tbuckley/cabot-search huggingface dataset:
Cotreatment with Vorinostat Enhances Activity of MK-0457 (VX-680) against Acute and Chronic Myelogenous Leukemia Cells
Authors: Warren Fiskus, Yongchao Wang, Rajeshree Joshi, Rekha Rao, Yonghua Yang, Jianguang Chen, Ravindra Kolhe, Ramesh Balusu, Kelly Eaton, Pearl Lee, Celalettin Ustun, Anand Jillella, Carolyn A. Buser, Stephen Peiper, Kapil Bhalla
Journal: Clinical Cancer Research (2008)

We determined the effects of vorinostat (suberoylanalide hydroxamic acid) and/or MK-0457 (VX-680), an Aurora kinase inhibitor on the cultured human (HL-60, OCI-AML3, and K562) and primary acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and mutant forms of Bcr-Abl.Following exposure to MK-0457 and/or vorinostat, apoptosis, loss of viability, as well as activity and levels of Aurora kinase and Bcr-Abl proteins were determined.Treatment with MK-0457 decreased the phosphorylation of Aurora kinase substrates including serine (S)10 on histone H3 and survivin, and led to aberrant mitosis, DNA endoreduplication as well as apoptosis of the cultured human acute leukemia HL-60, OCI-AML3, and K562 cells. Combined treatment with vorinostat and MK-0457 resulted in greater attenuation of Aurora and Bcr-Abl (in K562) kinase activity and levels as well as synergistically induced apoptosis of OCI-AML3, HL-60, and K562 cells. MK-0457 plus vorinostat also induced synergistic apoptosis of BaF3 cells with ectopic overexpression of wild-type or mutant Bcr-Abl. Finally, cotreatment with MK-0457 and vorinostat induced more loss of viability of primary AML and imatinib-refractory CML than treatment with either agent alone, but exhibited minimal toxicity to normal CD34+ progenitor cells.Combined in vitro treatment with MK-0457 and vorinostat is highly active against cultured and primary leukemia cells. These findings merit in vivo testing of the combination against human AML and CML cells, especially against imatinib mesylate-resistant Bcr-AblT315I-expressing CML Cells.
Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells
Authors: Gennaro Di Maro, Paolo Salerno, Kristian Unger, Francesca Maria Orlandella, Mario Monaco, Gennaro Chiappetta, Gerry Thomas, Malgorzata Oczko-Wojciechowska, Mariorosario Masullo, Barbara Jarzab, Massimo Santoro, Giuliana Salvatore
Journal: Molecular Cancer (2014)

Abstract Background Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in several human carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression of AGR2 in PTC and its functional role. Methods Expression of AGR2 was studied by immunohistochemistry and real time PCR in normal thyroids and in PTC samples. The function of AGR2 was studied by knockdown in PTC cells and by ectopic expression in non-transformed thyroid cells. The role of AGR2 in the ER stress was analyzed upon treatment of cells, expressing or not AGR2, with Bortezomib and analyzing by Western blot the expression levels of GADD153. Results PTC over-expressed AGR2 at mRNA and protein levels. Knockdown of AGR2 in PTC cells induced apoptosis and decreased migration and invasion. Ectopic expression of AGR2 in non-transformed human thyroid cells increased migration and invasion and protected cells from ER stress induced by Bortezomib. Conclusions AGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion and protection from ER stress.
Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk
Authors: W.H. Wilson Tang, Zeneng Wang, Bruce S. Levison, Robert A. Koeth, Earl B. Britt, Xiaoming Fu, Yuping Wu, Stanley L. Hazen
Journal: New England Journal of Medicine (2013)

Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.
Post-treatment Levels of α-Fetoprotein Predict Incidence of Hepatocellular Carcinoma After Interferon Therapy
Authors: Tsugiko Oze, Naoki Hiramatsu, Takayuki Yakushijin, Masanori Miyazaki, Akira Yamada, Masahide Oshita, Hideki Hagiwara, Eiji Mita, Toshifumi Ito, Hiroyuki Fukui, Yoshiaki Inui, Taizo Hijioka, Masami Inada, Kazuhiro Katayama, Shinji Tamura, Harumasa Yoshihara, Atsuo Inoue, Yasuharu Imai, Eijiro Hayashi, Michio Kato, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi, Akinori Kasahara, Toshimitsu Hamasaki, Norio Hayashi, Tetsuo Takehara
Journal: Clinical Gastroenterology and Hepatology (2013)
Quality of life and hospital re-admission in patients with chronic obstructive pulmonary disease
Authors: I. M. Osman, D. J. Godden, J. A. Friend, J. S. Legge, J. G. Douglas
Journal: Thorax (1997)

BACKGROUND: There is some evidence that quality of life (QOL) in patients with chronic obstructive pulmonary disease (COPD) may predict clinical outcomes and use of resources. This study examined whether QOL scores could prospectively predict re-admission for COPD or death within 12 months of an original admission, and whether QOL scores predicted home nebuliser provision. METHODS: The study was carried out in all acute medical wards of Aberdeen Royal Infirmary, Woodend and City Hospitals, Aberdeen over 12 months. A total of 377 patients admitted with an exacerbation of COPD were identified in this time, 111 of whom were not included in the study because they refused the interview or died before discharge. The remaining 266 patients completed the St George9s Respiratory Questionnaire (SGRQ). Information on spirometric parameters, nebuliser provision at discharge, provision of domiciliary oxygen, and re-admission within 12 months was collected from patient notes. RESULTS: The mean age of the patients was 68 years and 53% were men. The mean (SD) forced expiratory volume in one second (FEV1) was 38.8 (18.0)% predicted and forced vital capacity (FVC) was 58.9 (23.8)% predicted. Higher (worse) scores on the SGRQ were significantly related to re-admission for COPD in the next 12 months (difference = 4.8, 95% CI 1.6 to 8.0). Patients who were re-admitted and died from COPD did not differ in SGRQ scores from those who were re-admitted and survived for more than 12 months. Re-admission was not related to sex, age, or pulmonary function. One hundred and thirty eight patients did not have a home nebuliser before admission. Of these, 14 were provided with a home nebuliser at discharge. Patients provided with nebulisers had significantly worse SGRQ scores and worse FVC. The 41 patients given domiciliary oxygen did not differ in SGRQ or spirometric parameters. Logistic regression analysis of the three SGRQ subscales (Symptom, Impact and Activity), adjusting for lung function, age and sex, showed that all three subscales were significantly related to hospital readmission and that Impact scores were related to nebuliser provision. Women did not differ from men in Symptom scores on the SGRQ but differed markedly on the Activity and Impact scales. CONCLUSIONS: It is concluded that poor scores on the SGRQ, a QOL scale which measures patient distress and coping, are associated with re-admission for COPD and use of resources such as nebulisers, independent of physiological measures of disease severity.
The genomic landscape of juvenile myelomonocytic leukemia
Authors: Elliot Stieglitz, Amaro N Taylor-Weiner, Tiffany Y Chang, Laura C Gelston, Yong-Dong Wang, Tali Mazor, Emilio Esquivel, Ariel Yu, Sara Seepo, Scott R Olsen, Mara Rosenberg, Sophie L Archambeault, Ghada Abusin, Kyle Beckman, Patrick A Brown, Michael Briones, Benjamin Carcamo, Todd Cooper, Gary V Dahl, Peter D Emanuel, Mark N Fluchel, Rakesh K Goyal, Robert J Hayashi, Johann Hitzler, Christopher Hugge, Y Lucy Liu, Yoav H Messinger, Donald H Mahoney, Philip Monteleone, Eneida R Nemecek, Philip A Roehrs, Reuven J Schore, Kimo C Stine, Clifford M Takemoto, Jeffrey A Toretsky, Joseph F Costello, Adam B Olshen, Chip Stewart, Yongjin Li, Jing Ma, Robert B Gerbing, Todd A Alonzo, Gad Getz, Tanja A Gruber, Todd R Golub, Kimberly Stegmaier, Mignon L Loh
Journal: Nature Genetics (2015)
Effect of Type 1 Diabetes on Carotid Structure and Function in Adolescents and Young Adults
Authors: Elaine M. Urbina, Dana Dabelea, Ralph B. D’Agostino, Amy S. Shah, Lawrence M. Dolan, Richard F. Hamman, Stephen R. Daniels, Santica Marcovina, R. Paul Wadwa
Journal: Diabetes Care (2013)

Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes.Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured. ANCOVA was used to assess differences controlling for demographic risk factors, cardiovascular risk factors, and HbA1c.Subjects were 18.9 ± 3.3 years old (50% male, 82.7% non-Hispanic white). Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. Age, sex, adiposity, and systolic blood pressure were consistent significant determinants of IMT. Adjustment for HbA1c eliminated the difference, suggesting the difference was attributable to poor glycemic control.Carotid IMT may be increased in youth with type 1 diabetes at high risk for cardiovascular disease. Better control of diabetes may be essential in preventing progression of atherosclerosis.
A multidimensional model of psychobiological interactions in functional dyspepsia: a structural equation modelling approach
Authors: Michael P Jones, Eline Coppens, Rita Vos, Lieselot Holvoet, Patrick Luyten, Jan Tack, Lukas Van Oudenhove
Journal: Gut (2012)

Gastric sensorimotor function, abuse history, 'trait' and 'state' psychological factors and 'somatisation' all play a role in functional dyspepsia (FD) and its associated impaired quality of life (QoL), but their interplay remains poorly understood. We aimed to test a comprehensive, a priori hypothesised model of interactions between these dimensions in FD.In 259 FD patients, we studied gastric sensitivity with a barostat. We measured abuse history (sexual/physical, childhood/adulthood), 'trait' (alexithymia, trait anxiety) and 'state' (positive/negative affect, depression, panic disorder) psychological factors, somatic symptom reporting (somatic symptom count, dyspepsia, irritable bowel syndrome and fatigue symptoms) and QoL (physical, mental) using validated questionnaires. Confirmatory factor analysis (CFA) was used to assess whether four a priori hypothesised latent variables ('abuse', 'trait affectivity', 'state affect' and 'somatic symptom reporting') were adequately supported by the data. Structural equation modelling (SEM) was used to test the a priori hypothesised relationships between these latent variables and the observed variables gastric sensitivity and QoL.Both the CFA and SEM models fitted the data adequately. Abuse exerted its effect directly on 'somatic symptom reporting', rather than indirectly through psychological factors. A reciprocal relationship between 'somatic symptom reporting' and 'state affect' was found. Gastric sensitivity influences 'somatic symptom reporting' but not vice versa. 'Somatic symptom reporting' and 'trait affectivity' are the main determinants of physical and mental QoL, respectively.We present the first comprehensive model elucidating the complex interactions between multiple dimensions (gastric sensitivity, abuse history, 'state' and 'trait' psychological factors, somatic symptom reporting and QoL) in FD.
Cariporide (HOE642), a Selective Na <sup>+</sup> -H <sup>+</sup> Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway
Authors: Yasushi Teshima, Masaharu Akao, Steven P. Jones, Eduardo Marbán
Journal: Circulation (2003)

