tbuckley/cabot-search huggingface dataset:
FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance
Authors: Hiroshi Yasui, Teru Hideshima, Noopur Raje, Aldo M. Roccaro, Norihiko Shiraishi, Shaji Kumar, Makoto Hamasaki, Kenji Ishitsuka, Yu-Tzu Tai, Klaus Podar, Laurence Catley, Constantine S. Mitsiades, Paul G. Richardson, Rainer Albert, Volker Brinkmann, Dharminder Chauhan, Kenneth C. Anderson
Journal: Cancer Research (2005)

Abstract The novel immunomodulator FTY720 down-modulates sphingosine-1-phosphate receptor 1 on lymphocytes at low nanomolar concentrations, thereby inhibiting sphingosine-1-phosphate receptor 1–dependent egress of lymphocytes from lymph nodes into efferent lymphatics and blood. At high micromolar concentration, FTY720 has been shown to induce growth inhibition and/or apoptosis in human cancer cells in vitro. In this study, we investigated the biological effects of FTY720 on multiple myeloma cells. We found that FTY720 induces potent cytotoxicity against drug-sensitive and drug-resistant multiple myeloma cell lines as well as freshly isolated tumor cells from multiple myeloma patients who do not respond to conventional agents. FTY720 triggers activation of caspase-8, -9, and -3, followed by poly(ADP-ribose) polymerase cleavage. Interestingly, FTY720 induces alterations in mitochondrial membrane potential (ΔΨm) and Bax cleavage, followed by translocation of cytochrome c and Smac/Diablo from mitochondria to the cytosol. In combination treatment studies, both dexamethasone and anti-Fas antibodies augment anti–multiple myeloma activity induced by FTY720. Neither interleukin-6 nor insulin-like growth factor-I, which both induce multiple myeloma cell growth and abrogate dexamethasone-induced apoptosis, protect against FTY720-induced growth inhibition. Importantly, growth of multiple myeloma cells adherent to bone marrow stromal cells is also significantly inhibited by FTY720. Finally, it down-regulates interleukin-6–induced phosphorylation of Akt, signal transducers and activators of transcription 3, and p42/44 mitogen-activated protein kinase; insulin-like growth factor-I–triggered Akt phosphorylation; and tumor necrosis factor α–induced IκBα and nuclear factor-κB p65 phosphorylation. These results suggest that FTY720 overcomes drug resistance in multiple myeloma cells and provide the rationale for its clinical evaluation to improve patient outcome in multiple myeloma.
Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease
Authors: H. P. Torok, J. Glas, L. Tonenchi, P. Lohse, B. Müller-Myhsok, O. Limbersky, C. Neugebauer, F. Schnitzler, J. Seiderer, C. Tillack, S. Brand, G. Brunnler, P. Jagiello, J. T. Epplen, T. Griga, W. Klein, U. Schiemann, M. Folwaczny, T. Ochsenkuhn, C. Folwaczny
Journal: Gut (2005)

Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions.The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed.No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery.Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.
Cyclooxygenase-dependent vasoconstricting factor(s) in remodelled rat femoral arteries
Authors: A. Hirao, K. Kondo, K. Takeuchi, N. Inui, K. Umemura, K. Ohashi, H. Watanabe
Journal: Cardiovascular Research (2008)

AimsDenudation and regeneration of the vascular endothelium are important in the pathogenesis of atherosclerosis. The aim of this study is to clarify the mechanisms of functional alterations in remodelled arteries following endothelial injury.
CORRELATION BETWEEN VARIOUS PROTEINS OF BOVINE SNOUT EPIDERMIS*
Authors: CHRISTOPHER CARRUTHERS, MALAYA BHATTACHARAYA
Journal: British Journal of Dermatology (1972)

