tbuckley/cabot-search huggingface dataset:
Expression of Erythropoietin Receptor and<i>In vitro</i>Functional Effects of Epoetins in B-Cell Malignancies
Authors: Parviz Kokhaei, Amir Osman Abdalla, Lotta Hansson, Eva Mikaelsson, Manfred Kubbies, Anton Haselbeck, Helena Jernberg-Wiklund, Håkan Mellstedt, Anders Österborg
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM). Experimental Design: Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti–EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [3H]thymidine incorporation and CD69 expression after exposure to epoetin α or β or darbepoetin α. Results: EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti–EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations. Conclusions: EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.
Point: Intensive Glycemic Control and Mortality in ACCORD—A Chance Finding?
Authors: John M. Lachin
Journal: Diabetes Care (2010)

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was designed to assess whether intensive glucose management aimed at a normal A1C (<6%) versus standard therapy aimed at an A1C of 7–8% would reduce the risk of cardiovascular disease as reflected by the incidence of a major adverse cardiac event (MACE) such as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (1). The study enrolled 10,251 patients, and a planned mean follow-up of 5.6 years was expected to provide 89% power to detect a 15% reduction in MACE risk with intensive versus conventional therapy. Patients received any one of six anti-hyperglycemic agents or a variety of insulins alone or in combination. Eligible subjects were also randomized to intensive versus conventional lipid and/or blood pressure control. However, after a mean of 3.6 years of follow-up, when 62.5% of the planned information had been accrued, the study was terminated by the Data and Safety Monitoring Board (DSMB) in the presence of an increased incidence of mortality with intensive therapy: 257 versus 203 deaths with standard therapy, corresponding to an adjusted hazard ratio (HR) of 1.22 (95% CI [1.01–1.46], P = 0.04). The database used to generate the final report to the DSMB was frozen and then used as the basis for analyses that were subsequently published (2).

The initial report (2) stated that “differences in the use of drugs (including rosiglitazone), weight change, and other factors did not identify an explanation for the mortality finding.” Since then the authors have searched in earnest for a biological mechanism that would account for this increase in mortality. None has been found. Herein I present a synopsis of these findings and then suggest another possible mechanism—that the observed excess mortality could have been a chance finding.

### Baseline factors

Subgroup analyses within strata defined by baseline …
Selective release of archidonic acid from the phospholipids of human platelets in response to thrombin.
Authors: T K Bills, J B Smith, M J Silver
Journal: Journal of Clinical Investigation (1977)

Arachidonic acid is unique amongst human platelet fatty acids in that it is the precursor of prostaglandins and thromboxanes. Since a number of these oxygenated products of arachidonic acid have potent effects on platelet function, an understanding of the metabolsim of their precursor is important. Human platelets have a mechanism for incorporating arachidonic acid from plasma into their phospholipids and, in response to thrombin, they reveal mechanisms for hydrolyzing this arachidonic acid from platelet phosphatidylcholine and phosphatidylinositol. This report deals with the specificity of these mechanisms. The present studies show that human platelets contain phospholipase A2 activities that preferentially release arachidonic acid. One of these activities specifically utilizes 1-acyl-2-arachidonyl-phosphatidyl-choline. Another utilizes platelet phosphatidylinositol and/or phosphatidylserine, both of which are highly enriched with arachidonic acid.
Transverse Myelitis Plus Syndrome and Acute Disseminated Encephalomyelitis Plus Syndrome
Authors: Allen DeSena, Donna Graves, Michael C. Morriss, Benjamin M. Greenberg
Journal: JAMA Neurology (2014)

Classically, transverse myelitis and acute disseminated encephalomyelitis are considered central nervous system demyelinating conditions. In both conditions, the spinal cord is involved to varying degrees, and there is a variety of presentations, usually involving some degree of progressive paralysis of the upper and/or lower extremities. Treatment usually consists of high-dose intravenous steroids in addition to plasma exchange and/or intravenous immunoglobulin. In some cases, immunosuppressive medications, such as intravenous cyclophosphamide, have been used with variable success. Cases with atypical features on examination, imaging, or with neurophysiological studies may be helpful in shedding light on the etiology and/or pathophysiology because many of these patients have permanent disabilities despite appropriate treatment.This case series presents 5 pediatric cases observed from 2009-2012 at our medical center, Children's Medical Center Dallas. These cases were notable because they provided evidence of autoimmune events affecting the central nervous system but with additional peripheral axonal pathology.We describe these cases with respect to findings that suggest a variant of these conditions that have concomitant nerve-root involvement. These patients had worse outcomes than typical patients with transverse myelitis/acute disseminated encephalomyelitis, and these observations build on previous work by other investigators that highlighted persistent flaccid paralysis and electrophysiological evidence of axonal loss portending a poorer prognosis. Furthermore, these cases suggest a potential role for approaching how we classify subtypes of transverse myelitis and acute disseminated encephalomyelitis.
Specific Regulation of T Helper Cell 1–mediated Murine Colitis by CEACAM1
Authors: Hideki Iijima, Markus F. Neurath, Takashi Nagaishi, Jonathan N. Glickman, Edward E. Nieuwenhuis, Atsushi Nakajima, Daohong Chen, Ivan J. Fuss, Nalan Utku, Daniel N. Lewicki, Christoph Becker, Thomas M. Gallagher, Kathryn V. Holmes, Richard S. Blumberg
Journal: The Journal of Experimental Medicine (2004)

