tbuckley/cabot-search huggingface dataset:
Aldehyde Dehydrogenase in Alcoholic Subjects
Authors: Kelvin R. Palmer, William J. Jenkins
Journal: Hepatology (1985)

Hepatic aldehyde dehydrogenase activity is depressed in alcoholic liver disease and may account for the observation that alcoholics develop high blood acetaldehyde concentrations following ethanol. To determine whether this is a specific defect in alcoholics, aldehyde dehydrogenase was studied in liver tissue obtained from three groups of subjects. Group I comprised 30 patients with alcoholic liver disease, Group II consisted of eight subjects with liver disease unrelated to alcohol abuse and Group III was a control group of 10 individuals with no significant liver disease. Mean hepatic aldehyde dehydrogenase activity was significantly lower in Group I than in Groups II or III [4.9 +/- 0.6 (mean +/- S.E.), compared to 10.2 +/- 1.8 and 12.4 +/- 1.1 nmoles of acetaldehyde oxidized per min X mg of protein, respectively]. Aldehyde dehydrogenase activity in Group II was relatively well maintained. Aldehyde dehydrogenase activity was found in cytosolic and mitochondrial fractions of liver homogenates. In alcoholic subjects, cytosolic aldehyde dehydrogenase activity was not more depressed than was mitochondrial aldehyde dehydrogenase. Isoelectric focusing demonstrated a single mitochondrial isoenzyme and a single cytosolic isoenzyme in most cases in Group III. In contrast, multiple cytosolic isoenzymes were consistently found in liver tissue from Group I subjects. These findings suggest that depressed aldehyde dehydrogenase activity in alcoholic subjects is not a consequence of liver disease.
The Effects of Angiotensin II on Renal Water and Electrolyte Excretion in Normal and Caval Dogs*
Authors: Jerome G. Porush, George J. Kaloyanides, Roy J. Cacciaguida, Stanley M. Rosen
Journal: Journal of Clinical Investigation (1967)

The effects of intravenous administration of angiotensin II on renal water and electrolyte excretion were examined during hydropenia, water diuresis, and hypotonic saline diuresis in anesthetized normal dogs and dogs with thoracic inferior vena cava constriction and ascites (caval dogs). The effects of unilateral renal artery infusion of a subpressor dose were also examined.During hydropenia angiotensin produced a decrease in tubular sodium reabsorption, with a considerably greater natriuresis in caval dogs, and associated with a decrease in free water reabsorption (T(c) (H(2)O)). Water and hypotonic saline diuresis resulted in an augmented angiotensin natriuresis, with a greater effect still observed in caval dogs. In these experiments free water excretion (C(H(2)O)) was limited to 8-10% of the glomerular filtration rate (GFR), although distal sodium load increased in every instance. In the renal artery infusion experiments a significant ipsilateral decrease in tubular sodium reabsorption was induced, particularly in caval dogs.These findings indicate that angiotensin has a direct effect on renal sodium reabsorption unrelated to a systemic circulatory alteration. The attenuation or prevention of the falls in GFR and effective renal plasma flow (ERPF) usually induced by angiotensin may partially account for the greater natriuretic response in caval dogs and the augmentation during water or hypotonic saline diuresis. However, a correlation between renal hemodynamics and the degree of natriuresis induced was not always present and, furthermore, GFR and ERPF decreased significantly during the intrarenal artery infusion experiments. Therefore, the present experiments indicate that another mechanism is operative in the control of the angiotensin natriuresis and suggest that alterations in intrarenal hemodynamics may play a role.The decrease in T(c) (H(2)O) and the apparent limitation of C(H(2)O) associated with an increase in distal sodium load localize the site of action of angiotensin to the ascending limb of Henle's loop and the proximal tubule.
Life-Science Research Within US Academic Medical Centers
Authors: Darren E. Zinner
Journal: JAMA (2009)

