tbuckley/cabot-search huggingface dataset:
Expression and regulation of gap junctions in rat cholangiocytes
Authors: Hans-Peter Bode, LiFu Wang, Doris Cassio, Fatima M. Leite, Marie V. St-Pierre, Keiji Hirata, Keisuke Okazaki, Marvin L. Sears, Paolo Meda, Michael H. Nathanson, Jean-François Dufour
Journal: Hepatology (2002)

Hepatocytes and other digestive epithelia exchange second messengers and coordinate their functions by communicating through gap junctions. However, little is known about intercellular communication in cholangiocytes. The aim of this study was to examine expression and regulation of gap junctions in cholangiocytes. Connexin expression was determined by confocal immunofluorescence in rat bile ducts and in normal rat cholangiocyte (NRC) cells, a polarized cholangiocyte cell line. Intercellular Ca 2+ signaling was monitored by fluorescent microscopy. Microinjection studies assessed regulation of gap junction permeability in NRC cells and in SKHep1 cells, a liver-derived cell line engineered to express connexin 43. Immunochemistry showed that cholangiocytes from normal rat liver as well as the NRC cells express connexin 43. Localization of apical, basolateral, and tight junction proteins confirmed that NRC cells are well polarized. Apical exposure to ATP induced Ca 2+ oscillations that were coordinated among neighboring NRC cells, and inhibition of gap junction conductance desynchronized the Ca 2+ oscillations. NRC cells transfected with a connexin 43 antisense were significantly less coupled. Transcellular dye spreading was inhibited by activation of protein kinase A or protein kinase C. The same was observed in transfected SKHep1 cells, which expressed only connexin 43. Rat cholangiocytes and NRC cells express connexin 43, which permits synchronization of Ca 2+ signals among cells. Permeability of connexin 43-gap junctions is negatively regulated by protein kinases A and C. In conclusion, cholangiocytes have the capacity for intercellular communication of second messenger signals via gap junctions in a fashion that is under hormonal control.
Hypoxia Induces Near-Native Mechanical Properties in Engineered Heart Valve Tissue
Authors: Angelique Balguid, Anita Mol, Marijke A.A. van Vlimmeren, Frank P.T. Baaijens, Carlijn V.C. Bouten
Journal: Circulation (2009)

Previous attempts in heart valve tissue engineering (TE) failed to produce autologous valve replacements with native-like mechanical behavior to allow for systemic pressure applications. Because hypoxia and insulin are known to promote protein synthesis by adaptive cellular responses, a physiologically relevant oxygen tension and insulin supplements were applied to the growing heart valve tissues to enhance their mechanical properties.Scaffolds of rapid-degrading polyglycolic acid meshes coated with poly-4-hydroxybutyrate were seeded with human saphenous vein myofibroblasts. The tissue-engineered constructs were cultured under normal oxygen tension (normoxia) or hypoxia (7% O(2)) and incubated with or without insulin. Glycosaminoglycan production in the constructs approached that of native values under the influence of hypoxia and under the influence of insulin. Both insulin and hypoxia were associated with enhanced matrix production and improved mechanical properties; however, a synergistic effect was not observed. Although the amount of collagen and cross-links in the engineered tissues was still lower than that in native adult human aortic valves, constructs cultured under hypoxic conditions reached native human aortic valve levels of tissue strength and stiffness after 4 weeks of culturing.These results indicate that oxygen tension may be a key parameter for the achievement of sufficient tissue quality and mechanical integrity in tissue-engineered heart valves. Engineered tissues of such strength, based on rapid-degrading polymers, have not been achieved to date. These findings bring the potential use of tissue-engineered heart valves for systemic applications a step closer and represent an important improvement in heart valve tissue engineering.
OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer
Authors: Yi Zhou, Jiangxue Wu, Xiang Fu, Wuying Du, Ling Zhou, Xiangqi Meng, Hongyan Yu, Jiaxin Lin, Wen Ye, Jiani Liu, Hui Peng, Ran-yi Liu, Changchuan Pan, Wenlin Huang
Journal: Molecular Cancer (2014)

OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) is a deubiquitinating enzyme (DUB) that belongs to the OTU (ovarian tumor) superfamily. The aim of this study was to clarify the role of OTUB1 in colorectal cancer (CRC) and to identify the mechanism underlying its function. Two hundred and sixty CRC samples were subjected to association analysis of OTUB1 expression and clinicopathological variables using immunohistochemical (IHC) staining. Overexpression of OTUB1 was achieved in SW480 and DLD-1 cells, and downregulation of OTUB1 was employed in SW620 cells. Then, migration and invasion assays were performed, and markers of the epithelial-mesenchymal transition (EMT) were analyzed. In addition, hepatic metastasis models in mice were used to validate the function of OTUB1 in vivo. OTUB1 was overexpressed in CRC tissues, and the expression level of OTUB1 was associated with metastasis. A high expression level of OTUB1 was also associated with poor survival, and OTUB1 served as an independent prognostic factor in multivariate analysis. OTUB1 also promoted the metastasis of CRC cell lines in vitro and in vivo by regulating EMT. OTUB1 promotes CRC metastasis by facilitating EMT and acts as a potential distant metastasis marker and prognostic factor in CRC. Targeting OTUB1 may be helpful for the treatment of CRC.
An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients
Authors: Andrew H. Limper, Kenneth S. Knox, George A. Sarosi, Neil M. Ampel, John E. Bennett, Antonino Catanzaro, Scott F. Davies, William E. Dismukes, Chadi A. Hage, Kieren A. Marr, Christopher H. Mody, John R. Perfect, David A. Stevens
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.
Whither Informed Consent?
Authors: Don Harper Mills
Journal: JAMA (1974)

Moderation is necessary in deciding how much to tell patients to ensure valid consents for surgical or other procedures. Since the courts will not tell physicians, except by hindsight, the extent of legally required disclosures, it is necessary to develop a reasonable approach—one that provides patients with sufficient basic information to exercise their right of refusal while, at the same time, offering physicians reasonable legal protection. The groundwork for such a plan has been formulated. (<i>JAMA</i>229:305-310, 1974)
A cell-mediated reaction against glomerular-bound immune complexes.
Authors: A K Bhan, A B Collins, E E Schneeberger, R T McCluskey
Journal: The Journal of Experimental Medicine (1979)

Lewis rats were given a single i.v. injection of soluble immune complexes containing human serum albumin (HSA) and rabbit anti-HSA antibodies, prepared in antigen excess. This resulted in localization of HSA and rabbit gamma globulin (RGG) in glomerular mesangial regions without producing definite histologic changes. 24 h after the injection of immune complexes, groups of these rats received lymph node cells or T-cell preparations from syngeneic donors sensitized to RGG, HSA, or ovalbumin; another group received no cells. All of these groups and a group of normal control rats were given injections of [3H]thymidine at 18, 27, and 44 h. The animals were killed 48 h after the time of cell transfer. In histologic sections, glomerular abnormalities were found only in some of the animals that had received immune complexes and lymph node cells or T-cell populations from donors sensitized to HSA or RGG; the lesions were characterized by focal and segmental increase in cells in mesangial regions. Autoradiographs revealed significantly greater numbers of labeled cells in mesangial regions and glomerular capillaries in the groups that had received immune complexes and cells from HSA- or RGG-sensitized donors than in any of the other groups. Electronmicroscopic studies suggested that the increase in cellularity in mesangial regions resulted from an influx of mononuclear phagocytes. The findings indicate that cell-mediated reactions can be initiated by the interaction between sensitized T lymphocytes and antigens present in immune complexes within mesangial regions.
Basilixmab induction in lung transplant, initial experience from Saudi Arabia
Authors: Basha Khan, Eid Almutairy, Imran Nizami
Journal: European Respiratory Journal (2012)

INDTRODUCTION . About 55% of lung transplant recipients experience acute cellular rejection within the first year after transplant. The number and severity of episodes of acute rejection can be reduced using induction therapy. Basiliximab, a chimeric anti-interleukin-2 monoclonal antibody, has shown safety and efficacy in the prophylaxis of acute solid organ rejection. The aim of our study was to evaluate the frequency and severity of acute cellular rejection in lung transplant patients surviving >30 days after the lung transplant surgery.

Method Retrospective chart review of all the patients transplanted between March 2010 and Jan 2012 and surviving >30 days. All patients recieved the first dose of Basiliximab induction intraoperatively. In some of the patients the second dose was omitted due to donor transmitted pneumonia. In addition all patients received the same triple immunosuppressive therapy as per our protocol. Episode and severity of acute rejection, infective episodes due to bacteria, virus(cmv),fugus were recorded.

RESULT 2O patients underwent lung transplant over a period of 2 year. M:F 9:11. Three patients were excluded due to early postoperative death. Eight patients received full dose (day0,4) [group 1]. Nine patient's recieved only one dose on day (0) [group 2]. In group 1 only 1/8 patients had acute cellular rejection grade ≥ 2, whereas in group 2, 3/9 patients had acute cellular rejection grade ≥ 2.

