tbuckley/cabot-search huggingface dataset:
Impact of clinically evident portal hypertension on the course of hepatocellular carcinoma in patients listed for liver transplantation
Authors: François Faitot, Marc‐Antoine Allard, Gabriella Pittau, Oriana Ciacio, René Adam, Denis Castaing, Antonio Sa Cunha, Gilles Pelletier, Daniel Cherqui, Didier Samuel, Eric Vibert
Journal: Hepatology (2015)

Liver transplantation (LT) is the best curative treatment for early hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the current shortage of organs causes prolonged waiting times and poorer intention-to-treat (ITT) survival (i.e., after listing) owing to tumor progression and dropout. Portal hypertension (PH) is a recognized risk factor of HCC development in patients with cirrhosis and its recurrence after resection. The aim of this study was to evaluate the potential impact of PHT on the results of LT on an ITT basis. Patients with cirrhosis listed for LT for HCC were included and their outcomes after listing were compared according to the presence or absence of PH defined as presence of esophageal varices or ascites or low platelet count and splenomegaly. Among 243 consecutively listed patients, 70% were affected by PH, which was associated with a significantly higher risk of tumor progression (38% vs. 22%; P = 0.017) and a higher risk of dropout (22% vs. 8%; P = 0.01). Transarterial chemoembolization (TACE) was similarly applied to the two groups (60% vs. 67%; P = 0.325). An absence of TACE was the only other independent risk factor of dropout owing to tumor progression. Under an ITT analysis, PH reduced overall survival (OS), but there was no difference in OS and time to recurrence post-LT. The only pathological feature that could potentially explain this observation was the lower complete response to TACE in the PHT group (12% vs. 36%; P = 0.001).PH should be regarded as a major risk factor of dropout owing to tumor progression and should be taken into consideration when managing patients with HCC who are waiting for LT.
Plasma membrane receptors.
Authors: R J Lefkowitz, T Michel
Journal: Journal of Clinical Investigation (1983)

Receptors are macromolecules in or on cells that me- diate physiological responses upon binding specific li- gands.Over the past few years, important advances have been made in the understanding of the biology of receptors, both at a basic and at a clinical level.Receptors bind their ligands with remarkable selectiv- ity and with high affinity, permitting a given physiological response to be elicited with great specificity in the target tissue.The specific binding of agonists to receptors leads to the generation of signals that influence cell functions.The signal may be expressed as an altered rate of enzyme activity or ion transport, which then leads to the characteristic physiological responses within the cell.A wide variety of molecules, including hormones, drugs, neurotransmitters, growth factors, chemotactic agents, antigens, viruses, plasma lipoproteins, and glycoproteins, elicit their biological effects by virtue of their binding to cellular receptors.The more lipid sol- uble of these agents, such as steroid and thyroid hor- mones, are able to diffuse through the cell's plasma membrane and bind to intracellular receptors.Many of these agents, however, interact with receptors ex- posed on the external surface of the cell imbedded in the cellular plasma membrane.It is the purpose of this short essay to assess the current status of research on these membrane-bound receptors.It is only within the past fifteen years that the most proximal event in receptor function, that of ligand binding, has become amenable to direct experimental investigation.Such ligand-binding studies have facil-
Oral Contraception by Sequential Approach
Authors: Bernadine Z. Paulshock
Journal: JAMA (1966)

<h3>To the Editor:—</h3> In the article by Tyler et al (<b>197</b>:943, 1966) entitled "Oral Contraception by Sequential Approach," the authors measured 17-ketosteroids and 17-ketogenic steroids in the baseline state, and again after the administration of the contraceptive combination. These were also measured after administration of metyrapone and corticotropin (ACTH). Because of lower values obtained while patients were on the drug regimen and decreased responses to corticotropin and metyrapone during drug administration, the authors conclude that there was minimal suppression of the adrenal cortex, with return to normal after discontinuation of the contraceptive drugs. It has been shown rather conclusively in recent years by Grant et al (<i>J Clin Endocr</i><b>25</b>:1057, 1965), as well as by others, that estrogen therapy causes a decreased turnover rate of cortisol because of an increase in transcortin and, therefore, in plasma binding of adrenal hormones. Although long-term, high-dosage estrogen therapy may suppress the
Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation
Authors: Laure Saias, Aurélie Gomes, Martine Cazales, Bernard Ducommun, Valérie Lobjois
Journal: Cancer Research (2015)