Besides the generic "basic" vs "applied" labels, little information is known about the types of life-science research conducted within academic medical centers (AMCs).To determine the relative proportion, characteristics, funding, and productivity of AMC faculty by the type of research they conduct.Mailed survey conducted in 2007 of 3080 life-science faculty at the 50 universities with medical schools that received the most funding from the National Institutes of Health in 2004. Response rate was 74%.Research faculty affiliated with a medical school or teaching hospital, representing 77% of respondents (n = 1663).Type of research (basic, translational, clinical trials, health services research/clinical epidemiology, multimode, other), total funding, industry funding, publications, professional activities, patenting behavior, and industry relationships.Among AMC research faculty, 33.6% exclusively conducted basic science research as principal investigators compared with translational researchers (9.1%), clinical trial investigators (7.1%), and health services researchers/clinical epidemiologists (9.0%). While principal investigators garnered a mean of $410,755 in total annual research funding, 22.1% of all AMC research faculty were unsponsored, a proportion that ranged from 11.5% for basic science researchers to 46.8% for health services researchers (P < .001). The average AMC faculty member received $33,417 in industry-sponsored funding, with most of this money concentrated among clinical trial ($110,869) and multimode ($59,916) principal investigators. Translational (61.3%), clinical trial (67.3%), and multimode (70.9%) researchers were significantly more likely than basic science researchers (41.9%) to report a relationship with industry and that these relationships contributed to their most important scientific work (P < .05 for all comparisons).The research function of AMCs is active and diverse, incorporating a substantial proportion of faculty who are conducting research and publishing without sponsorship.
Effect of SMURF2 Targeting on Susceptibility to MEK Inhibitors in Melanoma
Authors: Michael P. Smith, Jennifer Ferguson, Imanol Arozarena, Robert Hayward, Richard Marais, Anna Chapman, Adam Hurlstone, Claudia Wellbrock
Journal: JNCI Journal of the National Cancer Institute (2012)

The mitogen-activated protein-kinase pathway consisting of the kinases RAF, MEK, and ERK is central to cell proliferation and survival and is deregulated in more than 90% of melanomas. MEK inhibitors are currently trialled in the clinic, but despite efficient target inhibition, cytostatic rather than cytotoxic activity limits their efficacy.
Studies on the phrenic nerve and diaphragmatic plexus in rabbits and gerbils
Authors: R. Mitchell, A. S. Wilson
Journal: Thorax (1972)

Studies on nerve fibres within the phrenic nerve and in the diaphragmatic plexus were carried out in one species, the gerbil, a small desert rodent. The resistance of this small mammal to surgical insult enabled experimental intrathoracic transection of the phrenic nerve to be carried out so that the results in 10 animals could be observed within the diaphragmatic plexus, the phrenic nerve, and the phrenic nucleus. The findings in the diaphragmatic plexus and in the nerve trunk strongly resemble corresponding results for other animals with regard to `persisting9 fibres. The phrenic nucleus, however, is much more extensive in this mammal than has been found in any other species; it is represented within the second to sixth cervical segment, its rostral extremity occupying the intermediolateral part of the spinal grey matter. The possible functional significance of these findings is discussed in the light of the mixed functions of the diaphragm, either voluntary or involuntary.
Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-Comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome
Authors: Eri Arai, Saori Ushijima, Hitoshi Tsuda, Hiroyuki Fujimoto, Fumie Hosoda, Tatsuhiro Shibata, Tadashi Kondo, Issei Imoto, Johji Inazawa, Setsuo Hirohashi, Yae Kanai
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of this study was to clarify genetic and epigenetic alterations occurring during renal carcinogenesis. Experimental Design: Copy number alterations were examined by array-based comparative genomic hybridization analysis using an array harboring 4,361 bacterial artificial chromosome clones, and DNA methylation alterations on CpG islands of the p16, human MutL homologue 1, von Hippel-Lindau, and thrombospondin 1 genes and the methylated in tumor (MINT-1, MINT-2, MINT-12, MINT-25, and MINT-31) clones were examined in 51 clear cell renal cell carcinomas (RCC). Results: By unsupervised hierarchical clustering analysis based on copy number alterations, clear cell RCCs were clustered into the two subclasses, clusters A (n = 34) and B (n = 17). Copy number alterations were accumulated in cluster B. Loss of chromosome 3p and gain of 5q and 7 were frequent in both clusters A and B, whereas loss of 1p, 4, 9, 13q, and 14q was frequent only in cluster B. The average number of methylated CpG islands in cluster B was significantly higher than those in cluster A. Clear cell RCCs showing higher histologic grades, vascular involvement, renal vein tumor thrombi, and higher pathologic stages were accumulated in cluster B. The recurrence-free and overall survival rates of patients in cluster B were significantly lower than those of patients in cluster A. Multivariate analysis revealed that genetic clustering was a predictor of recurrence-free survival and was independent of histologic grade and pathologic stage. Conclusions: This genetic clustering of clear cell RCC is significantly associated with regional DNA hypermethylation and may become a prognostic indicator for patients with RCC.
Heat-Shock Protein 60-Reactive CD4 <sup>+</sup> CD28 <sup>null</sup> T Cells in Patients With Acute Coronary Syndromes
Authors: Behnam Zal, Juan Carlos Kaski, Gavin Arno, Julius P. Akiyu, Qingbo Xu, Della Cole, Michael Whelan, Nick Russell, J. Alejandro Madrigal, I. Anthony Dodi, Christina Baboonian
Journal: Circulation (2004)

