tbuckley/cabot-search huggingface dataset:
Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation
Authors: Matthias Ernst, Melissa Inglese, Paul Waring, Ian K. Campbell, Shisan Bao, Fiona J. Clay, Warren S. Alexander, Ian P. Wicks, David M. Tarlinton, Ulrike Novak, Joan K. Heath, Ashley R. Dunn
Journal: The Journal of Experimental Medicine (2001)

The receptor subunit gp130 transduces multiple cell type-specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130(DeltaSTAT) "knock-in" mutation which deleted all STAT-binding sites. gp130(DeltaSTAT) mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130(DeltaSTAT) mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130(DeltaSTAT) mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.
Effect of concomitant statins on rituximab efficacy in patients with rheumatoid arthritis
Authors: P B Lehane, S Lacey, E W Hessey, A Jahreis
Journal: Annals of the Rheumatic Diseases (2014)

Effect of concomitant statins on rituximab efficacy in patients with rheumatoid arthritisPatients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease.In order to lower this risk, statins are used in clinical practice in addition to biologics. 1 Rituximab, an anti-CD20 antibody approved for the treatment of RA, induces B-cell apoptosis by crosslinking and redistributing CD20 to cholesterol-rich lipid rafts. 2 Statins have been shown in vitro to induce conformational changes on the CD20 epitope, potentially influencing the apoptotic effect of rituximab. 3here are conflicting reports about the effect of statins on the clinical efficacy of rituximab in RA. [4][5][6] We investigated the impact of statin coadministration on rituximab efficacy in patients from a global clinical trial programme in RA.This was a retrospective, pooled, observed case analysis from four placebo-controlled phase II/III randomised clinical trials (DANCER, REFLEX, SERENE and IMAGE) 7-10 in patients with moderate-to-severe active RA.All patients received concomitant methotrexate 10-25 mg/week at a stable dose and were permitted to receive stable background doses of oral corticosteroids (prednisolone ≤10 mg/day or equivalent) and non-steroidal antiinflammatory drugs throughout.Efficacy responses (change in Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR) from baseline, American College of Rheumatology 20% or 50% (ACR20/50) response) and and peripheral blood CD19+ B-cell counts at 24 weeks following one course of rituximab were compared between patients who received concomitant statins for ≥8 weeks ('statins', STY) and those who received statins for <8 weeks or not at all ('no statins', STN).Differences in outcome measures between STN and STY groups were tested using either an analysis of covariance model for continuous 1906
Immune Monitoring of T-Cell Responses in Cancer Vaccine Development
Authors: Ulrich Keilholz, Peter Martus, Carmen Scheibenbogen
Journal: Clinical Cancer Research (2006)

Abstract Monitoring cellular immune responses is one prerequisite for rational development of cancer vaccines. The primary objective of immune monitoring is to determine the efficacy of a vaccine to induce or augment a specific T-cell response. Further questions relate to the prevalence and functional relevance of spontaneous tumor-directed immune responses, the functional characteristics of T-cell responses, and, finally and most importantly, the relationship between immune monitoring assay results and clinical end points. The issue of T-cell monitoring has become more complex as different types and generations of assays have been adopted during the past decade and both standardization and validation of assays have often been insufficient. Because the development of assays parallel the clinical development of cancer vaccines, technical advances have been achieved simultaneously with broadening understanding of cancer immunity. Suitable animal models for immune monitoring are, however, lacking, because preclinical vaccine development in rodents does not allow serial immune monitoring of the peripheral blood, as is commonly used in patients. The current situation is characterized by a lack of universal standards for T-cell assessment, uncertainty about the association between immune monitoring assay results and clinical antitumor end points, and lack of knowledge regarding the contribution of different aspects of T-cell function to clinical efficacy. It is acknowledged that T-cell monitoring will have to be validated in large trials with clinically effective vaccines, but this necessity should not discourage the current application of novel assays within clinical trials of all stages.
Two-Dimensional Differential In-Gel Electrophoresis Proteomic Approaches Reveal Urine Candidate Biomarkers in Pediatric Obstructive Sleep Apnea
Authors: David Gozal, Saeed Jortani, Ayelet B. Snow, Leila Kheirandish-Gozal, Rakesh Bhattacharjee, Jinkwan Kim, Oscar Sans Capdevila
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Sleep studies are laborious, expensive, inaccessible, and inconvenient for diagnosing obstructive sleep apnea (OSA) in children.
Comparing the effects of oxidative stress on mitochondrial function and antiviral responses in primary bronchial epithelial cells of asthmatics and non-asthmatics
Authors: Faezeh Fathi Aghdam, Lisa Wood, Alan Hsu, Kristy Parsons, Simon Keely, Peter Wark
Journal: European Respiratory Journal (2014)