The Na+-H+ exchanger figures prominently in cardiac ischemia-reperfusion injury. Several experimental and clinical studies have demonstrated a cardioprotective effect of Na+-H+ exchanger inhibition; however, the precise mechanisms have not been established.We examined the effects of cariporide (HOE642, 10 micromol/L) on cell death induced by oxidative stress (H2O2, 100 micromol/L) in cultured neonatal rat cardiomyocytes. Cariporide significantly suppressed markers of cell death, such as TUNEL positivity and caspase-3 cleavage, at 8 or 16 hours after H2O2. The early phase of cell death, reported by increases in phosphatidylserine exposure and propidium iodide uptake, was also inhibited by cariporide. To explore the mechanisms of cell protection, we examined the effects of cariporide on increases in intracellular Na+ and Ca2+ induced by oxidative stress. Cariporide remarkably suppressed cytosolic Na+ and Ca2+ accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca2+ overload induced by H2O2 was remarkably suppressed by cariporide. Loss of mitochondrial membrane potential is a critical step of the death pathway; cariporide prevented mitochondrial membrane potential loss induced by H2O2.Cariporide protects cardiomyocytes against oxidant-induced cell death by preserving intracellular ion homeostasis and mitochondrial integrity.
THE EFFECT OF NITROGEN MUSTARDS ON ENZYMES AND TISSUE METABOLISM
Authors: E. S. Guzman Barron, Grant R. Bartlett, Zelma Baker Miller, Joe Meyer, J. E. Seegmiller
Journal: The Journal of Experimental Medicine (1948)

Nitrogen mustards at a concentration forty times the minimum lethal dose inhibited the respiration of all tissues studied but affected anaerobic glycolysis very little. The inhibiting effect increased with time. The respiration of lymphoid tissue was extremely sensitive to nitrogen mustard, as concentrations below the LD(50) definitely inhibited the respiration of rabbit lymph nodes. In tissue slices nitrogen mustards inhibited the oxidation of pyruvate and of l-amino acids and the utilization of NH(3). A number of synthesis reactions were also inhibited, such as the synthesis of carbohydrate, of creatine, and of urea. When added to growing seeds, nitrogen mustards inhibited their growth. In rats given lethal doses of nitrogen mustards there were found complete inhibition of choline oxidation and strong inhibition of pyruvate oxidation by the kidney and partial inhibition of urea synthesis by the liver. Inhibition of bone marrow respiration by nitrogen mustards was prevented by the addition of choline, and of dimethylaminoethanol plus methionine The possible mechanism of nitrogen mustard intoxication is discussed.
CD8+ T-Cell Content in Diagnostic Lymph Nodes Measured by Flow Cytometry Is a Predictor of Survival in Follicular Lymphoma
Authors: Björn Engelbrekt Wahlin, Birgitta Sander, Birger Christensson, Eva Kimby
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Follicular lymphoma is a heterogeneous disease with variable prognosis and clinical course. We hypothesized that the presence of nonmalignant T cells in the microenvironment of the tumor may affect the outcome. Experimental Design: Using flow cytometry, we evaluated the T-cell subsets in the lymph node microenvironment of follicular lymphoma. All patients in South Stockholm County with indolent follicular lymphoma and with flow cytometry done on a diagnostic lymph node between 1994 and 2004 were included (N = 139). Diagnosis and grade (1, 2, and 3a) were confirmed by re-review. Flow cytometry results were reanalyzed. Lymphocyte subsets, the Follicular Lymphoma International Prognostic Index, grade, and clinical characteristics were evaluated in univariable and multivariable Cox analysis with respect to overall survival (OS) and disease-specific survival (DSS). Results: Higher CD8+ T-cell levels correlated with longer OS and DSS, independently of the Follicular Lymphoma International Prognostic Index (OS, P = 0.017; DSS, P = 0.020) and independently of all other prognostic factors (OS, P = 0.001; DSS, P = 0.004). Median OS was not reached for patients in the upper quarter of CD8+ T-cell levels (&amp;gt;8.6%), 10.4 years for patients in the middle half (4.2-8.6%), and 6.0 years for patients in the lower quarter (&amp;lt;4.2%). Furthermore, patients who had not required treatment within 6 months from diagnosis had more CD8+ T cells (P = 0.011). Conclusions: Higher levels of CD8+ T cells predict a better prognosis, and these data support an important role for nonmalignant immune cells in the biology of follicular lymphoma. Evaluating the CD8+ T cells by flow cytometry at diagnosis may provide prognostic information.
Pneumonia and Respiratory Failure from Swine-Origin Influenza A (H1N1) in Mexico
Authors: Rogelio Perez-Padilla, Daniela de la Rosa-Zamboni, Samuel Ponce de Leon, Mauricio Hernandez, Francisco Quiñones-Falconi, Edgar Bautista, Alejandra Ramirez-Venegas, Jorge Rojas-Serrano, Christopher E. Ormsby, Ariel Corrales, Anjarath Higuera, Edgar Mondragon, Jose Angel Cordova-Villalobos
Journal: New England Journal of Medicine (2009)

