tbuckley/cabot-search huggingface dataset:
Activation of phosphatidylinositol 3-kinase in hepatocyte growth and hepatocellular transformation
Authors: Y SASAKI
Journal: Hepatology (1995)

The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway is a highly conserved signaling pathway that regulates diverse cellular processes including differentiation, proliferation, and survival. Kinase suppressor of Ras-1 (KSR1) binds each of the three ERK cascade components to facilitate pathway activation. Even though KSR1 contains a C-terminal kinase domain, evidence supporting the catalytic function of KSR1 remains controversial. In this study, we produced recombinant wild-type or kinase-inactive (D683A/D700A) KSR1 proteins in Escherichia coli to test the hypothesis that KSR1 is a functional protein kinase. Recombinant wild-type KSR1, but not recombinant kinase-inactive KSR1, underwent autophosphorylation on serine residue(s), phosphorylated myelin basic protein (MBP) as a generic substrate, and phosphorylated recombinant kinase-inactive MAPK/ERK kinase-1 (MEK1). Furthermore, FLAG immunoprecipitates from KSR1−/− colon epithelial cells stably expressing FLAG-tagged wild-type KSR1 (+KSR1), but not vector (+vector) or FLAG-tagged kinase-inactive KSR1 (+D683A/D700A), were able to phosphorylate kinase-inactive MEK1. Since TNF activates the ERK pathway in colon epithelial cells, we tested the biological effects of KSR1 in the survival response downstream of TNF. We found that +vector and +D683A/D700A cells underwent apoptosis when treated with TNF, whereas +KSR1 cells were resistant. However, +KSR1 cells were sensitized to TNF-induced cell loss in the absence of MEK kinase activity. These data provide clear evidence that KSR1 is a functional protein kinase, MEK1 is an in vitro substrate of KSR1, and the catalytic activities of both proteins are required for eliciting cell survival responses downstream of TNF.
Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats
Authors: Paul E. Goss, Shangle Qi, Angela M. Cheung, Haiqing Hu, Maria Mendes, Kenneth P. H. Pritzker
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats. Experimental Design: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined. Results: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls. Conclusions: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.
Diagnostic accuracy and clinical utility of a simplified low cost method of counting CD4 cells with flow cytometry in Malawi: diagnostic accuracy study
Authors: Calman A MacLennan, Michael K P Liu, Sarah A White, Joep J G van Oosterhout, Felanji Simukonda, Joseph Bwanali, Michael J Moore, Eduard E Zijlstra, Mark T Drayson, Malcolm E Molyneux
Journal: BMJ (2007)

<b>Objectives</b> To assess the diagnostic accuracy and clinical utility of a simplified low cost method for measuring absolute and percentage CD4 counts with flow cytometry. <b>Design</b> A CD4 counting method (Blantyre count) using a CD4 and CD45 antibody combination with reduced blood and reagent volumes. Diagnostic accuracy was assessed by measuring agreement of the index test with two other assays (TruCount and FACSCount). Clinical utility was investigated by comparing CD4 counts with the new assay with WHO clinical staging in patients with HIV. <b>Setting</b> Research laboratories and antiretroviral therapy clinic at a medical school and large government hospital in southern Malawi. <b>Participants</b> Assay comparisons were performed on consecutive blood samples sent for CD4 counting from 129 patients with HIV. Comparison of CD4 count with staging was conducted on 253 consecutive new patients attending the antiretroviral therapy clinic. <b>Main outcome measures</b> Limits of agreement with 95% confidence intervals between index test and reference standards. <b>Results</b> The limits of agreement for Blantyre count and TruCount were excellent (cell count −48.9 to 27.0 cells/µl for absolute counts in the CD4 range &lt;400 cells/µl and −2.42% to 2.37% for CD4 percentage). The assay was affordable with reagent costs per test of $0.44 (£0.22, €0.33) for both absolute count and CD4 percentage, and $0.11 for CD4 percentage alone. Of 193 patients with clinical stage I or II disease, who were ineligible for antiretroviral therapy by clinical staging criteria, 73 (38%) had CD4 counts &lt;200 cells/µl. By contrast, 12 (20%) of 60 patients with stage III or IV disease had CD4 counts &gt;350 cells/µl. <b>Conclusions</b> This simplified method of counting CD4 cells with flow cytometry has good agreement with established commercial assays, is affordable for routine clinical use in Africa, and could improve clinical decision making in patients with HIV.
OUTLOOK FOR PATIENTS WITH GLOMERULONEPHRITIS
Authors: Norman M. Keith
Journal: JAMA (1953)

