tbuckley/cabot-search huggingface dataset:
Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload
Authors: Gabriele G. Schiattarella, Joseph A. Hill
Journal: Circulation (2015)

H ypertrophic growth of ventricular myocytes is a hallmark feature of numerous forms of cardiovascular disease. 1 The hypertrophic process is complex, involving a vast array of structural, signaling, transcriptional, electrophysiological, metabolic, and functional events within the growing cell. 2,3ther cellular elements within the ventricle, fibroblasts, vascular smooth muscle cells, and endothelium, also manifest intricate stress responses, resulting in fibrosis, inflammatory cell infiltration, endothelial dysfunction, and vascular stiffness.Current thinking holds that these events, the reaction of the heart to a host of pathological stresses, provide short-term benefit.However, if disease-related stress remains unchecked, these remodeling events become maladaptive and predispose to cardiovascular morbidity and mortality. Response by Crozatier and Ventura-Clapier on p 1447Among the risks conferred by disease-related ventricular hypertrophy are ventricular tachyarrhythmia, predisposing to sudden cardiac death, and transition to heart failure.Ultimately, these events derive from wholesale reprogramming and relative dedifferentiation of the cardiac myocyte, coupled with similar events in other cell types.Conventional thinking holds that hypertrophic growth of the myocardium is a compensatory response of the heart to increases in workload demand, serving to minimize wall stress and maintain contractile function.However, several lines of evidence, preclinical and epidemiological, highlight the maladaptive features of chronic ventricular hypertrophy.Indeed, in many instances, suppression of load-induced growth is well tolerated. 4Furthermore, left ventricular hypertrophy is among the most robust markers of increased risk for developing chronic heart failure. 5Therefore, we submit that suppression of load-induced ventricular hypertrophy warrants careful consideration as a therapeutic strategy. Cardiomyocyte Hypertrophy: Comprehensive Reprogramming of the CellAlthough evidence suggests that a small fraction of cells within the ventricle are capable of re-entering the cell cycle, [6][7][8] the majority of cardiomyocytes are postmitotic and, hence, do not retain the ability to divide.Rather, they respond to stress by growing, shrinking, or dying.In the context of many disease-related stresses, cardiac myocytes undergo hypertrophic transformation, which entails significant cellular growth.In the setting of uncontrolled hypertension, for example, cardiomyocytes hypertrophy.Similarly, after myocardial infarction, surviving cardiac myocytes in border and remote zones of tissue increase in size in response to increases in hemodynamic
The electrophysiology of rabbit hearts with left ventricular hypertrophy under normal and ischaemic conditions
Authors: M.N. Hicks, M.A. McIntosh, K.A. Kane, A.C. Rankin, S.M. Cobbe
Journal: Cardiovascular Research (1995)