Cell aggregation is frequently impaired during the growth of primary tumors and the formation of metastatic lesions. Cell aggregation depends on cell-cell adhesion; however, no rigorous approach exists to monitor and quantify it accurately in the absence of the confounding factors of cell-substrate adhesion and the resulting cell motility on the substrate. We report here a highly reproducible, automated, microscopy-based quantification of tumor-cell spheroid formation in the absence of cell-substrate adhesion and use it to characterize cell aggregation dynamics in the early steps of this process. This method is based on fluorescence and bright-field microscopy and on a custom MATLAB program to quantify automatically the cells' aggregation kinetics. We demonstrate that the cell-cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation. Furthermore, we show that inhibition or silencing of myosin IIa enhances aggregation, suggesting that cytoskeleton tension inhibits tumor cell aggregation. This work opens new avenues to study the principles that govern multicellular aggregation, to characterize the aggregation properties of various tumor cell types, as well as to screen for drugs that inhibit or promote aggregation.
Successful treatment of acquired pure red cell aplasia (PRCA) by allogeneic peripheral blood stem cell transplantation
Authors: Shih‐Bin Tseng, Sheng‐Fung Lin, Chao‐Sung Chang, Ta‐Chih Liu, Hui‐Hua Hsiao, Yi‐Chang Liu, Hui‐Jen Tsai, Tyen‐Po Chen
Journal: American Journal of Hematology (2003)

Abstract A 37‐year‐old male was treated successfully by peripheral blood stem cell transplantation (PBSCT) from his HLA‐identical sister for refractory acquired pure red cell aplasia (PRCA). The conditioning regimen was cyclophosphamide 50 mg/kg/day for 4 days plus TBI 300 cGy in a single fraction. Absolute neutrophil count (ANC) &gt;500/μl and platelet counts &gt;20,000/μl were achieved 8 days after PBSCT without transfusion. Chimerism study on day 218 revealed full donor chimerism. The hemoglobin level was stable around 12–13 g/dl with normal leukocyte and platelet counts after PBSCT during a long follow‐up period. From this case, PBSCT should be considered for patients with refractory acquired PRCA with an HLA‐identical donor. Am. J. Hematol. 74:273–275, 2003. © 2003 Wiley‐Liss, Inc.
Current Status of Hypertension Control in an Industrial Population
Authors: James A. Schoenberger, Jeremiah Stamler, Richard B. Shekelle, Susan Shekelle
Journal: JAMA (1972)

Evidence for the beneficial effect of antihypertensive treatment has recently been obtained in controlled clinical trials.<sup>1,2</sup>For men with moderate and severe hypertension, there can now be little doubt of the efficacy of current available drug treatment in preventing serious complications, including death. Although statistically significant evidence has not yet been obtained for patients with the mildest degrees of hypertension, it is likely that for them, too, treatment will be beneficial. In the absence to date of a definitive trial, it is also reasonable to infer that the consequences of hypertension in women will be ameliorated by effective treatment. The recent findings on the value of antihypertensive therapy highlight the need to assess the current status of efforts to identify and treat persons with this disease. From 1967 on, the Chicago Heart Association Detection Project in Industry has been systematically investigating these matters in an extensive survey of men
Perioperative N-acetylcysteine to Prevent Renal Dysfunction in High-Risk Patients Undergoing CABG Surgery
Authors: Karen E. A. Burns, Michael W. A. Chu, Richard J. Novick, Stephanie A. Fox, Kerri Gallo, Claudio M. Martin, Larry W. Stitt, A. Paul Heidenheim, M. Lee Myers, Louise Moist
Journal: JAMA (2005)

Renal dysfunction is a complication of coronary artery bypass graft (CABG) surgery performed with cardiopulmonary bypass (CPB) that is associated with increased morbidity and mortality. N-acetylcysteine, an antioxidant and vasodilator, counteracts renal ischemia and hypoxia.To determine whether perioperative intravenous (IV) N-acetylcysteine preserves renal function in high-risk patients undergoing CABG surgery with CPB compared with placebo.Randomized, quadruple blind, placebo-controlled trial (October 2003-September 2004) in operating rooms and general intensive care units (ICUs) of 2 Ontario tertiary care centers. The 295 patients required elective or urgent CABG and had at least 1 of the following: preexisting renal dysfunction, at least 70 years old, diabetes mellitus, impaired left ventricular function, or undergoing concomitant valve or redo surgery.Patients received 4 (2 intraoperative and 2 postoperative) doses of IV N-acetylcysteine (600 mg) (n = 148) or placebo (n = 147) over 24 hours.The primary outcome was the proportion of patients developing postoperative renal dysfunction, defined by an increase in serum creatinine level greater than 0.5 mg/dL (44 micromol/L) or a 25% increase from baseline within the first 5 postoperative days. Secondary outcomes included postoperative interventions and complications, the requirement for renal replacement therapy (RRT), adverse events, hospital mortality, and ICU and hospital length of stay.There was no difference in the proportion of patients with postoperative renal dysfunction (29.7% vs 29.0%, P = .89; relative risk [RR], 1.03 [95% confidence interval {CI}, 0.72-1.46]) in the N-acetylcysteine and placebo groups, respectively. We noted nonsignificant differences in postoperative interventions and complications, the need for RRT (0.7% vs 2.1%; P = .37), total (6.1% vs 9.6%; P = .26) and serious adverse events, hospital mortality (3.4% vs 2.7%; P>.99), and ICU and hospital length of stay between the N-acetylcysteine and placebo groups. A post hoc subgroup analysis of patients (baseline creatinine level >1.4 mg/dL [120 micromol/L]) showed a nonsignificant trend toward fewer patients experiencing postoperative renal dysfunction in the N-acetylcysteine group compared with the placebo group (25.0% vs 37.1%; P = .29).N-acetylcysteine did not prevent postoperative renal dysfunction, interventions, complications, or mortality in high-risk patients undergoing CABG surgery with CPB. Further research is required to identify CABG patients at risk for postoperative renal events, valid markers of renal dysfunction, and to establish renal thresholds associated with important clinical outcomes.
Effect of Elastase-induced Emphysema on the Force-generating Ability of the Diaphragm
Authors: Gerald S. Supinski, Steven G. Kelsen
Journal: Journal of Clinical Investigation (1982)