Background— CD4 + CD28 null T cells are present in increased numbers in the peripheral blood of patients with acute coronary syndrome (ACS) compared with patients with chronic stable angina (CSA). The triggers of activation and expansion of these cells to date remain unclear. Methods and Results— Twenty-one patients with ACS and 12 CSA patients with angiographically confirmed coronary artery disease and 9 healthy volunteers were investigated. Peripheral blood leukocytes were stimulated with human cytomegalovirus (HCMV), Chlamydia pneumoniae , human heat-shock protein 60 (hHSP60), or oxidized LDL (ox-LDL). CD4 + CD28 null cells were separated by flow cytometry and assessed for antigen recognition using upregulation of interferon-γ and perforin mRNA transcription as criteria for activation. CD4 + CD28 null cells from 12 of 21 patients with ACS reacted with hHSP60. No response was detected to HCMV, C pneumoniae , or ox-LDL. Incubation of the cells with anti-MHC class II and anti-CD4 antibodies but not anti-class I antibodies blocked antigen presentation, confirming recognition of the hHSP60 to be via the MHC class II pathway. Patients with CSA had low numbers of CD4 + CD28 null cells. These cells were nonreactive to any of the antigens used. Circulating CD4 + CD28 null cells were present in 5 of the 9 healthy controls. None reacted with hHSP60. Conclusions— We have shown that hHSP60 is an antigen recognized by CD4 + CD28 null T cells of ACS patients. Endothelial cells express hHSP60 either constitutively or under stress conditions. Circulating hHSP60-specific CD4 + CD28 null cells may, along other inflammatory mechanisms, contribute to vascular damage in these patients.
STUDIES OF THE HUMAN LYMPHOCYTE RECEPTOR FOR HEAT-AGGREGATED OR ANTIGEN-COMPLEXED IMMUNOGLOBULIN
Authors: Howard B. Dickler
Journal: The Journal of Experimental Medicine (1974)

The lymphocyte receptor for complexed immunoglobulin was shown not to bind heat-aggregated human serum albumin, bovine serum albumin, transferrin, F(ab')(2), reduced and alkylated Ig, and mildly oxidized Ig, which indicated that the receptor is specific for a site dependent on disulfide bond(s) on the Fc portion of complexed Ig. Inhibition experiments provided evidence that the same receptor binds both heat-aggregated Ig and antigen-antibody complexes. Lymphocytes treated with pronase were no longer able to bind Ig complexes, which suggested that the receptor is a protein or glycoprotein. Additional evidence was obtained that lymphocyte surface Ig and the receptor for complexed Ig are distinct since the former could be capped without affecting the distribution of the latter, and surface Ig was not detectable after trypsinization of lymphocytes, whereas the binding of Ig complexes was unaffected by such treatment. Incubation of lymphocytes which had bound Ig complexes in tissue culture medium at 37 degrees C revealed that the complexes remained on the surface membrane for several hours, and that only a minority of lymphocytes binding complexes showed cap formation. Lymphocytes which had heat-aggregated IgG specifically bound to their receptors for complexed Ig were markedly inhibited in their ability to mediate antibody-dependent cytotoxicity, thus providing strong evidence for the necessity of the receptor in this immune activity. Titration of this inhibition with varying amounts of complexes revealed distinct plateaus in the dose-response curve. This suggested that there may be more than one kind of receptor and/or different populations of lymphocytes which bear the receptor.
Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease
Authors: J. Bourbeau, M. Y Rouleau, S. Boucher
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Inhaled corticosteroids are known to be beneficial for patients with asthma, but their role in treating patients with stable chronic obstructive pulmonary disease (COPD) remains controversial. A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids. <h3>METHODS</h3> In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids. In phase II a double blind, randomised, parallel group trial of inhaled budesonide 1600 μg per day versus placebo was carried out in 79 non-responders to oral corticosteroids. The primary outcome measure was forced expiratory volume in one second (FEV<sub>1</sub>), and secondary outcome measures were exercise capacity, dyspnoea with exertion, quality of life, peak expiration flow rate, and respiratory symptoms. <h3>RESULTS</h3> Randomisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo. There was no difference in the change in FEV<sub>1</sub> from baseline between the treatment and placebo groups; mean difference –12 ml (95% CI –88 to 63) at three months and –4 ml (95% CI –95 to 87) at six months. The proportion of patients with a 15% or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits. Changes in secondary outcomes were also no different. <h3>CONCLUSIONS</h3> Inhaledcorticosteroids, even at high doses, were of no physiological or functional benefit in these patients with advanced COPD.
CYTOTOXIC IMMUNE CELLS WITH SPECIFICITY FOR DEFINED SOLUBLE ANTIGENS
Authors: Volker Schirrmacher, Bent Rubin, Hugh Pross, Hans Wigzell
Journal: The Journal of Experimental Medicine (1974)