CONCLUSION Our preliminary study shows basiliximab induction reduces incidence of acute rejection without significantly increasing the risk of CMV and invasive fungal infections.
Restriction of Calpain3 Expression to the Skeletal Muscle Prevents Cardiac Toxicity and Corrects Pathology in a Murine Model of Limb-Girdle Muscular Dystrophy
Authors: Carinne Roudaut, Florence Le Roy, Laurence Suel, Jérôme Poupiot, Karine Charton, Marc Bartoli, Isabelle Richard
Journal: Circulation (2013)

Genetic defects in calpain3 (CAPN3) lead to limb-girdle muscular dystrophy type 2A, a disease of the skeletal muscle that affects predominantly the proximal limb muscles. We previously demonstrated the potential of adeno-associated virus-mediated transfer of the CAPN3 gene to correct the pathological signs in a murine model for limb-girdle muscular dystrophy type 2A after intramuscular and locoregional administrations.Here, we showed that intravenous injection of calpain3-expressing vector in mice can induce mortality in a dose-dependent manner. An anatomopathological investigation revealed large areas of fibrosis in the heart that we related to unregulated proteolytic activity of calpain3. To circumvent this toxicity, we developed new adeno-associated virus vectors with skeletal muscle-restricted expression by using new muscle-specific promoters that include the CAPN3 promoter itself and by introducing a target sequence of the cardiac-specific microRNA-208a in the cassette. Our results show that CAPN3 transgene expression can be successfully suppressed in the cardiac tissue, preventing the cardiac toxicity, whereas expression of the transgene in skeletal muscle reverts the pathological signs of calpain3 deficiency.The molecular strategies used in this study may be useful for any gene transfer strategy with potential toxicity in the heart.
Obstructive sleep apnea and periodontitis among patients attending primary health care setting in Jordan
Authors: Basheer Khassawneh, Rola Al Habashneh, Yousef Khader, Yousef Abu-jamous
Journal: European Respiratory Journal (2012)

Objectives:  To determine the association between periodontitis and the high risk for obstructive sleep apnea (HR-OSA).   Methods:  296 males with a mean (SD) age 40 (8.5) years were enrolled. Participants completed the Berlin questionnaire (BQ) after periodontal examination. Periodontitis was defined as the presence of four or more teeth with one or more sites with pocket depth (PPD) ≥4mm and clinical attachment level (CAL≥ 3mm). OSA risk was assessed using BQ. Scoring positive in two or more categories of Berlin questionnaire was considered HR-OSA.   Results:  Based on the BQ, 15% of patients were considered as at HR-OSA. Patients with HR-OSA showed higher mean score of PPD and CAL compared with those with low risk for obstructive sleep apnea (LR-OSA) (2.35 (0. 69) vs. 1.97(0.34) p=0.000) and (2.95(0.82) vs. 2.12 (0.55) p=0.000, respectively). The extent of periodontitis as assessed by CAL was significantly higher among patients with HR-OSA. Patients with HR-OSA were more likely to have periodontitis (OR = 2.3 (95% CI: 1.03, 5.10)) compared to patients with LR-OSA. Prevalence of periodontitis varies significantly only among patients according to their response to category 1 (37% in those responded positive and 20% in those responded negative (P=0.003). When the OSA variable was replaced by the individual categories (1,2, and 3), patients with positive category 1 (OR2.27, 95% CI: 11.14,4.45) were more likely to have periodontitis compared to patients with negative response.   Conclusions  :  Periodontitis risk in HR-OSA patients doubles that of LR-OSA patients. Habitual snoring was a risk factor for periodontitis. Further studies are needed to clarify this relationship.
Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice
Authors: Christian Sina, Simone Lipinski, Olga Gavrilova, Konrad Aden, Ateequr Rehman, Andreas Till, Andrea Rittger, Rainer Podschun, Ulf Meyer-Hoffert, Robert Haesler, Emilie Midtling, Katrin Pütsep, Michael A McGuckin, Stefan Schreiber, Paul Saftig, Philip Rosenstiel
Journal: Gut (2012)

<h3>Objective</h3> Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (<i>Ctsk<sup>−/−</sup></i>) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. <h3>Design</h3> Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed <i>Ctsk<sup>−/−</sup></i> mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. <h3>Results</h3> Using <i>Ctsk<sup>−/−</sup></i> mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in <i>Ctsk<sup>−/−</sup></i> mice. Rectal administration of recombinant cathepsin K in DSS-treated <i>Ctsk<sup>−/−</sup></i> mice ameliorates the severity of intestinal inflammation. <h3>Conclusion</h3> These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.
Regional variation in appearance of vascular contractile endothelin-B receptors following organ culture
Authors: M Adner
Journal: Cardiovascular Research (1998)