The effect of emphysema on the ability of the diaphragm to generate force was examined in costal diaphragm muscle strips from 10 Golden hamsters killed 18 mo after intratracheal injection of pancreatic elastase in a dose producing hyperinflation (mean total lung capacity [TLC] = 163% of control) and generalized panacinar emphysema. 13 saline-injected normal animals served as controls. The time course of isometric tension and the effect of alterations in muscle fiber and sarcomere length on the isometric tension (T) generated in response to tetanizing electrical stimuli (length-tension [L-T] relationship) were examined. Elastase administration caused an increase in diaphragm muscle thickness and reduction in the length of costal diaphragm muscle fibers measured in situ. Emphysema significantly increased the maximum tetanic tension as a result of hypertrophy. Maximal tension corrected for increases in muscle cross-sectional area (T/cm2), however, was the same in emphysematous (E) and control (C) animals. Emphysema also shifted the muscle fiber L-T curve of the diaphragm but not of a control muscle, the soleus, toward shorter lengths. In contrast to the effects of E on the diaphragm muscle fiber L-T curve, the sarcomere L-T curve was the same in E and C. Since the length at which tension was maximal correlated closely with sarcomere number (r = 0.94; P < 0.001) reduction in the number of sarcomeres in series in muscles from emphysematous animals appeared to explain the shift in the muscle fiber L-T curve. We conclude that in elastase-induced emphysema adaptive changes both in diaphragm cross-sectional area and sarcomere number augment the force-generating ability of the diaphragm. We speculate that changes in sarcomere number compensate for alterations in muscle fiber length resulting from chronic hyperinflation of the thorax, while diaphragmatic muscle hypertrophy represents a response to changes in respiratory load and/or diaphragm configuration (LaPlace relationship).
163 THE CHEMOKINE RECEPTOR CXCR3 IS PROTECTIVE DURING ACUTE CCL4 INDUCED LIVER INJURY
Authors: M. Moreno Zaldivar, M.L. Berres, P. Schmitz, C. offermanns, K.R. Karlmark, F. Tacke, N. Gassler, C. Trautwein, H.E. Wasmuth
Journal: Journal of Hepatology (2008)
Abstract 979: microRNA-mediated leukemia-initiating cell activity
Authors: Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Sara Meyer, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes
Journal: Cancer Research (2014)

Abstract The HoxA9 transcription activator and the Gfi1 transcriptional repressor compete for the regulation of common target genes. We exploited HoxA9 versus Gfi1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of Hox-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b significantly inhibits in vitro colony forming activity, and quantitatively depletes in vivo leukemia-initiating-cell activity of Hox-based leukemias leading to leukemia-free survival of murine AML and significant delay in disease onset in xenograft models. A novel microRNA target identification platform both validates therapeutic intervention and reveals biological impact of disrupting microRNA function. These data establish microRNA as functional effectors of endogenous HoxA9 and Hox-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML. Citation Format: Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Sara Meyer, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes. microRNA-mediated leukemia-initiating cell activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2014-979
Volume versus wiring transmission in the brain: A new theoretical frame for neuropsychopharmacology
Authors: Luigi F. Agnati, Böurje Bjelke, Kjell Fuxe
Journal: Medicinal Research Reviews (1995)