Background:  Asthma has been associated with an increase in reactive oxidant species(ROS) in the airways. ROS are known to affect mitochondrial function and this may impact on bronchial epithelial cell responses, including antiviral responses to rhinovirus(RV) infection.   AIM:  To compare mitochondrial function and antiviral responses in primary bronchial epithelial cells(pBECs) to RV infection from asthmatics and healthy controls(HC).   METHODS:  pBECs from asthmatics and healthy subjects were infected with RV at an MOI of 1 and were then treated with 1% CSE and 0.2mM H 2 O 2 . CXCL10, CXCL8, interferon (IFN)- λ, cytochrome c and 8-isoprostane were measured by ELISA. ATP levels were measured by bioluminescent assay. Mitochondrial transcription factors (mTFA, mTB1 and mTB2) were measured by RT-PCR. Viral replication was measured by TCID50.   RESULTS:  Treatment with CSE and H 2 O 2  resulted in ROS-induced mitochondrial damage; with increased expression of mitochondrial transcription factors, release of cytochrome-C and 8-isoprostane which were more significant in asthmatics. Treatment with CSE/H 2 O 2  followed by RV infection further increased mTFA expression, extracellular ATP and cytochrome-C release in asthmatics. Also in asthmatics, there was a marked reduction in antiviral responses; CXCL-10 and IFN- λ release, but there was an increase in CXCL8 release. In the case of CSE and H 2 O 2 , there was an increase in RV replication which was only seen in asthmatics.   CONCLUSION:  Asthmatic pBECs are more sensitive to the effects of ROS, demonstrating an impaired mitochondrial response, and leading to impaired antiviral response to RV infection.
Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis
Authors: Motoaki Miyazono, Daling Zhu, Raphael Nemenoff, Elizabeth R. Jacobs, Ethan P. Carter
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA2 expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA2 enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA2 in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion. E-mail: [email protected]
Effect of fruit and vegetable intake on oxidative stress and inflammation in COPD: a randomised controlled trial
Authors: Francina R. Baldrick, J. Stuart Elborn, Jayne V. Woodside, Katherine Treacy, Judy M. Bradley, Chris C. Patterson, Bettina C. Schock, Madeleine Ennis, Ian S. Young, Michelle C. McKinley
Journal: European Respiratory Journal (2011)

Epidemiological evidence supports a positive relationship between fruit and vegetable (FV) intake, lung function and chronic obstructive pulmonary disease (COPD). Increasing FV intake may attenuate the oxidative stress and inflammation associated with COPD. An exploratory randomised controlled trial to examine the effect of increased consumption of FV on oxidative stress and inflammation in moderate-to-severe COPD was conducted. 81 symptomatically stable patients with a habitually low FV intake (two or fewer portions of FV per day) were randomised to the intervention group (five or more portions of FV per day) or the control group (two or fewer portions of FV per day). Each participant received self-selected weekly home deliveries of FV for 12 weeks. 75 participants completed the intervention. There was a significant between-group change in self-reported FV intake and biomarkers of FV intake (zeaxanthin (p=0.034) and β-cryptoxanthin (p=0.015)), indicating good compliance; post-intervention intakes in intervention and control groups were 6.1 and 1.9 portions of FV per day, respectively. There were no significant changes in biomarkers of airway inflammation (interleukin-8 and myeloperoxidase) and systemic inflammation (C-reactive protein) or airway and systemic oxidative stress (8-isoprostane). This exploratory study demonstrated that patients with moderate-to-severe COPD were able to comply with an intervention to increase FV intake; however, this had no significant effect on airway or systemic oxidative stress and inflammation.
Oncogenic Role of <i>miR-483-3p</i> at the <i>IGF2/483</i> Locus
Authors: Angelo Veronese, Laura Lupini, Jessica Consiglio, Rosa Visone, Manuela Ferracin, Francesca Fornari, Nicola Zanesi, Hansjuerg Alder, Gemma D'Elia, Laura Gramantieri, Luigi Bolondi, Giovanni Lanza, Patrizia Querzoli, Adriano Angioni, Carlo M. Croce, Massimo Negrini
Journal: Cancer Research (2010)