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet–mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti–mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-γ production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-γ and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-γ gene–deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.
A model for implantation of the human blastocyst and early placentation
Authors: P Bischof
Journal: Human Reproduction Update (1996)

We describe here a molecular model of blastocyst implantation which is based on two assumptions: (i) that implantation of the human blastocyst into the endometrium is a process which is very similar to tumour invasion of a host tissue; and (ii) that the cytotrophoblastic cells of a first trimester pregnancy retain almost all the properties of the trophectodermal cells of the blastocyst and can thus be used as surrogates to study the implantation process in vitro. Our model considers that the trophectodermal cells, once they reach the endometrial basement membrane, express integrins (alpha 6 beta 4) which anchor them into the basement membrane and induce their secretion of gelatinases. These proteases digest the basement membrane, allowing the embryo to make contact with the endometrial extracellular matrix (ECM). Integrins (alpha 5 beta 1) anchor the embryo into the ECM and induce its secretion of collagenases. These enzymes digest the ECM, allowing the embryo to burrow into the endometrium. This process is under the paracrine control of endometrial cytokines and ECM glycoproteins.
Evolution of Hepatitis B Virus Polymerase Gene Mutations in Hepatitis B E Antigen-Negative Patients Receiving Lamivudine Therapy
Authors: Anna Suk-Fong Lok, Munira Hussain, Carmela Cursano, Marzia Margotti, Annagiulia Gramenzi, Gian Luca Grazi, Elio Jovine, Mauro Benardi, Pietro Andreone
Journal: Hepatology (2000)

Lamivudine has been shown to be effective in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, but its long-term efficacy and the rate of resistant mutations in patients with HBeAg-negative chronic hepatitis B is less clear. Twenty-nine patients with HBeAg-negative chronic hepatitis B, who have received lamivudine for at least 1 year were studied to determine the antiviral response, the rate and pattern of lamivudine-resistant mutations, and the effect of lamivudine-resistant mutations on HBeAg status. The mean duration of treatment was 21 +/- 7 months. Before treatment, core promoter variant was detected in 16 (55%) patients and precore stop codon variant in 18 (62%) patients. Serum hepatitis B virus (HBV) DNA was detected by solution hybridization assay in 62%, 4%, and 24% and by polymerase chain reaction (PCR) assay in 100%, 31%, and 40% at months 0, 6, and 24, respectively. The cumulative rates of detection of lamivudine-resistant mutations after 1 and 2 years of treatment were 10% and 56%, respectively. In addition to the duration of treatment, core promoter mutation was associated with the selection of lamivudine-resistant mutants. Three patients with lamivudine-resistant mutations had reversion of the precore stop codon mutation; in 2 patients this was accompanied by the reappearance of HBeAg. We found that lamivudine-resistant mutants were detected at similar rates in patients with HBeAg-negative as in patients with HBeAg-positive chronic hepatitis B. Additional changes in other parts of the HBV genome may restore the replication fitness of lamivudine-resistant mutants.
RhoA-Dependent Regulation of Cell Migration by the Tumor Suppressor <i>hSNF5/INI1</i>
Authors: Julie Caramel, Frédérique Quignon, Olivier Delattre
Journal: Cancer Research (2008)