Journal Article CORRELATION BETWEEN VARIOUS PROTEINS OF BOVINE SNOUT EPIDERMIS Get access CHRISTOPHER CARRUTHERS, CHRISTOPHER CARRUTHERS Department of Biochemistry Research, Roswell Park Memorial Institute (a Unit of the New York State Department of Health), Buffalo, New York 14203, U.S.A Search for other works by this author on: Oxford Academic Google Scholar MALAYA BHATTACHARAYA MALAYA BHATTACHARAYA Department of Biochemistry Research, Roswell Park Memorial Institute (a Unit of the New York State Department of Health), Buffalo, New York 14203, U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 86, Issue 5, 1 May 1972, Pages 495–505, https://doi.org/10.1111/j.1365-2133.1972.tb16102.x Published: 01 May 1972 Article history Accepted: 11 December 1971 Published: 01 May 1972
Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2
Authors: Darshan Dalal, Lorraine H. Molin, Jonathan Piccini, Crystal Tichnell, Cynthia James, Chandra Bomma, Kalpana Prakasa, Jeffrey A. Towbin, Frank I. Marcus, Philip J. Spevak, David A. Bluemke, Theodore Abraham, Stuart D. Russell, Hugh Calkins, Daniel P. Judge
Journal: Circulation (2006)

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2 , encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results— DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2 . Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28±11 years) than in those without (36±16 years) ( P &lt;0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation ( P &lt;0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation ( P &lt;0.05). Conclusions— Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.
Sympathetic Vasoconstrictive Responses during Exercise- or Drug-Induced Vasodilatation
Authors: DEREK J. ROWLANDS, DAVID E. DONALD
Journal: Circulation Research (1968)

The effect of exercise on the vasoconstrictive response to sympathetic stimulation was studied by observing the changes in perfusion pressure in dogs' hindlimbs perfused at constant flow. During steady-state simulated exercise, a time-dependent increase occurred between 10 and 30 minutes in the magnitude of response to lumbar trunk stimulation or carotid sinus hypotension. This was present (although to a reduced Degrees) in drug-induced vasodilatation and in exercising limbs perfused at constant pressure. The time-dependent change was not due to (1) repetition of stimulus, (2) artifact from muscle electrodes, (3) circulating vasoactive substances, (4) skin circulation, or (5) pH, P CO 2 , or temperature of the perfusing blood. When norepinephrine was used as the vasoconstrictive stimulus, no time-dependent change was noted. After stabilization, the frequency-response curve of exercising muscle exceeded that at rest at all blood concentrations of norepinephrine and at all save the lowest frequencies of stimulation. It was concluded that vascular smooth muscle can develop greater tension from greater initial length. However, during exercise some factor which operates between the sympathetic nerve ending and the receptor site on vascular smooth muscle initially tends to depress this enhanced ability to develop tension.
Epithelial to Mesenchymal Transition Contributes to Drug Resistance in Pancreatic Cancer
Authors: Thiruvengadam Arumugam, Vijaya Ramachandran, Keith F. Fournier, Huamin Wang, Lauren Marquis, James L. Abbruzzese, Gary E. Gallick, Craig D. Logsdon, David J. McConkey, Woonyoung Choi
Journal: Cancer Research (2009)

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.
Stress and the Hypothalamic Pituitary Adrenal Axis in the Developmental Course of Schizophrenia
Authors: Elaine Walker, Vijay Mittal, Kevin Tessner
Journal: Annual Review of Clinical Psychology (2008)

Diathesis-stress models of schizophrenia and other psychotic disorders have dominated theorizing about etiology for over three decades. More recently, with advances in our understanding of the biological processes mediating the effects of stress, these models have incorporated mechanisms to account for the adverse impact of stress on brain function. This review examines recent scientific findings on the role of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary neural systems triggered by stress exposure, in the expression of vulnerability for schizophrenia. The results indicate that psychotic disorders are associated with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms. The cumulative findings are discussed in light of a neural diathesis-stress model that postulates that cortisol has the potential to increase activity of dopamine pathways that have been implicated in schizophrenia and other psychotic disorders.
OSGOOD SCHLATTER'S SYNDROME AND FUNCTIONAL IMPAIRMENT OF THE KNEE IN YOUNG FOOTBALL PLAYERS
Authors: Marcio Domingues
Journal: British Journal of Sports Medicine (2013)