Bright realized early in his studies that renal disease was a complex problem.1He stressed the relationship of renal dysfunction and abnormality to general edema and cardiovascular abnormalities. In addition, he recognized the development of metabolic disturbances as the disease progressed and, for a better understanding of their significance, invited the cooperation of the chemist. The results of this joint venture, though meager, anticipated by 75 years some of the biochemical findings now thoroughly appreciated by the medical profession.  The early students of diffuse nephritis realized the serious outlook for the patient suffering from the progressive form of the disease. They learned slowly, however, that there was an acute reversible type2that often healed, and that some of the patients with the chronic form lived and were able to work for a number of years. Bright, after a decade of study,1bpartially reversed his earlier gloomy predictions
Loco-regional treatment of hepatocellular carcinoma
Authors: Riccardo Lencioni
Journal: Hepatology (2010)

Loco-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded. Radiofrequency ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation—including microwave ablation, irreversible electroporation, and light-activated drug therapy—seem to have potential to overcome the limitations of radiofrequency ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic, noninvasive multinodular tumors at the intermediate stage. The recent introduction of embolic microspheres that have the ability to release the drug in a controlled and sustained fashion has been shown to significantly increase safety and efficacy of TACE with respect to conventional, lipiodol-based regimens. The available data for radioembolization with yttrium-90 suggests that this is a potential new option for patients with HCC, which should be investigated in the setting of randomized controlled trials. Despite the advances and refinements in loco-regional approaches, the long-term survival outcomes of patients managed with interventional techniques are not fully satisfactory, mainly because of the high rates of tumor recurrence. The recent addition of molecular targeted drugs with antiangiogenic and antiproliferative properties to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between loco-regional and systemic treatments. The outcomes of these trials are eagerly awaited, because they have the potential to revolutionize the treatment of HCC. (HEPATOLOGY 2010;)
Motility of the jejunum after proctocolectomy and ileal pouch anastomosis.
Authors: S Chaussade, F Merite, M Hautefeuille, P Valleur, P Hautefeuille, D Couturier
Journal: Gut (1989)

Proctocolectomy with ileal pouch anastomosis could modify motility of the small intestine through two mechanisms: obstruction or bacterial overgrowth. Motility of the jejunum was measured in 11 patients with ileoanal anastomosis six (n = 6), or 12 (n = 5) months after closure of the loop ileostomy. Manometric recording from the jejunum were made during fasting (four hours) and after a liquid meal (one hour). These findings were compared with those of six healthy volunteers. Motor events were classified as follows: migrating motor complex (MMC), propagated contractions, or discrete clustered contractions. All patients were investigated for bacterial overgrowth (D-glucose breath test). Only two patients had bacterial overgrowth. The frequency of MMC remained unchanged after ileo-anal anastomosis (2.83 (0.37)/four hours) compared with normal volunteers (2.81 (0.29)/four hours). During fasting, four patients had numerous propagated contractions in the jejunum. This condition was associated in two with bacterial overgrowth and in two with intubation of the reservoir. Discrete clustered contractions were found in the seven patients studied postprandially (7.6 (2.5)/h), but not in volunteers. These seven patients emptied their pouch spontaneously and bacterial overgrowth was found in only one. As this motility pattern was previously described in partial small intestinal obstruction, it is postulated that discrete clustered contractions could be the consequence of a functional obstruction as a result of anastomosis of the small intestine to the high pressure zone of the anal sphincters.
In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function
Authors: Amelia Barilli, Rossana Visigalli, Roberto Sala, Gian C. Gazzola, Alessandro Parolari, Elena Tremoli, Sabrina Bonomini, Alexandra Simon, Ellen I. Closs, Valeria Dall’Asta, Ovidio Bussolati
Journal: Cardiovascular Research (2008)