A volume transmission mode of communication in brain was implicit already in the early work of Golgi, who postulated the existence of electrical signals in the extracellular fluid (ECF) based on Volta's "wet conductor" made by solutions. The term volume transmission is taken from the term volume conduction describing the flow of ionic currents in the ECF as a basis for the electrocorticogram. The slow VT mode includes also chemical signals and is opposed to the fast synaptic (wiring) transmission. Every neuron may function in a dual mode, the synaptic and the volume transmission mode, when considering the autocrine and synaptic classes of communication. The paracrine- and neuroendocrine-like classes only involve the VT mode in the latter case including the CSF as a route. The chemical signals for VT are the neuropeptides, but also the classical transmitters, the monoamines, acetylcholine, GABA, and glutamate can participate, when they operate via slow, high affinity G protein coupled receptors. Ions such as K+, Ca++, and H+ also function as VT signals. The hypothesis is also introduced that CO2 can act as a multifacit long-distance VT and WT regulator besides being part of the CO2/HCO3 buffer. CO2 via regulating NMDA receptor sensitivity can also regulate NO formation, which represents a paracrine and fast VT signal. The therapy of CNS disorders is also discussed in the frame of the wiring and VT concept. Two therapeutical approaches can therefore be developed, one based on increasing WT and one based on increasing VT. In contrast to the WT therapy, which must preserve the electrotemporal code, the VT therapy can operate also with postsynaptic agonists. Therefore, a therapeutic effect with such a drug indicates that the deficiency in the communication process operates via VT. In view of the lack of very effective negative feedbacks in VT vs. WT, VT therapy may produce less tolerance and drug dependency.
The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis
Authors: Geraldine Siegfried, Ajoy Basak, James A. Cromlish, Suzanne Benjannet, Jadwiga Marcinkiewicz, Michel Chrétien, Nabil G. Seidah, Abdel-Majid Khatib
Journal: Journal of Clinical Investigation (2003)

The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR227SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C (220Q-VHSIIRR↓SLP230). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR227SL to HSIISS227SL) inhibits angiogenesis and lymphangiogenesis as well as tumor growth. Our findings demonstrate the processing of proVEGF-C by PCs and highlight the potential use of PC inhibitors as agents for inhibiting malignancies induced by VEGF-C.
Big Doctoring in America: Profiles in Primary Care
Authors: Todd Simon
Journal: Annals of Internal Medicine (2003)

Medical Writings: Book Notes4 March 2003Big Doctoring in America: Profiles in Primary CareTodd Simon, MD, MSEdTodd Simon, MD, MSEdMount Sinai School of Medicine, New York, New York.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-138-5-200303040-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Mullan F, ed. 302 pages. Berkeley, CA: Univ of California Pr; $29.95. ISBN 0520226704. Order at www.ucpress.edu.Field of medicine: Primary care.Format: Hardcover book.Audience: Primary care clinicians, including internists, family physicians, pediatricians, nurse practitioners, and physician assistants; house officers and students training in these fields; and policymakers and public health officials, as well as anyone in the general public interested in health care reform in the United States.Purpose: To describe the roles and viewpoints of primary care practitioners in the United States and to advocate for building a strong base of primary care as the central feature ... Author, Article, and Disclosure InformationAffiliations: Mount Sinai School of Medicine, New York, New York. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 March 2003Volume 138, Issue 5Page: 444KeywordsChild healthForecastingHealth careHealth care policyNursesPrevention, policy, and public healthPrimary careSoftware tools ePublished: 4 March 2003 Issue Published: 4 March 2003 Copyright & PermissionsCopyright © 2003 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia
Authors: Chi Keung Cheng, Libby Li, Suk Hang Cheng, Kitty Ng, Natalie P. H. Chan, Rosalina K. L. Ip, Raymond S. M. Wong, Matthew M. K. Shing, Chi Kong Li, Margaret H. L. Ng
Journal: Blood (2011)
Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice
Authors: Li L. Yang, Robert Gros, M. Golam Kabir, Almuktafi Sadi, Avrum I. Gotlieb, Mansoor Husain, Duncan J. Stewart
Journal: Circulation (2004)

Myocardial expression of endothelin-1 (ET-1) and its receptors ET(A) and ET(B) is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear.Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET+) was bred with one harboring cardiac myocyte-restricted expression of tTA (alphaMHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET+/tTA+) compared with nonbinary transgenic (NBT, ET+/tTA-; ET-/tTA+; ET-/tTA-) or DOX-treated BT littermates (40.1+/-4.7 versus 2.6+/-1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673+/-468 versus 5585+/-658 mm Hg/s, P<0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-kappaB translocation and expression of tumor necrosis factor-alpha, interferon-gamma, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET(A)/ET(B) antagonist LU420627 (n=8, P<0.05) in BT mice but not the ET(A)-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ET(B) in this model.These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.