Abstract hsa-mir-483 is located within intron 2 of the IGF2 locus. We found that the mature microRNA (miRNA) miR-483-3p is overexpressed in 100% of Wilms' tumors. In addition, colon, breast, and liver cancers exhibit high or even extremely high levels of miR-483-3p in ∼30% of the cases. A coregulation with IGF2 mRNA was detected, although some tumors exhibited high expression of miR-483-3p without a concomitant increase of IGF2. These findings suggested that miR-483-3p could cooperate with IGF2 or act as an autonomous oncogene. Indeed, here we prove that an anti-miRNA oligonucleotide against miR-483-3p could inhibit the miRNAs without affecting IGF2 mRNA and it could suppress tumorigenicity of HepG2 cells, a cell line that overexpresses miR-483-3p and IGF2. Conversely, no antitumor effect was elicited by inhibition of IGF2. The oncogenic mechanism of miR-483-3p was at least partially clarified by the finding that it could modulate the proapoptotic protein BBC3/PUMA and miR-483-3p enforced expression could protect cells from apoptosis. Our results indicate that miR-483-3p could function as an antiapoptotic oncogene in various human cancers and reveal a new, potentially important target for anticancer therapy. Cancer Res; 70(8); 3140–9. ©2010 AACR.
Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease
Authors: Shmuel Fuchs, Lowell F Satler, Ran Kornowski, Petros Okubagzi, Giora Weisz, Richard Baffour, Ron Waksman, Neil J Weissman, Manuel Cerqueira, Martin B Leon, Stephen E Epstein
Journal: Journal of the American College of Cardiology (2003)
Evidence for Early Central Nervous System Involvement in the Acquired Immunodeficiency Syndrome (AIDS) and Other Human Immunodeficiency Virus (HIV) Infections
Authors: IGOR GRANT
Journal: Annals of Internal Medicine (1987)

Although a high prevalence of central nervous system disease is seen in persons with the acquired immunodeficiency syndrome (AIDS), the natural history of brain involvement with human immunodeficiency virus (HIV) remains poorly understood. Neuropsychologic evaluations of 55 ambulatory homosexual men revealed abnormalities in 13 of 15 with AIDS, 7 of 16 with AIDS-related complex, 7 of 13 with HIV-seropositivity only, and 1 of 11 with HIV-seronegativity. Common neuropsychologic problems included impaired abstracting ability, learning difficulties, and slowed speed of information processing. Magnetic resonance imaging had abnormal findings in 9 of 13 patients with AIDS and 5 of 10 patients with AIDS-related complex who were available for scans. The commonest abnormalities were sulcal and ventricular enlargement and bilateral patchy areas of high signal intensity in the white matter. We postulate that central nervous system involvement by HIV may begin early in the course of AIDS and cause mild cognitive deficits in otherwise asymptomatic persons.
Serotonin as an alternative transmitter in sympathetic nerves of large cerebral arteries of the rabbit.
Authors: A Saito, T J Lee
Journal: Circulation Research (1987)

The distribution of serotonin (5-HT)-like immunoreactive (5-HT-LI) nerves and the potential role of 5-HT as a vasoconstrictor transmitter in large cerebral arteries of the rabbit were examined. 5-HT-LI fibers with weak immunofluorescence were observed in the anterior cerebral, middle cerebral, and basilar arteries when fixed by immersion after dissection from exsanguinated animals. The 5-HT-LI fibers, however, were not detected in these arteries when fixed either in vitro or in situ after first being perfused with Krebs solution in situ to flush the blood component from the lumen prior to dissection. In these arteries, 5-HT-LI nerve fibers with intense immunofluorescence, however, reappeared following incubation with 5-HT in vitro. The intensity of the 5-HT-LI fibers seemed to be proportional to the duration and 5-HT concentration during incubation. Following chronic surgical sympathectomy, 5-HT-LI fibers were not detected in arteries before or after incubation with 5-HT. Transmural nerve stimulation elicited constriction in 50% of the control arterial segments examined. The constriction was not affected by ketanserin but was prevented by guanethidine and chronic surgical sympathectomy. The remaining arterial segments that did not respond on transmural nerve stimulation, however, became constrictive on transmural nerve stimulation following incubation with 5-HT in vitro. The constriction was blocked by ketanserin and clonidine. These results demonstrate that the large cerebral artery of the rabbit brain has extremely sparse or no authentic 5-HT-LI nerves.(ABSTRACT TRUNCATED AT 250 WORDS)
Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial Comparing Adjuvant Interferon Alfa and Isotretinoin With Interferon Alfa Alone in Stage IIA and IIB Melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group
Authors: Erika Richtig, H. Peter Soyer, Martin Posch, Ulrike Mossbacher, Peter Bauer, Ligia Teban, Gerhard Svolba, Ingrid H. Wolf, Peter Fritsch, Bernhard Zelger, Beatrix Volc-Platzer, Walter Gebhart, Paul Mischer, Andreas Steiner, Wolf Pachinger, Helmut Hintner, Friedrich Gschnait, Klemens Rappersberger, Peter Pilarski, Hubert Pehamberger
Journal: Journal of Clinical Oncology (2005)