Spleen cells from mice immunized against ovalbumin (OA) or dinitrophenylated mouse serum albumin (DM) were found to be specifically cytotoxic in vitro towards target cells (chicken red blood cells) coated with these antigens. Inhibition of specific cytotoxicity was observed when free soluble antigen was added to the incubation mixtures. DM-immune cell cytotoxicity could be specifically and completely inhibited by DNP-lysine and was thus shown to be hapten specific. Complete and specific inhibition was also observed for OA-immune cell cytotoxicity using OA as inhibitor, but compared with the inhibition curves obtained with DNP-lysine, the OA cytotoxicity inhibition curves were shifted by a factor of about one hundred towards lower molar inhibitor concentrations. Very similar results were observed when the serum antibodies of DM- and OA-immune animals were analyzed by passive hemagglutination inhibition. With increasing time after immunization, both cytotoxicity inhibition curves and agglutination inhibition curves, shifted to lower antigen or hapten concentrations. Specific cytotoxicity against antigen-coated target cells was induced in nonimmune spleen cells (a) by serum from immune animals, and (b) by supernatants from in vitro immune cell cultures. In both instances, the factor which induced antigen-specific cytotoxic activity could be absorbed on anti-mouse Ig columns, thus demonstrating its immunoglobulin nature. The ability of target cell bound antibodies to induce cytotoxicity in nonimmune spleen cells was restricted to the 7S antibody class.
Calcium and inositolphosphates in the activation of T cell-mediated cytotoxicity.
Authors: S Treves, F Di Virgilio, V Cerundolo, P Zanovello, D Collavo, T Pozzan
Journal: The Journal of Experimental Medicine (1987)

Reports from a number of laboratories have shown that mAbs against the T3-Ti receptor complex cause an increase in cytosolic-free Ca2+ [( Ca2+]i) and the hydrolysis of phosphatidylinositolbisphosphate (PIP2) in CTLs. In the present report we show that activation of CTLs by their specific targets causes: (a) release of Ca2+ from intracellular stores; (b) transient formation of inositol trisphosphate (InsP3); and (c) an increased permeability to Ca2+ of CTL plasma membrane. Killing of unrelated targets could be induced by cocentrifugation of the unrelated targets with CTLs in the presence of A23187 or PMA. We conclude that: (a) activation of CTLs by specific antigens triggers the generation of the same intracellular mediators generated by stimulation of lymphocytes with anti-T3-Ti receptor antibodies and/or with polyclonal mitogens; and (b) intracellular signals that mediate the delivery of the lethal hit by CTLs are indistinguishable from those that induce cell proliferation.
Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion.
Authors: X L Ma, P S Tsao, A M Lefer
Journal: Journal of Clinical Investigation (1991)