Abstract Malignant rhabdoid tumors (MRT) are extremely aggressive pediatric tumors caused by the inactivation of the hSNF5/INI1 tumor suppressor gene, which encodes a core member of the SWI/SNF chromatin remodeling complex. Roles for hSNF5/INI1 in cell cycle and differentiation have been documented. Based on the observation that MRTs are highly invasive, we investigated a role for hSNF5/INI1 in cell migration. MRT cell lines exhibit high migration properties that are dramatically reduced upon hSNF5/INI1 expression. This effect is associated with the disorganization of the actin stress fiber network and is mediated by the inhibition of the activity of the small GTPase RhoA, through a nuclear, SWI/SNF-dependent transcriptional mechanism. We further show that the knockdown of hSNF5/INI1 in epithelial 293T or MCF7 cells results in increased cell size, loss of cell-cell adhesions, and enhanced migration, associated with an increased RhoA activity. Finally, we show that the SNF5 homology domain is required for hSNF5/INI1-mediated inhibition of migration, and that a missense mutation (S284L) associated with cancer is sufficient to impair hSNF5/INI1 function in migration. We conclude that the inhibition of migration is another crucial tumor suppressor function of hSNF5/INI1, in addition to its previously described functions in proliferation and differentiation, and that its loss-of-function in MRTs may account for the high invasiveness and metastatic potential of these tumors. [Cancer Res 2008;68(15):6154–61]
I-PLA2 Activation during Apoptosis Promotes the Exposure of Membrane Lysophosphatidylcholine Leading to Binding by Natural Immunoglobulin M Antibodies and Complement Activation
Authors: Sun Jun Kim, Debra Gershov, Xiaojing Ma, Nathan Brot, Keith B. Elkon
Journal: The Journal of Experimental Medicine (2002)

Deficiency of serum immunoglobulin (Ig)M is associated with the development of a lupus-like disease in mice. Recent studies suggest that classical complement components facilitate the clearance of apoptotic cells and that failure to do so predisposes mice to lupus. Since IgM is a potent activator of the classical complement pathway, we examined IgM binding to dying cells. IgM, but not IgG, bound to apoptotic T cells through the Fab' portion of the antibody. Exposure of apoptotic cell membranes to phospholipase (PL) A2 increased, whereas PLD reduced, IgM binding and complement activation. Absorption studies combined with direct plate binding assays, revealed that IgM antibodies failed to bind to phosphatidyl lipids, but did recognize lysophosphatidylcholine and the phosphorylcholine head group. Both iPLA(2) and cPLA(2) are activated during apoptosis. Since inhibition of iPLA2, but not cPLA2, attenuated IgM binding to apoptotic cells, these results strongly suggest that the endogenous calcium independent PLA(2), iPLA(2), is involved in the hydrolysis of plasma membrane phospholipids and exposure of the epitope(s) recognized by IgM. We propose that recognition of dying cells by natural IgM antibodies is, in part, responsible for complement activation on dying cells leading to their safe clearance.
Comparison of Orally Administered Cannabis Extract and Delta-9-Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the Cannabis-In-Cachexia-Study-Group
Authors: Florian Strasser, Diana Luftner, Kurt Possinger, Gernot Ernst, Thomas Ruhstaller, Winfried Meissner, You-Dschun Ko, Martin Schnelle, Marcus Reif, Thomas Cerny
Journal: Journal of Clinical Oncology (2006)

To compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo (PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS).Adult patients with advanced cancer, CACS, weight loss (> or = 5% over 6 months), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 were randomly assigned (2:2:1) to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally, twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analog scale (VAS); QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks.Of 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100 patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age (mean, 61 years), sex (54% men), weight loss (32% > or = 10%), PS (13% ECOG = 2), antineoplastic treatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patients receiving CE, THC, or PL, respectively. An independent data review board recommended termination of recruitment because of insufficient differences between study arms.CE at the oral dose administered was well tolerated by these patients with CACS. No differences in patients' appetite or QOL were found either between CE, THC, and PL or between CE and THC at the dosages investigated.
HCV iatrogenic and intrafamilial transmission in Greater Cairo, Egypt
Authors: A. Paez Jimenez, N. Sharaf Eldin, F. Rimlinger, M. El-Daly, H. El-Hariri, M. El-Hoseiny, A. Mohsen, A. Mostafa, E. Delarocque-Astagneau, M. Abdel-Hamid, A. Fontanet, M. K. Mohamed, V. Thiers
Journal: Gut (2010)