Objectives: To examine the cardiac electrophysiological effects of left ventricular hypertrophy (LVH) and to determine whether any observed differences are modified by global zero-flow ischaemia. Methods: LVH was induced by perinephritic hypertension in New Zealand White rabbits. Transmembrane action potential recordings were made using conventional floating glass microelectrodes and effective refractory periods (ERP) determined by programmed stimulation in isolated arterially perfused interventricular septa during normal perfusion and a 30-min period of global ischaemia. The electrophysiological data were pooled into 6-min periods during ischaemia. Results: The post-operative blood pressure was 76(2) mmHg (mean(s.e.m.)) and 113(2) mmHg (P < 0.0005) in the sham and perinephritic rabbits respectively. The left ventricular to body weight ratio was 0.27(0.01) g kg−1 in the sham and 0.36(0.02) g kg−1 in the perinephritic group (P < 0.005) representing 33% hypertrophy. In the isolated septa, prior to ischaemia, the hypertrophied group exhibited significant prolongations in action potential duration to 50% and 90% repolarisation (APD50, APD90) and ERP of 20%, 12% and 19% respectively (P < 0.005) without any differences in resting membrane potential (Em), upstroke velocity (dV/dtmax) or amplitude (APA) of the action potential. During ischaemia Em, APA and dV/dtmax progressively decreased to a similar extent in both groups. Ischaemia resulted in shortenings in APD50, APD90 and ERP in the hypertrophy group of 122(9) ms, 131(8) ms and 99 (6) ms respectively which were greater than those observed in the control group (84 (7) ms, 115 (7) ms and 50 (13) ms, P < 0.05). These differences resulted in loss of the preischaemic prolongation of repolarisation and refractoriness in the hypertrophy group. Conclusions: There was enhanced shortening of APD and ventricular refractoriness in hypertrophied muscle during global ischaemia. This could increase the dispersion of repolarization and refractoriness between normal and ischaemic hypertrophied muscle during regional ischaemia which may explain the increased susceptibility of hypertrophied hearts to arrhythmias.
Acute graft-versus-host disease after liver transplantation diagnosed by fluorescent in situ hybridization testing of skin biopsy specimens
Authors: Alexander Meves, Rokea A. el-Azhary, Jayant A. Talwalkar, S. Breanndan Moore, Jerry D. Brewer, Catherine Motsonelidze, Kelly T. McNallan, Ann M. Reed, Charles B. Rosen
Journal: Journal of the American Academy of Dermatology (2006)
Abstract 1137: Expression of specific apoptotic mediators predicts sensitivity to combined MEK and PI3K inhibition in KRAS mutant non-small cell lung cancer according to TP53 mutational status.
Authors: Aaron Hata, Anthony Faber, Alan Yeo, Zhao Chen, Kwok-Kin Wong, Jeffrey Engelman
Journal: Cancer Research (2013)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer death world-wide. Though targeted therapies have been developed for NSCLC with activating EGFR mutations or the EML4-ALK translocation, no highly effective targeted therapies exist for cancers harboring activating KRAS mutations. We previously observed that concomitant use of MEK and PI3K inhibitors (MEKi/PI3Ki) led to tumor regressions in a mouse model of KRAS mutant NSCLC, and clinical trials investigating this strategy are underway. However, KRAS mutant NSCLCs are a heterogeneous group of cancers, and the molecular determinants of sensitivity to MEKi/PI3Ki are unknown. Here we report that human KRAS mutant NSCLC cell lines exhibit variability in responsiveness to MEKi/PI3Ki resulting from differential apoptotic responses. We identified key pro- and anti-apoptotic regulators regulators of the apoptotic response induced by MEKi/PI3Ki. Loss of the apoptotic response due to down-regulation of pro-apoptotic mediators was associated with acquired resistance to MEKi/PI3Ki. The responsiveness of KRAS mutant NSCLCs to combined MEKi/PI3Ki could be predicted by the relative expression levels of specific apoptotic regulators, depending on TP53 mutational status. These results reveal genotype-specific mechanisms of apoptosis necessary for responsiveness to targeted therapies and suggest biomarkers for predicting responsiveness of KRAS mutant NSCLC to MEKi/PI3Ki. Citation Format: Aaron Hata, Anthony Faber, Alan Yeo, Zhao Chen, Kwok-Kin Wong, Jeffrey Engelman. Expression of specific apoptotic mediators predicts sensitivity to combined MEK and PI3K inhibition in KRAS mutant non-small cell lung cancer according to TP53 mutational status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2013-1137
FAMILIAL AMYOTONIA CONGENITA
Authors: Gerald R. Allaben
Journal: JAMA (1924)

