tbuckley/cabot-search huggingface dataset:
Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters
Authors: H KONDOH, Y SAWA, S MIYAGAWA, S SAKAKIDAKITAGAWA, I MEMON, N KAWAGUCHI, N MATSUURA, T SHIMIZU, T OKANO, H MATSUDA
Journal: Cardiovascular Research (2006)

Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct injection method has limitations for generalized cell delivery, especially in dilated cardiomyopathy (DCM). We hypothesized that a sheet-shaped myoblast graft would be superior to direct injection for improving cardiac performance in DCM.Male 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide), a temperature-responsive polymer, and spontaneously detached as a sheet-shaped graft at 20 degrees C without enzymatic treatment. Three different therapies were conducted: (1) sheet-shaped myoblast graft implantation (S group, n=29); (2) myoblast injection (M group, n=28); and (3) sham operation (C group, n=28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls.After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperative level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group.Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and re-organization of the cytoskeletal proteins in DCM hamsters. Thus, sheet-shaped autologous myoblast graft implantation may induce restoration of the heart in DCM.
Assay of Renin and Hypertensin with the Isolated Guinea-Pig Ileum
Authors: ZULEIKA P. PICARELLI, REGINA KUPPER, ELINE S. PRADO, J. L. PRADO, J. R. VALLE
Journal: Circulation Research (1954)

Renin and hypertensin may be easily assayed with the isolated guinea-pig ileum, which is as sensitive as the vascular toad preparation. Hypertensin itself is the substance which acts on the smooth muscle of the ileum.
Synchronous primary lung cancers: prevalence in surgical material and clinical implications.
Authors: F A Carey, S C Donnelly, W S Walker, E W Cameron, D Lamb
Journal: Thorax (1993)

BACKGROUND--The prevalence of synchronous primary lung neoplasms in surgical resection specimens was assessed. The associated clinical features and prognostic implications were investigated. METHODS--All surgical resections for lung cancer performed during seven years were reviewed. Synchronous tumours were defined by the presence of more than one tumour mass in the lung, by differences in histological subtype, by the presence of separate bronchial origins, or by differences in DNA stemlines. Clinical data were abstracted from case notes and information from the tumour registry. RESULTS--Just under 2% of all surgical specimens in the study period contained more than one primary carcinoma. The patients did not differ clinically from the general population of patients having surgery for lung cancer. The overall prognosis was poor (mean survival 27 months) but was significantly better for patients with synchronous squamous carcinomas (mean survival 49 months). CONCLUSION--Synchronous primary lung carcinomas are associated with a poor prognosis except in patients having tumours only of squamous histological type.
Genomics in cardiac metabolism
Authors: J.-L. Samuel, M. C. Schaub, M. Zaugg, M. Mamas, W. B. Dunn, B. Swynghedauw
Journal: Cardiovascular Research (2008)

Cell biology is in transition from reductionism to a more integrated science. Large-scale analysis of genome structure, gene expression, and metabolites are new technologies available for studying cardiac metabolism in diseases known to modify cardiac function. These technologies have several limitations and this review aims both to assess and take a critical look at some important results obtained in genomics restricted to molecular genetics, transcriptomics and metabolomics of cardiac metabolism in pathophysiological processes known to alter myocardial function. Therefore, our goal was to delineate new signalling pathways and new areas of research from the vast amount of data already published on genomics as applied to cardiac metabolism in diseases such as coronary heart disease, heart failure, and ischaemic reperfusion.
Systematic assessment of difficult-to-treat asthma
Authors: D.S. Robinson, D.A. Campbell, S.R. Durham, J. Pfeffer, P.J. Barnes, K.F. Chung
Journal: European Respiratory Journal (2003)

Five per cent of asthmatics remain symptomatic despite high-dose treatment. The aim of the study was to investigate how often such difficult-to-treat asthma is due to intractable asthma, misdiagnosis, non-adherence with therapy, or psychiatric problems. Difficult asthma was defined as persistence of symptoms despite treatment at step 4 of British guidelines or requirement for long-term oral glucocorticoids (step 5). One-hundred patients with a respiratory physician diagnosis of asthma were investigated in a single tertiary respiratory unit in an open and descriptive study. Twelve of the patients studied did not have asthma and a further seven had additional diagnoses. Of the remainder, 55 had an asthma diagnosis confirmed by demonstration of reversible airflow narrowing or peak flow variability, whilst 20 did not. Noncompliance with prednisolone therapy was more frequent in the 55 with confirmed asthma (nine of 18 prescribed oral prednisolone at a dose of ≥15 mg·day −1 ) and was not detected in the “unconfirmed asthma” group. There were no other significant differences between these groups. A major psychiatric component was detected in 10 patients. Systematic evaluation of difficult asthma is useful as it can identify alternative or additional diagnoses, psychiatric illness or nonconcordance with therapy in a substantial proportion of cases (32% in the present series).
Cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy: results from a randomised trial
Authors: M. Sculpher
Journal: BMJ (2004)