Football, like any contact sport it is susceptible to various kinds of injuries. Long-term planning is a characteristic and requirement of modern training as it can greatly increase training efficiency for future competitions (Bompa, 1999). Epidemiological findings suggest that little is known about the injury risk among the youngest players between six and twelve years and also the injury risk is low (Froholdt, Olsen and Bahr, 2009). This article focus on the understanding of microtraumatology in youth sports and examines one specific injury Osgood Schlatter disease, and the main mechanisms whereby such injury occur. It is referred the link between methodology of training and the prevention of overuse injuries in youth as it relates to maladaptive sport programs. There is an increasing awareness to growth related conditions and the relation of musculoskeletal development and the onset of youth related conditions. The aethology is complex and the risk factors underpinning injury occurrence are considered, along with injury avoidance tactics. Functional treatment is justified even if there is an increased formation of ossicles on non-immobilization of the joint, since such ossification occurs with only 20–25% of all cases of Osgood-Schlatter disease and the duration of the complaints is markedly less enhanced than with immobilization measures (Engel &amp; Windhager, 1987). Treatment and recovery should attend to athletes specific conditions and involves activity modification and pain relief.
Increased concanavalin A induced suppression in treated and untreated coeliac disease.
Authors: C O'Farrelly, U McKeever, C Feighery, D G Weir
Journal: Gut (1984)

The generation of suppression by concanavalin A in peripheral blood mononuclear cells in treated and untreated coeliac subjects using an in vitro assay was found to be significantly increased when compared with controls. The response of peripheral blood mononuclear cells to the plant mitogen concanavalin A (con A) was also significantly depressed in both groups of coeliac patients. It is proposed that the depressed cell mediated immunity found in this and other studies in coeliac patients is because of increased suppression. The possible connection between these findings and the increased incidence of malignancy also found in coeliac disease is discussed.
Signalling in cardiac metabolism
Authors: G. D. Lopaschuk, D. P. Kelly
Journal: Cardiovascular Research (2008)

The heart requires large amounts of energy to sustain contractile function, and is the major consumer of energy in the body on a weight basis. Energy reserves are limited in the heart, so energy in the form of adenosine triphosphate (ATP) must be produced continually by the catabolism of different energy carbon substrates. The heart is an ‘omnivore’ and can use a number of different energy substrates, including fatty acids, glucose, lactate, pyruvate, ketones, and amino acids.1–4 Myocardial energy metabolism must be tightly regulated, as the heart cannot afford to produce either too little or too much ATP. In the normal healthy heart, almost all (>95%) of the ATP generated in the heart comes from mitochondrial oxidative phosphorylation, with the remainder being derived from glycolysis.1–4 Of these, fatty acids, glucose, and lactate normally make the greatest contribution to overall energy metabolism, primarily because the heart sees the highest concentration of these energy substrates. Mitochondrial metabolism of fatty acids accounts for ∼60–90% of the total energy production (in the form of ATP), with carbohydrates contributing the remaining 10–40%.3 The contribution of fatty acids and carbohydrates to oxidative ATP production in the heart is influenced by a number of conditions, including alterations in hormonal control, workload, energy substrate supply, and oxygen supply to the heart. The control of these energy-producing pathways is complex, but the different pathways normally work in perfect harmony to ensure the energy needs of the myocardium are met. The energy homeostasis mechanisms of the heart maintain constant ATP production despite periods of dramatic shifts in workload to the heart, and changes in energy substrate and/or oxygen supply to the heart. A complex and integrated cardiac signalling pathway has evolved to allow a precise match between cardiac energy production and usage. This … 

*Corresponding author. Tel: +1 780 492 2170; fax: +1 780 492 9753. E-mail address: gary.lopaschuk{at}ualberta.ca
Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate
Authors: Joel M. Kremer
Journal: Annals of Internal Medicine (2002)

Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. Setting: 20 centers in the United States and Canada. Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. Intervention: Leflunomide or matching placebo added to existing methotrexate therapy. Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.
Epigenetic Regulation of MicroRNAs in Acute Lymphoblastic Leukemia
Authors: Jose Roman-Gomez, Xabier Agirre, Antonio Jiménez-Velasco, Victor Arqueros, Amaia Vilas-Zornoza, Paula Rodriguez-Otero, Iñaki Martin-Subero, Leire Garate, Lucia Cordeu, Edurne San José-Eneriz, Vanesa Martin, Juan Antonio Castillejo, Eva Bandrés, María José Calasanz, Reiner Siebert, Anabel Heiniger, Antonio Torres, Felipe Prosper
Journal: Journal of Clinical Oncology (2009)

To identify microRNAs (miRNAs) epigenetically regulated in acute lymphoblastic leukemia (ALL).We first examined ALL-derived cell lines for the presence of abnormal levels of two different histone modifications (trimethylation of H3 lysine 4 [K4H3me3] and dimethylation of H3 lysine 9 [K9H3me2]) in the 5'UTR regions around CpG islands of 78 miRNAs by chromatin immunoprecipitation (ChIP)-on-ChIP analysis. Methylation status (methylation-specific polymerase chain reaction [PCR]) and expression (quantitative PCR) of miRNAs showing a pattern of histone modifications linked to a closed chromatin structure were analyzed in a panel of six ALL cell lines and in 353 ALL patients.CpG islands around 13 miRNAs disclosed high levels of K9H3me2 and/or low levels of K4H3me3, a pattern of histone modifications underlying a closed chromatin structure associated with repressive gene expression. Complete consistency in the correlation between both histone marks, the presence of DNA methylation around these miRNAs, and their expression patterns was confirmed in the six ALL cell lines. Treatment with 5-Aza-2'-deoxycytidine upregulated the expression levels of these genes, suggesting that epigenetic mechanisms deregulate the expression of these miRNAs. A total of 65% of the ALL samples had at least one miRNA methylated (methylated group). Estimated disease-free survival (DFS) and overall survival (OS) at 14 years were 78% and 71% for nonmethylated patients and 24% and 28% for methylated patients (P = .00001 for both). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor for predicting DFS (P = .0001) and OS (P = .0001).Aberrant miRNA methylation is a common phenomenon in ALL that affects the clinical outcome of these patients.
Impact of Prior Use or Recent Withdrawal of Oral Antiplatelet Agents on Acute Coronary Syndromes
Authors: J.P. Collet, G. Montalescot, B. Blanchet, M.L. Tanguy, J.L. Golmard, R. Choussat, F. Beygui, L. Payot, N. Vignolles, J.P. Metzger, D. Thomas
Journal: Circulation (2004)

Oral antiplatelet agents (OAAs) can prevent further vascular events in cardiovascular disease. How prior use or recent discontinuation of OAA affects clinical presentation of acute coronary syndromes (ACS) and clinical outcomes (death, myocardial infarction [MI]) is unclear.We studied and followed up for up to 30 days a cohort of 1358 consecutive patients admitted for a suspected ACS; of these, 930 were nonusers, 355 were prior users of OAA, and 73 had recently withdrawn OAA. Nonusers were at lower risk, more frequently presented with ST-elevation MI on admission, and more frequently had Q-wave MI at discharge than prior users (36.6% versus 17.5%, P<0.001; and 47.8% versus 28.2%, P<0.001, respectively). However, there was no difference regarding the incidence of death or MI at 30 days between nonusers and prior users (10.3% versus 12.4%, P=NS). In addition, prior users experienced more major bleeds within 30 days compared with nonusers (3.4% versus 1.4%, respectively; P=0.04). Recent withdrawers were admitted on average 11.9+/-0.8 days after OAA withdrawal. Interruption was primarily a physician decision for scheduled surgery (n=47 of 73). Despite a similar cardiovascular risk profile, recent withdrawers had higher 30-day rates of death or MI (21.9% versus 12.4%, P=0.04) and bleedings (13.7% versus 5.9%, P=0.03) than prior users. After multivariate analysis, OAA withdrawal was found to be an independent predictor of both mortality and bleedings at 30 days.Among ACS patients, prior users represent a higher-risk population and present more frequently with non-ST-elevation ACS than nonusers. Although patients with a recent interruption of OAA resemble those chronically treated by OAA, they display worse clinical outcomes.