<h3>To the Editor:</h3> —I was pleased to learn through Dr. Joseph Popper's communication (The Journal, September 20, p. 941) that he had reported two cases of amyotonia congenita in the same family, and sorry that in reviewing the literature I did not note this report. Faber also pointed out familial occurrence in three instances. In a letter, Dr. S. J. Goodman of Columbus, Ohio, states that he saw two cases, both fatal, in the same family, with Dr. H. H. Fisher of the same city, but does not say whether or not these cases were reported. Morgan and Stuart (The Journal, April 15, 1922, p. 1106) write: "It does not appear to be hereditary, nor is there any special familial tendency to its occurrence," which is true, although apparently there have been a few such cases. Pearce (<i>Am. J. Dis. Child.</i><b>20</b>:393 [Nov.] 1920) reports two sets of cases
COORDINATIVE ABILITY VARIABLES AMONG TENNIS AND SQUASH MEN PLAYERS – A COMPARATIVE STUDY
Authors: I Syed, A Kanniyan, H Al Moslim, MA Syed
Journal: British Journal of Sports Medicine (2014)

Background Sports performance is achieved through working, training of all major components i.e. technique coordination, tactics, physical fitness and psychological qualities. This apart coordinative abilities like orientation, differentiation, reaction, balance and rhythm play a big role. Objective The objective of the study was to determine the relationship among coordinative abilities between Tennis and Squash men players. Design Cross-sectional. Participants The samples were 20 Tennis and 30 Squash Inter University players between 18–25 years. Main outcome measurements The coordinative abilities studied were orientation, differentiation, reaction, balance and rhythmic. Test items used for different abilities were Zigzag run, backward medicine ball throw, lateral jumping ability, beam walk and long nose tests to find the difference in performance of the players. Mean, standard deviation and ‘t’ test were used as statistical tools and level of significance was 0.05 . Results The study showed quite interesting results as the game of tennis and squash are racket games and have many skills very similar to each other. The difference lies in the area of the court, the equipment used for play and the time limit of game. Tennis players have shown better performance in Orientation, differentiation, balance and rhythmic abilities due to the above difference and is in line with other studies done by Lees (2008), Miller, et al. (2001) etc. The only variable in which the squash players have shown some significance is the reaction ability which may be due to small area of play and the need to be quick as the time is too short to respond to the shots during the game. Conclusion It is concluded that there exists significant difference in terms of all the coordinating abilities between the tennis and squash players and that the tennis players possessed better coordinating abilities than the squash players.
UK blood products are banned
Authors: J. Warden
Journal: BMJ (1998)

Precautionary measures to protect patients against the theoretical risk of contracting variant Creutzfeldt-Jakob Disease (CJD) from blood products from donors in the United Kingdom were announced last week by the Department of Health.

Imported plasma will now be used while a review of plasma from donors in Britain is conducted over the next four months. The action, initiated by the Committee on Safety of Medicines, follows three recalls of …
Inhibition of Poly(ADP-Ribose) Polymerase Modulates Tumor-Related Gene Expression, Including Hypoxia-Inducible Factor-1 Activation, during Skin Carcinogenesis
Authors: David Martin-Oliva, Rocío Aguilar-Quesada, Francisco O'Valle, Jose Antonio Muñoz-Gámez, Rubén Martínez-Romero, Raimundo García del Moral, José Mariano Ruiz de Almodóvar, Raquel Villuendas, Miguel Angel Piris, F. Javier Oliver
Journal: Cancer Research (2006)