<b>Objective</b> To assess the cost effectiveness of laparoscopic hysterectomy compared with conventional hysterectomy (abdominal or vaginal). <b>Design</b> Cost effectiveness analysis based on two parallel trials: laparoscopic (n = 324) compared with vaginal hysterectomy (n = 163); and laparoscopic (n = 573) compared with abdominal hysterectomy (n = 286). <b>Participants</b> 1346 women requiring a hysterectomy for reasons other than malignancy. <b>Main outcome measure</b> One year costs estimated from NHS perspective. Health outcomes expressed in terms of QALYs based on women9s responses to the EQ-5D at baseline and at three points during up to 52 weeks9 follow up. <b>Results</b> Laparoscopic hysterectomy cost an average of £401 ($708; €571) more (95% confidence interval £271 to £542) than vaginal hysterectomy but produced little difference in mean QALYs (0.0015, -0.015 to 0.018). Mean differences in cost and QALYs generated an incremental cost per QALY gained of £267 333 ($471 789; €380 437). The probability that laparoscopic hysterectomy is cost effective was below 50% for a large range of values of willingness to pay for an additional QALY. Laparoscopic hysterectomy cost an average of £186 ($328; € 265) more than abdominal hysterectomy, although 95% confidence intervals crossed zero (-£26 to £375); there was little difference in mean QALYs (0.007, -0.008 to 0.023), resulting in an incremental cost per QALY gained of £26 571 ($46 893; €37 813). If the NHS is willing to pay £30 000 for an additional QALY, the probability that laparoscopic hysterectomy is cost effective is 56%. <b>Conclusions</b> Laparoscopic hysterectomy is not cost effective relative to vaginal hysterectomy. Its cost effectiveness relative to the abdominal procedure is finely balanced.
A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia
Authors: Rong Chen, Varsha Gandhi, William Plunkett
Journal: Cancer Research (2006)

Abstract Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II–directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors. (Cancer Res 2006; 66(22): 10959-66)
Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells
Authors: Prabir K Chakraborty, Wing-Kee Lee, Malte Molitor, Natascha A Wolff, Frank Thévenod
Journal: Molecular Cancer (2010)

The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/beta-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/beta-catenin signaling are known to contribute to carcinogenesis.We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd2+ (25 microM, 3-9 h) caused nuclear translocation of beta-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability.Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.
Antitumor Activity of SNX-2112, a Synthetic Heat Shock Protein-90 Inhibitor, in <i>MET</i>-Amplified Tumor Cells with or without Resistance to Selective MET Inhibition
Authors: Thomas Bachleitner-Hofmann, Mark Y. Sun, Chin-Tung Chen, David Liska, Zhaoshi Zeng, Agnes Viale, Adam B. Olshen, Martina Mittlboeck, James G. Christensen, Neal Rosen, David B. Solit, Martin R. Weiser
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. Experimental Design: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition. Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. Clin Cancer Res; 17(1); 122–33. ©2011 AACR.
REGULATION OF THE EXPRESSION OF LIPOGENIC ENZYME GENES BY CARBOHYDRATE
Authors: Howard C. Towle, Elizabeth N. Kaytor, Hsiu-Ming Shih
Journal: Annual Review of Nutrition (1997)

Diets high in simple carbohydrates and low in fats lead in the mammalian liver to induction of a set of enzymes involved in lipogenesis. This induction occurs, in part, through transcriptional mechanisms that lead to elevated levels of the mRNA for these enzymes. For most of the lipogenic enzymes, an increase in glucose metabolism is required to trigger the transcriptional response. The intracellular mediator of this signaling pathway is unknown, although evidence suggests either glucose-6-phosphate or xylulose-5-phosphate. Studies to map the regulatory sequences of lipogenic enzyme genes involved in the transcriptional response have been performed for the L-type pyruvate kinase, S14, and acetyl-coenzyme A carboxylase genes. These studies have identified the DNA sequences necessary to link the signal generated by carbohydrate metabolism to specific nuclear transcription factors.
A Community-Based Study of Stroke Incidence after Myocardial Infarction
Authors: Brandi J. Witt, Robert D. Brown, Steven J. Jacobsen, Susan A. Weston, Barbara P. Yawn, Véronique L. Roger
Journal: Annals of Internal Medicine (2005)