We studied the effects of MAbR15.7, an antibody directed against the common beta-chain (CD-18) of a family of neutrophil adherence glycoproteins, on endothelial dysfunction and myocardial injury in a model of myocardial ischemia and reperfusion in cats. Pentobarbital-anesthetized cats were subjected to 1.5 h occlusion of the left anterior descending coronary artery (LAD) and 4.5 h of reperfusion. MI + R resulted in severe myocardial injury and endothelial dysfunction, including significant elevation of plasma creatine kinase (CK) activity, marked myocardial necrosis, high cardiac myeloperoxidase (MPO) activity in ischemic cardiac tissue, and loss of response of LAD coronary rings to the endothelium-dependent vasodilators, acetylcholine (ACh) and A-23187. In contrast, MAbR15.7-treated cats exhibited a lower plasma CK activity at every time point observed after 2 h, a reduced area of cardiac necrosis (2 +/- 1 vs. 30.8 +/- 2.5% of area-at-risk, P less than 0.001), lower MPO activity in the ischemic region (P less than 0.01), and significantly preserved vasorelaxant responses of LAD coronary rings to endothelium-dependent vasodilators, ACh (P less than 0.001), and A-23187 (P less than 0.001). These results indicate that myocardial ischemia and reperfusion induces significant myocardial injury and endothelial dysfunction in the cat involving a CD18-dependent neutrophil adherence mechanism. Inhibition of neutrophil adherence to the endothelium exerts significant protective effects in this model of reperfusion injury.
Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1α during Hypoxia in Human Cancer Cells
Authors: Isabelle Ader, Leyre Brizuela, Pierre Bouquerel, Bernard Malavaud, Olivier Cuvillier
Journal: Cancer Research (2008)

Abstract Here, we provide the first evidence that sphingosine kinase 1 (SphK1), an oncogenic lipid kinase balancing the intracellular level of key signaling sphingolipids, modulates the transcription factor hypoxia inducible factor 1α (HIF-1α), master regulator of hypoxia. SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1α levels is mediated by the Akt/glycogen synthase kinase-3β signaling pathway that prevents its von Hippel-Lindau protein–mediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1α and its transcriptional activity in several human cancer cell lineages (prostate, brain, breast, kidney, and lung), suggesting a canonical pathway. Therefore, we propose that SphK1 can act as a master regulator for hypoxia, giving support to its inhibition as a valid strategy to control tumor hypoxia and its molecular consequences. [Cancer Res 2008;68(20):8635–42]
Clinical Perspectives on Antidepressant Therapy
Authors: HEINZ E. LEHMANN
Journal: American Journal of Psychiatry (1968)

The author discusses some of the practical considerations confronting the clinician in the treatment of depression, including differential diagnosis and choosing among the various treatment modalities. He feels that the particular antidepressant drug chosen is not so important for treatment outcome as the proper dosage and correct timing, based on a careful, sensitive assessment of each patient.
Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial
Authors: Cora N Sternberg, Daniel Castellano, Gedske Daugaard, Lajos Géczi, Sebastien J Hotte, Paul N Mainwaring, Fred Saad, Ciro Souza, Miah H Tay, José M Tello Garrido, Luca Galli, Anil Londhe, Peter De Porre, Betty Goon, Emma Lee, Tracy McGowan, Vahid Naini, Mary B Todd, Arturo Molina, Daniel J George
Journal: The Lancet Oncology (2014)
Gout in liver transplant patients receiving tacrolimus
Authors: J C Gerster
Journal: Annals of the Rheumatic Diseases (2004)

Hyperuricaemia and gout have been reported in organ transplant patients treated with cyclosporin, an immunosuppressant inhibiting calcineurin.1,2 Tacrolimus, another calcineurin inhibitor, is nowadays widely used in place of cyclosporin. Hyperuricaemia has been seen in patients receiving tacrolimus3 but, to our knowledge, only rare cases of gout have been mentioned so far.4

Since 1998, 31 patients (22 men, 9 women; current mean age 53 years (range 24–67)) have regularly received tacrolimus for immunosuppression after liver transplantation in the surgical department of Lausanne University Hospital. The mean duration of follow up with tacrolimus treatment was 27.8 months (range 7–57).

In two cases the first manifestations of gout appeared after liver transplantation when these two patients were receiving tacrolimus for immunosuppression.

### Patient 1

A 31 year old man received a liver transplant in November 1998. He was treated …