Drug-eluting stents are widely used to prevent restenosis but are associated with late endothelial damage. To understand the basis for this effect, we have studied the consequences of a prolonged incubation with rapamycin on the viability and functions of endothelial cells. Human umbilical vein or aorta endothelial cells were exposed to rapamycin in the absence or in the presence of tumour necrosis factor α (TNFα). After a 24 h-incubation, rapamycin (100 nM) caused a significant cell loss associated with the increase of both apoptosis and necrosis, as quantified by propidium iodide staining, caspase 3 activity, and lactate dehydrogenase release. Rapamycin also impaired cell mobility, as assessed by a wound test, and promoted the formation of actin stress fibres, as determined with confocal microscopy. Moreover, the inhibitor prolonged TNFα-dependent E-selectin induction, inhibited endothelial nitric oxide synthase expression at both mRNA (quantitative real-time polymerase chain reaction) and protein level (enzyme-linked immunosorbent assay and western blot), and lowered bioactive nitric oxide output (RFL-6 reporter cell assay). Under the conditions adopted, rapamycin inhibited both mammalian target-of-rapamycin complexes (mTORC1 and mTORC2), as indicated by the reduced amount of raptor and rictor bound to mTOR in immunoprecipitates and by the marked hypophosphorylation of protein S6 kinase I (p70S6K) and Akt, determined by western blotting. The selective inhibition of mTORC1 by AICAR did not affect endothelial viability. A prolonged treatment with rapamycin impairs endothelial function and hinders cell viability. Endothelial damage seems dependent on mTORC2 inhibition.
Value of radionuclide rest and exercise left ventricular ejection fraction in assessing survival of patients after thrombolytic therapy for acute myocardial infarction: Results of thrombolysis in myocardial infarction (TIMI) phase II study
Authors: Barry L. Zaret, Frans J.Th. Wackers, Michael L. Terrin, Sandra A. Forman, David O. Williams, Genell L. Knatterud, Eugene Braunwald
Journal: Journal of the American College of Cardiology (1995)

This study sought to determine the prognostic value of rest and exercise left ventricular ejection fraction in patients receiving thrombolytic therapy as part of the Thrombolysis in Myocardial Infarction (TIMI) trial. In the prethrombolytic era, ejection fraction at rest as well as during exercise was an important prognostic index in patients recovering from acute myocardial infarction. The prognostic value of these measurements in the thrombolytic era is not clear. As part of the TIMI II protocol, we obtained radio-nuclide left ventricular ejection fraction at rest and during symptom-limited submaximal supine exercise. Measurements were related to 1-year all-cause as well as cardiac mortality. In addition, the relation between ejection fraction obtained at rest and 1-year cardiac mortality in this study was compared with the relation established previously in the prethrombolytic era by the Multicenter Postinfarction Research Group. A distinct relation was noted between left ventricular ejection fraction at rest and all-cause mortality. The highest mortality rate (9.9%) was noted in patients with an ejection fraction <30%. Those not undergoing a study had a 1-year mortality rate of 6.2%. Peak exercise ejection fraction provided prognostic information similar to that of rest ejection fraction. Likewise, change in ejection fraction from rest to exercise did not appreciably improve prognostic impact. Rest left ventricular ejection fraction is an important prognostic index in patients receiving thrombolytic therapy. Peak exercise ejection fraction and the change in ejection fraction from rest to exercise do not provide appreciable prognostic data beyond those obtained at rest. Patients unable to exercise or those not having a rest study have a poor prognosis. When compared with the Multicenter Postinfarction Research Group data, there was strong evidence of a difference in survival in the two studies. At any level of ejection fraction, mortality was lower in TIMI II patients than in patients in the prethrombolytic era.
REM Sleep–like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and Serotonergic Inputs
Authors: Victor B. Fenik, Richard O. Davies, Leszek Kubin
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused by withdrawal of excitation mediated by norepinephrine and serotonin.
Anaplastic large-cell lymphoma which showed severe inflammatory status and myelodysplasia with increased VEGF and IL-6 serum levels after long-term immunosuppressive therapy
Authors: Takashi Shimamoto, Shigefumi Hayashi, Keiko Ando, Makoto Yguchi, Keisuke Miyazawa, Yukihiko Kimura, Kiyoshi Mukai, Hiromi Serizawa, Kazuma Ohyashiki
Journal: American Journal of Hematology (2000)