Objective: The aim of this study was to investigate the appearance of contractile endothelin (ET)-B receptors following organ culture in different vascular regions. Method: The contractile responses of vascular smooth muscle induced by ET-1 and the selective ETB receptor agonist sarafotoxin 6c (S6c) were investigated in circular segments representing eight vascular regions in the rat (aorta, femoral artery, mesenteric artery, branch of the mesenteric artery, proximal and distal parts of the caudal artery, femoral and mesenteric veins). To allow the ETB receptor to be expressed, the segments were placed in organ culture for 1 to 5 days. Pharmacological characterisation of the ET receptors was performed in mesenteric arterial segments. All contractile responses were measured in percentage of K+-induced contraction. Results: ET-1 induced strong concentration-dependent contractions of all fresh (not cultured) segments. S6c had negligible effects on all fresh vessels with the exception of the mesenteric vein, where a small contraction was seen. After 1 day of organ culture all tested segments, with the exception of aorta and the proximal part of the caudal artery, showed concentration-dependent contractile responses to S6c which were further augmented after 5 days of culture. The ET-1-induced responses were only slightly affected by organ culture. Contractions induced by S6c were more enhanced in small arteries and veins than in larger arteries. Furthermore, the S6c-induced response was more pronounced in the mesenteric region as compared to the hindlimb. In fresh mesenteric arterial segments FR139317 (ETA receptor antagonist) and bosentan (ETA/ETB receptor antagonist) but not IRL 2500 (ETB receptor antagonist) shifted the ET-1-induced concentration–response curve in parallel to the right. In contrast, after organ culture the S6c-induced concentration–response curves were shifted parallel to the right in the following potency order: IRL 2500>bosentan>FR139317. Conclusion: During normal conditions, the ETA receptor is the dominating mediator of endothelin-induced contraction in eight different vascular regions. Furthermore, this study indicates that most of the vessels have the ability to develop contractile ETB receptors and that this plasticity differs in vascular regions.
Failure of rabbit neutrophils to secrete endogenous pyrogen when stimulated with staphylococci.
Authors: D F Hanson, P A Murphy, B E Windle
Journal: The Journal of Experimental Medicine (1980)

Cells obtained from acute peritoneal exudates in rabbits were separated into neutrophil and mononuclear populations by centrifugation on colloidal silica gradients. When these populations were separately incubated in tissue culture medium in the presence of opsonized Staphylococcus epidermidis, endogenous pyrogen was secreted only by the adherent cells of the mononuclear population. Pyrogen production by neutrophils could not have amounted to as much as 1% of the pyrogen produced by macrophages. When mononuclear cells were added back to purified neutrophils, no pyrogen was produced that could not be accounted for by the number of macrophages added. Rabbit blood cells were similarly fractionated on colloidal silica gradients. Again, endogenous pyrogen was made only by the adherent mononuclear population. The neutrophils isolated on these gradients appeared to be morphologically normal and were 85% viable as judged by dye exclusion. They showed normal random motility. Both blood and exudate neutrophils responded chemotactically to N-formyl Met-Leu-Phe, and blood neutrophils responded chemotactically to zymosan-activated serum. Both kinds of neutrophils phagocytosed zymosan particles and both killed opsonized S. epidermidis in a roller tube system. Both blood and exudate neutrophils showed normal superoxide production when stimulated with opsonized zymosan particles. This evidence suggests that macrophages are the only source of endogenous pyrogens, and that pyrogens secreted by cell populations that are rich in neutrophils are to be attributed to the monocytes or macrophages that they contain.
Monoclonal Antibodies to Six-Transmembrane Epithelial Antigen of the Prostate-1 Inhibit Intercellular Communication <i>In vitro</i> and Growth of Human Tumor Xenografts <i>In vivo</i>
Authors: Pia M. Challita-Eid, Kendall Morrison, Soudabeh Etessami, Zili An, Karen J. Morrison, Juan J. Perez-Villar, Arthur B. Raitano, Xiao-Chi Jia, Jean M. Gudas, Steven B. Kanner, Aya Jakobovits
Journal: Cancer Research (2007)

Abstract Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1–induced intercellular communication in a dose-dependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patient-derived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition. [Cancer Res 2007;67(12):5798–805]