Purpose The combination of interferon alfa (IFNα) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNα alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNα and isotretinoin compared with IFNα alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. Patients and Methods In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNα and isotretinoin (isotretinoin group; 206 patients) or IFNα and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNα was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients ≤ 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. Results A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. Conclusion The addition of isotretinoin to an adjuvant treatment of low-dose IFNα in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.
PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell–expressed ecto-NTPDases
Authors: Thomas Weissmüller, Eric L. Campbell, Peter Rosenberger, Melanie Scully, Paul L. Beck, Glenn T. Furuta, Sean P. Colgan
Journal: Journal of Clinical Investigation (2008)

Mucosal diseases are often characterized by an inflammatory infiltrate that includes polymorphonuclear leukocytes (PMNs), monocytes, lymphocytes, and platelets. A number of studies have suggested that the interaction of platelets with leukocytes has an essential proinflammatory role. Here, we examined whether platelets migrate across mucosal epithelium, as PMNs are known to do, and whether platelets influence epithelial cell function. Initial studies revealed that human platelets did not efficiently transmigrate across human epithelial cell monolayers. However, in the presence of human PMNs, platelet movement across the epithelium was proportional to the extent of PMN transmigration, and strategies that blocked PMN transmigration diminished platelet movement. Furthermore, platelet-PMN comigration was observed in intestinal tissue derived from human patients with inflammatory bowel disease (IBD). The translocated platelets were found to release large quantities of ATP, which was metabolized to adenosine via a 2-step enzymatic reaction mediated by ecto-nucleotidases, including CD73 and ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases), expressed on the apical membrane of the intestinal epithelial cells. In vitro studies and a mouse model of intestinal inflammation were employed to define a mechanism involving adenosine-mediated induction of electrogenic chloride secretion, with concomitant water movement into the intestinal lumen. These studies demonstrate that ecto-NTPDases are expressed on the apical membrane of epithelial cells and are involved in what we believe to be a previously unappreciated function for platelets in the inflamed intestine, which might promote bacterial clearance under inflammatory conditions.
Continuous Home Monitoring of Glucose
Authors: Satish K. Garg, William C. Kelly, Mary K. Voelmle, Peter J. Ritchie, Peter A. Gottlieb, Kim K. McFann, Samuel L. Ellis
Journal: Diabetes Care (2007)

Improving metabolic control reduces micro- and macrovascular complications of diabetes. However, intensive insulin therapy increases severe hypoglycemia more than threefold (1–3). Continuous glucose monitoring (CGM) is being introduced into routine clinical care despite a lack of reimbursement. Registration studies for the Food and Drug Administration (FDA) documented that subjects using real-time CGM improve glucose excursions, reduce variability, decrease time spent in hypoglycemia and hyperglycemia, and improve A1C values (4–9). Despite these reports, there are data unsupportive of new technologies such as CGM (10) or personal digital assistants (11) for reducing hypoglycemia. This study evaluates glucose control and its relationship with glucose target ranges with continuous home monitoring of glucose (CHMG).

Inclusion criteria limited analysis to subjects with A1C values and downloaded CHMG data at baseline and 3 months, as well as software to download receivers (not available for the first 9 months). Patients who were pregnant or planning a pregnancy were excluded.

A total of 24 subjects on CHMG were included in this analysis. All patients in this study used the DexCom STS sensor (DexCoM, San Diego, CA). Subjects were computer matched for baseline A1C (± 0.3%), sex, age, and duration of diabetes except for one subject in the CHMG group, who had diabetes for 57 years. Baseline demographics were similar between groups (Table 1). This protocol was institutional review board approved.

Subjects initiating CHMG attended a session on glucose trends, features of the CHMG …