoma may be related to a decrease in the concentration of the glutathione component of one of its protein-degrading mechanisms.
Abstract 21196: Validity of the Seattle Heart Failure Model in Predicting Outcomes on the Transplant Candidate List
Authors: Nandu Gourineni, Archana Sodagam, Pranav Ravi, Siva Soma, Deeanne Seeger, Diane Vido, Robert Moraca, Stephen Bailey, George Sokos, Raymond Benza, Srinivas Murali
Journal: Circulation (2010)

Background:  Mortality in advanced heart failure (HF) patients (pts) on the transplant (TX) candidate list remains high and reliable assessment of prognosis to allow for timely life saving intervention such as implantation of a left ventricular assist device (LVAD) or urgent TX (UNOS Status 1A) remains a clinical challenge. The Seattle Heart Failure Model (SHFM) uses easily available clinical variables to derive one-, two-, and three-yr survival rates and average yrs of survival for ambulatory, stable, chronic HF pts. Though, SHFM has been shown to underestimate risk of death in advanced HF pts referred for TX, the use of SHFM in predicting absolute risk among listed TX candidates remains unknown.   Methods:  Data on 88 consecutive pts (mean age 55± 11 yrs; 80% males; 88% caucasian; mean LVEF 19± 8%; 82% on angiotensin II modulation; 59% on beta blockers; 31% on aldosterone antagonists; 71% with ICD± CRT) listed for TX between January 1, 2006 and April 30 th , 2009 were retrospectively abstracted to calculate the SHFM predicted 1 yr risk of death. This was compared to the observed 1 yr risk of death, and the observed cumulative risk of death or LVAD insertion or urgent TX. The chi-square test and the C statistic were used to evaluate the differences.   Results:    Conclusions:  The SHFM tends to overestimate risk of death among TX candidates and significantly underestimates the cumulative risk of death/LVAD insertion/urgent TX. Other models are therefore needed to reliably assess prognosis in TX candidates.
Abstract 5492: Risk of Major Adverse Cardiovascular Events in Patients on Clopidogrel and Proton Pump Inhibitors: A Meta-analysis
Authors: Mukesh Singh, Sarabjeet Singh, Janos Molnar, Rohit Arora
Journal: Circulation (2009)

Background: The anti-platelet properties of clopidogrel are thought to be activated by cytochrome P450 2C19. This isoenzyme is potently inhibited by the most commonly prescribed proton pump inhibitors (PPIs) and therefore may interfere with clopidogrel activation and its anti-platelet effects. However, recently published studies have yielded mixed results, leaving the question unanswered. Hence a meta-analysis was performed to evaluate the potential impact of PPIs on the effectiveness of clopidogrel to prevent major adverse cardiovascular events (MACE). Methods: A systematic review of literature revealed 5 studies involving 29749 patients. End points analyzed were major adverse cardiovascular events (acute myocardial infarction, repeat revascularization, death due to cardiac causes. Combined relative risks (RR) across all the studies and the 95% confidence intervals were computed using the Mantel-Haenszel fixed-effect model. A two-sided alpha error &lt; 0.05 was considered to be statistically significant. Results: There were no significant differences in patient demographics between both groups. Compared with patients on clopidogrel without PPI, the risk of MACE was significantly higher in patients taking clopidogrel with PPI (RR: 1.65, CI: 1.55 – 1.76; p=0.000). Conclusions: The present meta-analysis suggests that combinig PPI with clopidogrel increases risk of MACE and it may be a class effect.
For and against: The male menopause---does it exist? For Against
Authors: D. C Gould
Journal: BMJ (2000)

<h3>Abstract</h3> Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover novel modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on results from spatial transcriptomic study of human postmortem brains. CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.
Improving outcomes for patients with acute myeloid leukemia in first relapse: A single center experience
Authors: Naveen Pemmaraju, Hagop Kantarjian, Guillermo Garcia‐Manero, Sherry Pierce, Marylou Cardenas‐Turanzas, Jorge Cortes, Farhad Ravandi
Journal: American Journal of Hematology (2014)

The outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory, with few available effective therapies. Increased understanding of the biology of the disease has led to the identification of novel therapeutic agents, several of which have been evaluated in recently conducted clinical trials. We sought to determine whether the introduction of these agents as well as modern supportive care measures has already translated to better outcomes. We examined the outcomes of 1,056 patients with AML in first relapse treated between January 1993 and December 2013 at our institution. As previously reported, the independent prognostic factors for survival after first relapse included age at relapse, cytogenetics, and duration of first complete remission. Upon multivariable analysis, treatment era was an independent predictor of survival, with significant improvement in overall survival between 2008 and 2013 as compared to prior time periods. Modern supportive care measures as well as participation in clinical trials of novel agents are already improving the outcomes in first relapse.
Abstract 9061: Relationships Among Satisfaction with Social Support, Perceived Stress, and Coping on Quality of Life and Survival 5 to 10 Years after Heart Transplantation
Authors: Connie White-Williams, Kathleen Grady, David Naftel, Susan Myers, Ed Wang, James Kirklin
Journal: Circulation (2009)

Introduction: Despite the fact that social support has been found to be important to cardiovascular health, there is a paucity of information regarding the relationship between social support and outcomes long-term after heart transplantation (HT). Thus, the purposes of this prospective, longitudinal study were to examine (1) the relationship between satisfaction with social support and post HT quality of life (QOL) and survival, (2) the predictability of two types of social support (emotional and tangible) and, (3) if social support is a mediator among stress, coping and QOL long-term after heart transplantation. Methods: Data were collected from 555 patients (pts) (78% male, 88% white, mean age=53.8 years) at 4 U.S. sites using the following instruments: Social Support Index, QOL Index, HT Stressor Scale, Jalowiec Coping Scale, and chart review. Statistical analyses included t-tests, correlations, and linear and multivariable regression. Results: Twenty percent and 70% of pts reported not needing social...