tbuckley/cabot-search huggingface dataset:
Mechanisms underlying the development of inflammatory bowel disease: the role of rankl in dendritic cell activity
Authors: T. S. Chew, L. Logunova, J. McLaughlin, S. Cruickshank
Journal: Gut (2011)

<h3>Introduction</h3> Up to 40% of patients with inflammatory bowel disease (IBD) also suffer with osteoporosis.1 Receptor activator of NF-kB ligand (RANKL) promotes the formation of bone resorbing osteoclasts and is linked to osteoporosis.2 RANKL is controlled by decoy receptors, osteoprotegerin (OPG) and TNF-stimulated gene-6 (TSG6) that bind to it and block osteoclast bone resorption.2 We have shown increased serum levels of RANKL in a mouse model of colitis and bone disease.3 RANKL may also increase the lifespan and activity of dendritic cells (DCs), which accumulate in the colon in colitis.3 We hypothesise that the RANKL pathway links the development of colitis with bone disease and aimed to determine the mechanism of action of RANKL, OPG and TSG6 on DC function. <h3>Methods</h3> We used the validated <i>Trichuris muris</i>, mouse whipworm induced model of colitis.4 After infection, wildtype C57BL/6 mice develop a resolving colitis while IL10-KO (knockout) mice develop a chronic colitis. Colitis was assessed histologically and expression of RANKL family members by immunofluorescence and quantitative real time PCR (qRT-PCR). Additionally, the effects of RANKL family members were assessed in cultured bone marrow derived DCs. <h3>Results</h3> The colitis was severe in the IL10-KO mice, with statistically significant increases in colitis scores and crypt length from a mean of 80 to 147 μm, p&lt;0.001 between uninfected and infected IL10-KO mice but not wildtype controls with resolving colitis. qRT-PCR of RANKL, OPG and TSG6 mRNA in colonic snips showed increased expression over the course of infection in wildtype mice but decreased expression in IL10-KO mice. Immunofluorescence staining of colonic sections showed expression of OPG and TSG6 in macrophages and epithelial cells. Finally, in vitro functional assays on bone marrow DCs from wildtype naïve mice surprisingly showed that RANKL had little effect on the expression of DC maturation markers (CD80, CD86, MHCII). In contrast, OPG and TSG6 promoted MHCII and CD86 expression but not CD80. <h3>Conclusion</h3> The results suggest that increased expression of RANKL, OPG and TSG6 may be important in the resolution of colitis, in contrast to their decreased expression in persistent colitis. This finding supports our hypothesis that molecules which control bone homeostasis are involved in controlling colitis. The direct effects of RANKL members on DCs is unclear as the decoy receptors may partially activate DC function or promote activation of specific DC subsets.
MIF Signal Transduction Initiated by Binding to CD74
Authors: Lin Leng, Christine N. Metz, Yan Fang, Jing Xu, Seamas Donnelly, John Baugh, Thomas Delohery, Yibang Chen, Robert A. Mitchell, Richard Bucala
Journal: The Journal of Experimental Medicine (2003)

Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 Kd, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.
Insights into the targeted elimination of BRCA1-defective cancer stem cells
Authors: Veena Somasundaram, Priya Srinivas
Journal: Medicinal Research Reviews (2010)

BRCA1 expression is involved in normal embryonic development, mammary stem cell differentiation, and prostate cancer development. Inactivation of BRCA1 plays an important role in cancer stem cells and also leads to the development of high-grade, basal-like tumor. This review discusses why BRCA1-defective cancer stem cells need a prospective analysis, how ER alpha could influence BRCA1-defective tumor progression, phenotype of BRCA1-defective cancers, role of BRCA1 in other cancers and finally at what perspective BRCA1-defective cancers can be targeted for better therapeutic outcome.
Epidemiology of shoulder impingement in upper arm sports events.
Authors: Y P Lo, Y C Hsu, K M Chan
Journal: British Journal of Sports Medicine (1990)