Background: The rate of stroke after myocardial infarction (MI) remains unclear. Objectives: To examine the rate of stroke after incident MI; compare it with that observed in the population of Rochester, Minnesota; determine how the rate of stroke after MI has changed over time; and examine the impact of stroke on survival after incident MI. Design: Community-based cohort. Setting: Olmsted County, Minnesota. Participants: Persons with incident (first-ever) MI between 1979 and 1998. Measurements: Ischemic or hemorrhagic stroke in hospitalized and nonhospitalized patients that was identified by screening of the medical record for stroke diagnostic codes and subsequent stroke confirmation by physician review of the recorded event. Medical record review was used to ascertain baseline characteristics and death. Results: A total of 2160 persons with incident MI were hospitalized between 1979 and 1998 and followed for a median of 5.6 years (range, 0 to 22.2 years). The rate of stroke was 22.6 per 1000 person-months (95% CI, 16.3 to 30.6 per 1000 person-months) during the first 30 days after MI, corresponding to a 44-fold increase (standardized morbidity ratio, 44 [95% CI, 32 to 59]) risk for stroke in the population of Rochester, Minnesota. The risk for stroke remained 2 to 3 times higher than expected during the first 3 years after MI. Older age, previous stroke, and diabetes increased the risk for stroke, which did not decline over the study period. Strokes were associated with a large increase in the risk for death after MI (hazard ratio, 2.89 [CI, 2.44 to 3.43]). Limitations: Findings may not be generalizable to different populations. The authors measured outcomes by reviewing medical records. Conclusions: In the community, the risk for stroke is markedly increased after MI, particularly early after MI, compared with the expected risk in population without MI. Stroke is associated with a large increase in the risk for death after MI.
Epigenetics of Nicotine: Another Nail in the Coughing
Authors: Nora D. Volkow
Journal: Science Translational Medicine (2011)

In a mouse model, chronic nicotine exposure before cocaine use exacerbated the epigenetic, gene-expression, electrophysiological, and behavioral effects that occur during the transition from acute to chronic responses to cocaine that have been linked with the addictive process. Nicotine enhancement of the effects can be mimicked with an inhibitor of chromatin-modifying enzymes (class I and II histone deacetylases). These findings may spur the discovery of therapeutics for the treatment of addiction.
Diabetic Nephropathy: Diagnosis, Prevention, and Treatment
Authors: Jorge L. Gross, Mirela J. de Azevedo, Sandra P. Silveiro, Luís Henrique Canani, Maria Luiza Caramori, Themis Zelmanovitz
Journal: Diabetes Care (2005)

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects ∼40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE &amp;gt;20 μg/min and ≤199 μg/min) and macroalbuminuria (UAE ≥200 μg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c &amp;lt;7%), treating hypertension (&amp;lt;130/80 mmHg or &amp;lt;125/75 mmHg if proteinuria &amp;gt;1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol &amp;lt;100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.
Induction of myelo-monocytic My7 antigen (CD13) expression by interferon-α in basal cells of cutaneous T-cell lymphomas
Authors: B. DRENO, M. FLEISHCHMANN, S. VALARD, W. GODEFROY, B. BUREAU, J.F. STADLER, P. LITOUX
Journal: British Journal of Dermatology (1992)

The My7 antigen that is expressed on the basal cells in normal skin and inflammatory disorders is absent in the lesions of cutaneous T-cell lymphoma (CTCL). Induction of My7 expression in basal cells in the cutaneous lesions of 12 patients with mycosis fungoides and three with Sézary syndrome treated with interferon-α2a (IFN-α2a) for 10 months was investigated. Biopsies were taken from the same area before treatment and after 2, 6 and 10 months of therapy with IFN-α2a. My7 antigen was expressed on the basal cells only in those patients who showed either a complete or partial response to therapy with IFN-α2a.
THE PERMEABILITY OF THE LINING OF THE LOWER RESPIRATORY TRACT FOR ANTIBODIES
Authors: F. S. Jones
Journal: The Journal of Experimental Medicine (1924)

The experimental results indicate that the walls of the lower respiratory tract are relatively as impermeable for antibodies as they are for serum proteins. The kind of serum employed does not influence this fact. Antibodies contained in homologous (rabbit) serum failed to enter the blood stream when injected into the trachea in greater concentration than those contained in heterologous (guinea pig and cow) sera. That a little serum and its contained substances are absorbed after intratracheal injection has been shown both by the experiments dealing with sensitization and anaphylaxis previously reported and by the experiments recorded in this paper. Besredka's assertion that the laryngotracheal method is an efficient one for the administration of serum in the treatment of disease has not been borne out by the experimental evidence here presented. From the results one would conclude that it is one of the least efficient routes for administration. In contrast to the relative impermeability for proteins of the mucous membranes of the lower respiratory tract is the relative permeability of the endothelium of the peritoneal cavity. Antibody is there absorbed readily, whether it be in heterologous or in homologous serum. The indications are that a considerable portion of the antibody injected into the peritoneal cavity reaches the blood stream in 2 or 3 hours.
Medical Perspectives on Alcoholism and Around-the-Clock Psychiatric Services
Authors: DANA L. FARNSWORTH
Journal: American Journal of Psychiatry (1968)

Views about alcohol abuse as a moral problem or as a specific diagnostic entity contribute little to the development of realistic preventive techniques. It may be more helpful, the author suggests, to consider the abuse of alcohol as one of many possible unsound approaches to coping with human problems which may culminate in a psychiatric emergency. Emergency psychiatric services help to resolve immediate crises; each emergency may also serve as a teaching situation to guide the participants in future preventive efforts.