To document hepatitis C virus (HCV) intrafamilial transmission and assess its relative importance in comparison to other current modes of transmission in the country with the largest HCV epidemic in the world. HCV intrafamilial transmission was defined as HCV transmission among relatives living in the same household.Case-control study. Cases were adult patients with acute hepatitis C diagnosed in two 'fever hospitals' of Cairo. Controls were adult patients with acute hepatitis A diagnosed in the same two hospitals, and family members of cases. All consenting household members of cases provided blood for HCV serological and RNA testing. Homology of viral sequences (NS5b region) within households was used to ascertain HCV intrafamilial transmission. Exposures at risk for HCV during the 1-6 months previous to onset of symptoms were assessed in all cases and controls.From April 2002 to June 2007, 100 cases with acute hepatitis C, and 678 controls (416 household members and 262 patients with acute hepatitis A) were recruited in the study. Factors independently associated with HCV infection and their attributable fractions (AFs) were the following: having had a catheter (OR=5.0, 95% CI=1.4 to 17.8; AF=6.7%), an intravenous perfusion (OR=5.8, 95% CI=2.5 to 13.3; AF=20.1%), stitches (OR=2.0, 95% CI=1.3 to 6.6; AF=10.7%), gum treatment (OR=3.7, 95% CI=1.1 to 11.9; AF=3.8%) and being illiterate (OR=2.4, 95% CI=1.4 to 4.4). Of the 100 cases, 18 had viraemic HCV-infected household members. Three long-married (>15&emsp14;years) couples were infected with virtually identical sequences and none of the three index patients reported any exposure at risk, suggesting HCV intra-familial transmission.While three new HCV infections out of 100 could be linked to intra-familial transmission, parenteral iatrogenic transmission (dental care included) was accountable for 34.6% of these new infections. Thus, the relative contribution of intrafamilial transmission to HCV spread seems to be limited.
Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus
Authors: Irma Rukhadze, Victor B. Fenik, Kate E. Benincasa, Andrea Price, Leszek Kubin
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Patients with obstructive sleep apnea (OSA) adapt to the anatomical vulnerability of their upper airway by generating increased activity in upper airway-dilating muscles during wakefulness. Norepinephrine (NE) and serotonin (5-HT) mediate, through α₁-adrenergic and 5-HT₂A receptors, a wake-related excitatory drive to upper airway motoneurons. In patients with OSA, this drive is necessary to maintain their upper airway open. We tested whether chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, affects aminergic innervation of XII motoneurons that innervate tongue-protruding muscles in a manner that could alter their airway-dilatory action.To determine the impact of CIH on neurochemical markers of NE and 5-HT innervation of the XII nucleus.NE and 5-HT terminal varicosities and α₁-adrenergic and 5-HT₂A receptors were immunohistochemically visualized and quantified in the XII nucleus in adult rats exposed to CIH or room air exchanges for 10 h/d for 34 to 40 days.CIH-exposed rats had approximately 40% higher density of NE terminals and approximately 20% higher density of 5-HT terminals in the ventromedial quadrant of the XII nucleus, the region that controls tongue protruder muscles, than sham-treated rats. XII motoneurons expressing α₁-adrenoceptors were also approximately 10% more numerous in CIH rats, whereas 5-HT₂A receptor density tended to be lower in CIH rats.CIH-elicited increase of NE and 5-HT terminal density and increased expression of α₁-adrenoceptors in the XII nucleus may lead to augmentation of endogenous aminergic excitatory drives to XII motoneurons, thereby contributing to the increased upper airway motor tone in patients with OSA.
Isomers of Albuterol and Formoterol Differentially Affect the Accumulation of Extracellular Matrix (ECM) Components, Hyaluronan and Versican by Human Lung Fibroblasts (HLF)
Authors: L.C. Altman, S. Perigo, C.K. Chan, K. Braun, T.N. Wight
Journal: Journal of Allergy and Clinical Immunology (2009)
“It's exercise or nothing”: a qualitative analysis of exercise dependence
Authors: D Bamber, I M Cockerill, S Rodgers, D Carroll
Journal: British Journal of Sports Medicine (2000)

To explore, using qualitative methods, the concept of exercise dependence. Semistructured interviews were undertaken with subjects screened for exercise dependence and eating disorders.Female exercisers, four in each case, were allocated a priori to four groups: primary exercise dependent; secondary exercise dependent, where there was a coincidence of exercise dependence and an eating disorder; eating disordered; control, where there was no evidence of either exercise dependence or eating disorder. They were asked about their exercise and eating attitudes and behaviour, as well as about any history of psychological distress. Their narratives were taped, transcribed, and analysed from a social constructionist perspective using QSR NUD*IST.Participants classified as primary exercise dependent either showed no evidence of exercise dependent attitudes and behaviour or, if they exhibited features of exercise dependence, displayed symptoms of an eating disorder. Only the latter reported a history of psychological distress, similar to that exhibited by women classified as secondary exercise dependent or eating disordered. For secondary exercise dependent and eating disordered women, as well as for controls, the narratives largely confirmed the a priori classification.Where exercise dependence was manifest, it was always in the context of an eating disorder, and it was this comorbidity, in addition to eating disorders per se, that was associated with psychological distress. As such, these qualitative data support the concept of secondary, but not primary, exercise dependence.