An epidemiological survey was conducted to collect data relating to the prevalence and frequency of shoulder pain and other related problems among different athletic groups that demanded vigorous upper arm activities. A questionnaire was administered on site thus ensuring that the response rate was 100 percent. Analysis of results revealed that of the 372 respondents there were 242 male (65.1 percent) and 130 female subjects (34.9 percent), with seven (1.9 percent) above the age of 40, 119 (32 percent) between the ages of 25 and 40, and 246 (66.1 percent) below 25 years of age. A total of 163 athletes (43.8 percent) indicated that they had shoulder problems, 109 (29 percent) suffering pain. Diffuse pain was indicated by 20 respondents (5.4 percent), while localized pain during movement was reported in 89 (23.9 percent). The prevalence of shoulder pain ranked highest among volley ball players (N = 28) followed by swimmers (N = 22), while badminton, basketball and tennis participants were equally affected (N = 10).
Bone Marrow Allograft Rejection Mediated by a Novel Murine NK Receptor, NKG2I
Authors: Junzo Koike, Hiroshi Wakao, Yuko Ishizuka, Taka-aki Sato, Masaru Hamaoki, Ken-ichiro Seino, Haruhiko Koseki, Toshinori Nakayama, Masaru Taniguchi
Journal: The Journal of Experimental Medicine (2004)

Natural killer (NK) cells mediate bone marrow allograft rejection. However, the molecular mechanisms underlying such a rejection remain elusive. In previous analyses, it has been shown that NK cells recognize allogeneic target cells through Ly-49s and CD94/NKG2 heterodimers. Here, we describe identification and characterization of a novel murine NK receptor, NKG2I, belonging to the NKG2 family. NKG2I, which was composed of 226 amino acids, showed approximately 40% homology to the murine NKG2D and CD94 in the C-type lectin domain. Flow cytometric analysis with anti-NKG2I monoclonal antibody (mAb) revealed that expression of NKG2I was largely confined to NK and NKT cells, but was not seen in T cells. Furthermore, anti-NKG2I mAb inhibited NK cell-mediated cytotoxicity, whereas cross-linking of NKG2I enhanced interleukin 2- and interleukin 12-dependent interferon-gamma production. Similarly, the injection of anti-NKG2I mAb before the allogeneic bone marrow transfer in vivo impinged on the function of NKG2I, resulting in the enhanced colony formation in the spleen. NKG2I is a novel activating receptor mediating recognition and rejection of allogeneic target cells.
Impaired Clearance of Apoptotic Cells Promotes Synergy between Atherogenesis and Autoimmune Disease
Authors: Tamar Aprahamian, Ian Rifkin, Ramon Bonegio, Bénédicte Hugel, Jean-Marie Freyssinet, Kaori Sato, John J. Castellot, Kenneth Walsh
Journal: The Journal of Experimental Medicine (2004)

To clarify the link between autoimmune disease and hypercholesterolemia, we created the gld.apoE(-/-) mouse as a model of accelerated atherosclerosis. Atherosclerotic lesion area was significantly increased in gld.apoE(-/-) mice compared with apoE(-/-) mice. gld.apoE(-/-) mice also displayed increases in lymphadenopathy, splenomegaly, and autoantibodies compared with gld mice, and these effects were exacerbated by high cholesterol diet. gld.apoE(-/-) mice exhibited higher levels of apoptotic cells, yet a reduced frequency of engulfed apoptotic nuclei within macrophages. Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background. These data suggest that defects in apoptotic cell clearance promote synergy between atherosclerotic and autoimmune diseases.
Angiopoietin-1 promotes lymphatic sprouting and hyperplasia
Authors: Tuomas Tammela, Anne Saaristo, Marja Lohela, Tohru Morisada, Jenny Tornberg, Camilla Norrmén, Yuichi Oike, Katri Pajusola, Gavin Thurston, Toshio Suda, Seppo Yla-Herttuala, Kari Alitalo
Journal: Blood (2005)
A Randomized, Placebo-Controlled Trial of Sertraline for Prophylactic Treatment of Highly Recurrent Major Depressive Disorder
Authors: Jean-Pierre Lépine, Vincent Caillard, Jean-Claude Bisserbe, Sylvie Troy, Jean-Michel Hotton, Patrice Boyer
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Previous antidepressant maintenance trials have used the same medication from acute through maintenance phases, confounding the interpretation of prophylactic effects. The purpose of this study was to determine whether sertraline prevents the recurrence of major depressive disorder among patients with recurrent depression who had been treated to remission with medications other than sertraline. METHOD: Patients who had experienced at least three documented episodes of major depressive disorder within the last 4 years and who were currently in full remission were eligible. The last episode must have been treated for at least 4 months with any antidepressant except sertraline. For the initial single-blind placebo lead-in phase, 371 patients were included; 288 were included in the analyses for the 18-month double-blind phase in which patients were randomly assigned to sertraline (50 or 100 mg) or placebo (two capsules per day). Recurrence was defined as a depressive episode that fulfilled DSM-IV criteria or the appearance of symptoms that required the administration of another antidepressant treatment. RESULTS: Sixty-one patients discontinued before the double-blind phase, including 33 who experienced a relapse. Out of the 288 who entered the double-blind prophylactic phase, 123 discontinued, including 65 for recurrences. Recurrences were significantly lower in the sertraline groups compared with placebo (sertraline, 50 mg: 16 [16.8%] of 95; sertraline, 100 mg: 16 [17.0%] of 94; placebo: 33 [33.3%] of 99). Patients treated with sertraline also had a significantly longer time until recurrence compared with placebo-treated patients. CONCLUSIONS: Among remitted patients with a history of multiple depressive episodes, sertraline at a dose of either 50 or 100 mg/day prevented recurrences significantly more than did placebo.
Distinct Strategies Are Required to Suppress Antigen-specific Responses to Genetically Modified Keratinocytes and Fibroblasts
Authors: Soosan Ghazizadeh, Li T Huang, Weibing Zhang
Journal: Molecular Therapy (2011)