We report a patient with anaplastic large-cell lymphoma (ALCL) who has been given immunosuppressive therapy for Evans syndrome for 10 years. He was admitted with spike fever, intra-abdominal lymphadenopathy, and multiple liver masses. Examination of biopsy specimens obtained by para-aortic lymph nodes and liver masses resulted in a diagnosis of ALCL. Immunohistochemically, these cells were reactive to anti-CD30 antibody but were not of B- or T-lineage. Bone marrow aspiration demonstrated the invasion of giant neoplastic cells and trilineage myelodysplasia. Because the patient showed severe inflammatory symptoms, we examined serum levels of various cytokines. Pretreatment levels of IL-6 and VEGF in this patient were significantly elevated compared to those of normal controls. He was treated with combination chemotherapy (ABVD regimen), achieving complete remmesion. Myelodysplasia and serum IL-6 and VEGF also normalized after treatment. We assumed that ALCL resulted from long-term immunosuppressive therapy and that the up-regulation of IL-6 and VEGF played a role in pathogenesis of this type of lymphoma. Am. J. Hematol. 66:49–52, 2001. © 2001 Wiley-Liss, Inc.
Blood Glucose and Risk of Incident and Fatal Cancer in the Metabolic Syndrome and Cancer Project (Me-Can): Analysis of Six Prospective Cohorts
Authors: Tanja Stocks, Kilian Rapp, Tone Bjørge, Jonas Manjer, Hanno Ulmer, Randi Selmer, Annekatrin Lukanova, Dorthe Johansen, Hans Concin, Steinar Tretli, Göran Hallmans, Håkan Jonsson, Pär Stattin
Journal: PLoS Medicine (2009)

Background Prospective studies have indicated that elevated blood glucose levels may be linked with increased cancer risk, but the strength of the association is unclear. We examined the association between blood glucose and cancer risk in a prospective study of six European cohorts. Methods and Findings The Metabolic syndrome and Cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included 274,126 men and 275,818 women. Mean age at baseline was 44.8 years and mean follow-up time was 10.4 years. Excluding the first year of follow-up, 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. We used Cox regression models to calculate relative risk (RR) for glucose levels, and included adjustment for body mass index (BMI) and smoking status in the analyses. RRs were corrected for regression dilution ratio of glucose. RR (95% confidence interval) per 1 mmol/l increment of glucose for overall incident cancer was 1.05 (1.01–1.10) in men and 1.11 (1.05–1.16) in women, and corresponding RRs for fatal cancer were 1.15 (1.07–1.22) and 1.21 (1.11–1.33), respectively. Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder, and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach. Conclusions Data from our study indicate that abnormal glucose metabolism, independent of BMI, is associated with an increased risk of cancer overall and at several cancer sites. Our data showed stronger associations among women than among men, and for fatal cancer compared to incident cancer. Please see later in the article for the Editors' Summary
Angiographic Diagnosis of Pheochromocytoma
Authors: Juri V. Kaude
Journal: JAMA (1969)

<h3>To the Editor:—</h3> In the past 18 months we have angiographically localized four pheochromocytomas. Since our experience mirrors that of Rossi and his co-workers,<sup>1</sup>a presentation of our cases might emphasize their conclusions. Each patient had a single neoplasm; all tumors were on the left—three in the adrenal and one lateral to the aortic bifurcation. Our angiographic technique was similar to Rossi's. Each patient's blood pressure was monitored during the study, and in two cases, before we used alpha-adrenergic blocking agents as premedication, we had to administer phentolamine (Regitine) hydrochloride for hypertensive episodes. One crisis could be related to the injection of contrast medium, while the other was a mechanical phenomenon, occurring with catheterization (no injection) of the middle suprarenal artery, shown on an earlier aortogram to feed the tumor. Though premedication with blocking agents has prevented further reactions, it mitigates but does not abolish pharmacoangiologic technique,<sup>2</sup>in
Activin eases asthma
Authors: Mitch Leslie
Journal: The Journal of Experimental Medicine (2009)

A mysterious cytokine quells asthma by triggering regulatory T (T reg) cells that prevent dendritic cells from growing up, Semitekolou et al. reveal ([page 1769][1]).

![Figure][2] 

Inflammation narrowed a mouse's airways when activin-A was blocked (right).



Like many cytokines, activin-A
Mechanical Devices to Assist the Failing Heart
Authors: Akio Suzuki
Journal: JAMA (1967)

This is a very timely monograph written by the top investigators in this field. In the welter of publicity that has surrounded initial trials of assisted circulation, the actual status and objectives of investigators in this field may be obscured. This monograph provides sufficient information and background on assisted circulation for both researchers and practicing physicians interested in the "artificial heart." Although this meeting was held two years ago, the development of research is so rapid that the contents of this book could not be kept up to date. The monograph consists of three parts. In part 1, the basic physiology of circulation, prolonged oxygenation, and hemodynamics are described. Part 2 reviews the currently available types of pumps and presents both the physiological and biological aspects of prolonged pumping, with special emphasis on non-pulsatile and pulsatile flow. Part 3 describes various methods for assisting the failing heart. Almost the entire