Abstract Poly(ADP-ribose) polymerase (PARP)-1, an enzyme that catalyzes the attachment of ADP ribose to target proteins, acts as a component of enhancer/promoter regulatory complexes. In the present study, we show that pharmacologic inhibition of PARP-1 with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) results in a strong delay in tumor formation and in a dramatic reduction in tumor size and multiplicity during 7,12-dimethylbenz(a)anthracene plus 12-O-tetradecanoylphorbol-13-acetate–induced skin carcinogenesis. This observation was parallel with a reduction in the skin inflammatory infiltrate in DPQ-treated mice and tumor vasculogenesis. Inhibition of PARP also affected activator protein-1 (AP-1) activation but not nuclear factor-κB (NF-κB). Using cDNA expression array analysis, a substantial difference in key tumor-related gene expression was found between chemically induced mice treated or not with PARP inhibitor and also between wild-type and parp-1 knockout mice. Most important differences were found in gene expression for Nfkbiz, S100a9, Hif-1α, and other genes involved in carcinogenesis and inflammation. These results were corroborated by real-time PCR. Moreover, the transcriptional activity of hypoxia-inducible factor-1α (HIF-1α) was compromised by PARP inhibition or in PARP-1–deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1α. Tumor vasculature was also strongly inhibited in PARP-1–deficient mice and by DPQ. In summary, this study shows that inhibition of PARP on itself is able to control tumor growth, and PARP inhibition or genetic deletion of PARP-1 prevents from tumor promotion through their ability to cooperate with the activation AP-1, NF-κB, and HIF-1α. (Cancer Res 2006; 66(11): 5744-56)
The Muddle of Diets for Gastrointestinal Disorders
Authors: Robert M. Donaldson
Journal: JAMA (1973)

What should the patient with a common gastrointestinal disorder eat? Only casual perusal of any hospital diet manual is needed to recognize that neither patient nor physician has any clear answer. More than a decade ago a detailed report by the AMA Council on Foods and Nutrition pointed out that diet therapy for most afflictions of the digestive tract is based on unsubstantiated opinion and tradition and that there was an urgent need to learn "exactly what foods do within the human digestive system."<sup>1</sup>Unfortunately, the situation today remains as muddled as ever. Dietary treatment of peptic ulcer provides a good example of the problem. Those who advocate dietary restrictions for ulcer patients<sup>2</sup>urge that only "bland" foods be allowed. In general that restriction has been implemented by presenting the patient with foods of a particular color (white), consistency (soft), and taste (mild) that fit the physician's or
Email contact with doctor helps patients control their diabetes, study finds
Authors: B. Roehr
Journal: BMJ (2010)

Patients with diabetes who kept in touch with their doctors through email had better control of their diabetes or hypertension, or both, than did matched patients who did not have such contact, shows an analysis of medical records at Kaiser Permanente, a large integrated healthcare system in the United States. The study was published in the July issue of Health Affairs (2010;29:1370-5, doi:10.1377/hlthaff.2010.0048).

Surveys have shown that US patients want to be able to exchange emails with their doctor in a way that protects the confidentiality of their electronic medical records. Kaiser Permanente built that capacity into the electronic records system of its regional affiliates and introduced it …
Diphenylhydantoin For Treatment of Alcohol Withdrawal Syndromes
Authors: Morris J. Finer
Journal: JAMA (1971)

To the Editor.—  In this large (1,400-bed) hospital, alcoholic patients enter three different services (neurology, medicine, psychiatry). Those who are in a special 30-bed unit of the psychiatry service come via transfer from the other two services either after detoxification or directly. Whatever the source, those on the alcoholism research and treatment program of the psychiatry service are supposed to be detoxified, but such is not always the case. Various sequelae of excessive alcohol intake are encountered and treated. This communication intends to call attention to an effective regime for the prevention and management of one such problem, the alcohol withdrawal syndromes (seizures, impending delirium tremens, psychomotor excitation).  Central nervous system depressants are commonly used to abate, prevent, or treat this complication of alcoholism. It is our belief that the tremors, apprehension, and psychomotor excitation are rebound phenomena from an abruptly discontinued central nervous system depressant (alcohol) and should not
Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis
Authors: Chahrazade Kantari, Magali Pederzoli-Ribeil, Omid Amir-Moazami, Valérie Gausson-Dorey, Ivan Cruz Moura, Marie-Christine Lecomte, Marc Benhamou, Véronique Witko-Sarsat
Journal: Blood (2007)
Abstract 5271: p16-LUC: an in vivo reporter allele for de novo tumor formation and therapeutic response
Authors: Christin E. Burd, Kelly Clark, Norman E. Sharpless
Journal: Cancer Research (2011)