Keratinocytes and fibroblasts are potential targets of gene/cell therapy for genodermatoses. Immune elimination of genetically modified cells, however, presents a major impediment to effective therapy. Using ex vivo approaches to gene transfer, we have previously shown that expression of an antigen by either cell type in skin induces immune rejection of transplanted cells, although the nature of immune responses induced by these two cell types are distinct. In this study, we explore the efficacy of local immunosuppressive strategies to divert destructive immune responses from genetically modified fibroblast and keratinocytes. Expression of CTLA4Ig and, to a lesser extent, PDL1, by antigenic fibroblasts protected them from immune rejection resulting in long-term graft survival (>18 weeks). Similar treatment was not effective for antigenic keratinocytes. Long-term protection of transgenic keratinocytes was achieved through transient blockade of CD40/CD154 interactions during the first 2 weeks of cell transplantation. Although neither of these strategies induced antigen-specific tolerance, they were sufficient to prevent rejection of genetically modified cells. These results indicate that different strategies are required to protect antigenic cell types even within the same tissue. Moreover, induction of antigen-specific tolerance is not a necessary requirement for long-term survival of genetically modified skin cells.
Do high impact exercises produce higher tibial strains than running?
Authors: Charles Milgrom, Aharon Finestone, Yael Levi, Ariel Simkin, Ingrid Ekenman, Stephen Mendelson, Michael Millgram, Meir Nyska, Nissim Benjuya, David Burr
Journal: British Journal of Sports Medicine (2000)