In late March 2009, an outbreak of a respiratory illness later proved to be caused by novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. We describe the clinical and epidemiologic characteristics of persons hospitalized for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico City who had laboratory-confirmed S-OIV infection, also known as swine flu.We used retrospective medical chart reviews to collect data on the hospitalized patients. S-OIV infection was confirmed in specimens with the use of a real-time reverse-transcriptase-polymerase-chain-reaction assay.From March 24 through April 24, 2009, a total of 18 cases of pneumonia and confirmed S-OIV infection were identified among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City. More than half of the 18 case patients were between 13 and 47 years of age, and only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the first hospitalization for their illness; the other 2 patients were referred from other hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common findings were an increased creatine kinase level (in 62% of patients) and lymphopenia (in 61%). Twelve patients required mechanical ventilation, and seven died. Within 7 days after contact with the initial case patients, a mild or moderate influenza-like illness developed in 22 health care workers; they were treated with oseltamivir, and none were hospitalized.S-OIV infection can cause severe illness, the acute respiratory distress syndrome, and death in previously healthy persons who are young to middle-aged. None of the secondary infections among health care workers were severe.
Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle
Authors: Lilli Winter, Ilona Staszewska, Eva Mihailovska, Irmgard Fischer, Wolfgang H. Goldmann, Rolf Schröder, Gerhard Wiche
Journal: Journal of Clinical Investigation (2014)

The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD.
Role of mast cells in the pathogenesis of hypersensitivity pneumonitis.
Authors: P Soler, S Nioche, D Valeyre, F Basset, J Benveniste, C Burtin, J P Battesti, R Georges, A J Hance
Journal: Thorax (1987)

To examine the possibility that mast cells have a central role in the pathogenesis of hypersensitivity pneumonitis, 20 patients with this disease were studied with the aim of seeking evidence for mast cell degranulation. The number of mast cells recovered by bronchoalveolar lavage from patients with hypersensitivity pneumonitis was more than 1,000 times greater than those recovered from normal individuals. Furthermore, discontinuation of antigen exposure resulted in an increase in the number of mast cells observed, consistent with the possibility that antigen exposure had induced mast cell degranulation. Cessation of antigen exposure also resulted in a rapid decrease in the number of neutrophils and eosinophils recovered by lavage, followed by an increase in the number of T8+ T lymphocytes present. In each case the time course of the changes was consistent with the possibility that mast cell degranulation had been important in regulating the number of the immune and inflammatory cells present in the lung. Histamine was present in lavage fluid supernatant from patients with hypersensitivity pneumonitis. The amount of histamine present was, however, closely correlated with the number of mast cells present and not with the interval since last antigen exposure. Delay in separating cells from lavage fluid supernatant resulted in an increase in histamine content. These results suggest that the free histamine in lavage fluid resulted from the degranulation of mast cells induced by the lavage procedure as histamine released in vivo has a short half life. We suggest that hypersensitivity pneumonitis results from a "late phase reaction" initiated by antigen induced mast cell degranulation.
Sindbis Virus Usurps the Cellular HuR Protein to Stabilize Its Transcripts and Promote Productive Infections in Mammalian and Mosquito Cells
Authors: Kevin J. Sokoloski, Alexa M. Dickson, Emily L. Chaskey, Nicole L. Garneau, Carol J. Wilusz, Jeffrey Wilusz
Journal: Cell Host & Microbe (2010)