Abstract The p16INK4a tumor suppressor is upregulated and serves to limit proliferation in response to cellular stressors and oncogenic events. Induction of p16INK4a is highly dynamic during tumorigenesis and aging, ranging from undetectable in unstressed cells to &amp;gt;105 mRNA copies per cell when maximally activated. This property, along with the well established activation of p16INK4a in response to a variety of oncogenic stressors, led to the hypothesis that p16INK4a could be an excellent marker of tumorigenesis and aging. Toward that end, we developed a novel knock-in mouse model, p16-LUC, wherein the endogenous p16INK4a promoter drives single-copy expression of firefly luciferase. Using homologous recombination in ES cells, the open reading frame of firefly luciferase was inserted in-frame at the transcriptional start site of p16INK4a, preserving the structure and regulation of other genes (p19ARF and p15INK4b) encoded by the Cdkn2a/b locus. Murine embryo fibroblasts (MEFs) derived from p16-LUC animals demonstrate marked (&amp;gt;105) upregulation of luciferase activity with culture, paralleling that observed for the endogenous allele. Such induction can also be monitored dynamically in vivo following treatment with DNA damaging stressors such as ionizing radiation. To test the ability of this allele to serve as a biomarker of oncogenic stress, we crossed the p16-LUC mouse to numerous genetically engineered mouse models (GEMMs) of human cancer. In these mice, potent induction of luciferase activity was apparent in tumors driven by a wide variety of oncogenes. Moreover, weeks before visual or palpable tumors could be detected, p16-LUC expression localized to future tumor sites. Treatment of these mice with a wide range of chemotherapeutic compounds also revealed novel insights into therapeutic efficacy and potential toxicities. Overall, the p16-LUC model has potential to advance the study of de novo tumor formation, therapeutic efficacy and toxicology by providing a reagent to conduct long-term, in vivo studies of GEMMs and potential anti-cancer compounds. 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 5271. doi:10.1158/1538-7445.AM2011-5271
CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy
Authors: Rudi Bao, Cheng-Jung Lai, Hui Qu, Dagong Wang, Ling Yin, Brian Zifcak, Ruzanna Atoyan, Jing Wang, Maria Samson, Jeffrey Forrester, Steven DellaRocca, Guang-Xin Xu, Xu Tao, Hai-Xiao Zhai, Xiong Cai, Changgeng Qian
Journal: Clinical Cancer Research (2009)

Abstract Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models. Results: CUDC-305 shows high affinity for HSP90α/β (IC50, ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non–small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.
Human Essential Hypertension: Implications of Animal Studies
Authors: LOUIS TOBIAN
Journal: Annals of Internal Medicine (1983)

Hypertension has been linked to dietary sodium intake in humans. It is possible that 9% to 20% of the population may be genetically susceptible to developing essential hypertension by middle life. The remainder of the population may be genetically resistant to developing essential hypertension. A person genetically resistant to hypertension can ingest as much as 200 meq/d of salt without developing elevated blood pressure. However, in persons genetically susceptible to hypertension, a lifelong restriction of salt intake of less than 60 meq/d in adults may prevent hypertension indefinitely, and subsequent hypertensive complications. The same restriction of salt enhances the effect of most antihypertensive drugs and is the only treatment necessary in some persons with mild or moderate hypertension, especially the elderly.
GW25-e3400 Epidemiological, clinical and pathological features of the unexplained sudden death clustered in the mountain area of Yunnan province in China: a retrospective study of 44 cases from 1975 to 2013
Authors: Zhao Su, Zhao Hong, Wang Hongyue, Wang Yuebing, Shi Guoqing, Li Zhaoxiang, Yang Lin, Zhang Jian, Lei Pu-Ping, Qu Yongqiang, Ma Lin, Li Jiaguo, Bao Jianzhong, Li Huachang, Ke Chunrong, Robert E. Fontaine, Yang Yuejin, Zeng Guang, Huang Wenli
Journal: Journal of the American College of Cardiology (2014)