Background —Bone must have sufficient strength to withstand both instantaneous forces and lower repetitive forces. Repetitive loading, especially when bone strain and/or strain rates are high, can create microdamage and result in stress fracture Aim —To measure in vivo strains and strain rates in human tibia during high impact and moderate impact exercises. Methods —Three strain gauged bone staples were mounted percutaneously in a rosette pattern in the mid diaphysis of the medial tibia in six normal subjects, and in vivo tibial strains were measured during running at 17 km/h and drop jumping from heights of 26, 39, and 52 cm. Results —Complete data for all three drop jumps were obtained for four of the six subjects. No statistically significant differences were found in compression, tension, or shear strains with increasing drop jump height, but, at the 52 cm height, shear strain rate was reduced by one third (p = 0.03). No relation was found between peak compression strain and calculated drop jump energy, indicating that subjects were able to dissipate part of the potential energy of successively higher drop jumps by increasing the range of motion of their knee and ankle joints and not transmitting the energy to their tibia. No statistically significant differences were found between the principal strains during running and drop jumping from 52 cm, but compression (p = 0.01) and tension (p = 0.004) strain rates were significantly higher during running. Conclusions —High impact exercises, as represented by drop jumping in this experiment, do not cause higher tibial strains and strain rates than running and therefore are unlikely to place an athlete who is accustomed to fast running at higher risk for bone fatigue.
Oral pilocarpine for the treatment of ocular symptoms in patients with Sjogren's syndrome: a randomised 12 week controlled study
Authors: N Tsifetaki
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To evaluate the efficacy and side effects of oral pilocarpine for the treatment of ocular symptoms in patients with primary Sjögren's syndrome (SS). <b>Methods:</b> A 12 week, single centre, randomised controlled study was performed. Twenty nine patients were randomly assigned to receive oral pilocarpine (5 mg twice a day), 28 only artificial tears, and 28 inferior puncta occlusion. Patients receiving oral pilocarpine and those with inferior puncta occlusion also received artificial tears. Patients were evaluated at baseline and throughout the study for their subjective global assessment of dry eyes and for their objective assessment of dry eyes (Schirmer's-I test, rose bengal test, and imprint test). <b>Results:</b> Patients taking oral pilocarpine had significant improvement in subjective global assessment of dry eyes, as was evaluated by improvement of &gt;55 mm on a visual analogue scale (VAS) for responses to the eye questionnaire, compared with patients treated with artificial tears (p&lt;0.001) and those with inferior puncta occlusion (p&lt;0.05). Furthermore, patients receiving oral pilocarpine also showed greater objective improvement, as measured by the rose bengal test (p&lt;0.05), while Schirmer's-I test showed no differences between the treated groups. Commonly reported adverse events were headache, increased sweating, nausea, and vomiting in the pilocarpine group, while one patient in the inferior puncta occlusion group had blepharitis and was withdrawn from the study. <b>Conclusion:</b> 10 mg of pilocarpine daily given to patients with SS for 12 weeks had a beneficial effect on subjective eye symptoms, as evaluated by improvement &gt;55 mm on a VAS. Additionally, an improvement of rose bengal staining was noted, but an increase in tear production, as measured by the Schirmer-I test, was not substantiated.
Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab
Authors: Luis Fayad, Fritz Offner, Mitchell R. Smith, Gregor Verhoef, Peter Johnson, Jonathan L. Kaufman, Ama Rohatiner, Anjali Advani, James Foran, Georg Hess, Bertrand Coiffier, Myron Czuczman, Eva Giné, Simon Durrant, Michelle Kneissl, Kenneth T. Luu, Steven Y. Hua, Joseph Boni, Erik Vandendries, Nam H. Dang
Journal: Journal of Clinical Oncology (2013)

Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20 + /CD22 + B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m 2 ) was confirmed to be the same as that for single-agent INO (1.8 mg/m 2 ). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20 + /CD22 + B-cell NHL.
1136 REGRESSION OF FIBROSIS AND REVERSAL OF CIRRHOSIS IN THIOACETAMIDE-INDUCED LIVER FIBROSIS FOLLOWING TREATMENT WITH GALECTIN INHIBITORS
Authors: P.G. Traber, H. Chou, E. Zomer, F. Hong, A. Klyosov, M.-I. Fiel, S.L. Friedman
Journal: Journal of Hepatology (2013)
Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease
Authors: Paul A. Gurbel, Kevin P. Bliden, Kathleen Butler, Udaya S. Tantry, Tania Gesheff, Cheryl Wei, Renli Teng, Mark J. Antonino, Shankar B. Patil, Arun Karunakaran, Dean J. Kereiakes, Cordel Parris, Drew Purdy, Vance Wilson, Gary S. Ledley, Robert F. Storey
Journal: Circulation (2009)

Background— Ticagrelor is the first reversibly binding oral P2Y 12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results— In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 μmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks ( P &lt;0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved &gt;50% IPA (98% versus 31%, P &lt;0.0001) and &gt;70% IPA (90% versus 16%, P &lt;0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72–hour slope [% IPA/h] −1.04 versus −0.48, P &lt;0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel ( P =NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo ( P =NS). Conclusions— Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00528411.
Pertussis toxin-insensitive phosphoinositide hydrolysis, membrane depolarization, and positive inotropic effect of carbachol in chick atria.
Authors: T Tajima, Y Tsuji, J H Brown, A J Pappano
Journal: Circulation Research (1987)

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.