tbuckley/cabot-search huggingface dataset:
Hypoxia induces the release of a pulmonary-selective, Ca2+-sensitising, vasoconstrictor from the perfused rat lung
Authors: T Robertson
Journal: Cardiovascular Research (2001)

Objective: Sustained hypoxic pulmonary vasoconstriction is dependent upon the presence of an intact endothelium, strongly suggesting that an endothelium-derived constrictor factor is involved in this response. In the present study we have attempted to determine whether hypoxia induces the release of a vasoconstrictor(s) from the lung, and whether this vasoconstrictor shares mechanistic features with the hypoxic constrictor response. Methods: The salt-perfused rat lung, coupled with a simple solid-phase extraction process, and a rat intrapulmonary artery functional bioassay were utilised in this study. Results: Hypoxic, but not normoxic, perfusion of the isolated lung of the rat induced the release of a vasoconstrictor(s) which appeared to be selective for pulmonary over mesenteric arteries of the rat. The vasoconstriction observed was unaffected by inhibition of voltage-gated Ca2+ channels, and was not associated with a rise in intracellular [Ca2+], suggesting Ca2+-sensitisation of the contractile apparatus. The vasoconstriction was also unaffected by the protein kinase C (PKC) inhibitor Ro-31-8220, or the endothelin-1 antagonists BQ123/BQ788 but was markedly potentiated in the presence of prostaglandin F2α. Conclusion: We conclude that hypoxic perfusion of the rat lung results in the release of a vasoconstrictor(s) which shares some of the facets of the sustained hypoxic constriction of isolated intrapulmonary arteries of the rat, since it involves PKC-independent Ca2+ sensitisation, is independent of voltage-gated Ca2+ entry, and is potentiated by the presence of preconstriction.
Effect of Glucagon on Cyclic 3',5'-AMP, Phosphorylase Activity and Contractility of Heart Muscle of the Rat
Authors: STEVEN E. MAYER, DONALD H. NAMM, LUCIAN RICE
Journal: Circulation Research (1970)

The purpose of this investigation was to contrast the effect of glucagon and that of epinephrine on the concentration of cyclic adenosine 3',5'-monophosphate (cyclic AMP), the activity of phosphorylase a and the contractile amplitude of isolated perfused rat hearts. The two drugs were about equally effective except that the maximal augmentation of contractility by epinephrine (5 x 10 -9 moles) was twice that produced by an equivalent dose of glucagon with a fourfold greater increase in cyclic AMP concentration. Combination of large doses of the two drugs caused increases in the cyclic nucleotide considerably greater than those required for maximal phosphorylase activation or associated with a maximal inotropic response. The effects of glucagon also developed more slowly than those of epinephrine. An increase in cyclic AMP was not detectable until after phosphorylase a and contractile amplitude had increased. The beta-receptor-blocking agents dichloroisoproterenol and pronethalol did not block the biochemical responses to glucagon in doses which abolished the epinephrine-induced increases in cyclic AMP and phosphorylase a . These results, along with those obtained by other investigators, indicate that glucagon can elicit the same biochemical responses in intact heart as have been obtained with epinephrine, but by action at a different receptor site.
The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers
Authors: Leng Han, Lixia Diao, Shuangxing Yu, Xiaoyan Xu, Jie Li, Rui Zhang, Yang Yang, Henrica M.J. Werner, A. Karina Eterovic, Yuan Yuan, Jun Li, Nikitha Nair, Rosalba Minelli, Yiu Huen Tsang, Lydia W.T. Cheung, Kang Jin Jeong, Jason Roszik, Zhenlin Ju, Scott E. Woodman, Yiling Lu, Kenneth L. Scott, Jin Billy Li, Gordon B. Mills, Han Liang
Journal: Cancer Cell (2015)
Effects of Pioglitazone Versus Diet and Exercise on Metabolic Health and Fat Distribution in Upper Body Obesity
Authors: Samyah Shadid, Michael D. Jensen
Journal: Diabetes Care (2003)

OBJECTIVE—Insulin resistance is associated with visceral adiposity, and interventions that reduce this depot, e.g., diet and exercise, improve insulin resistance. Thiazolidinediones (TZDs) also improve insulin action but paradoxically increase total fat mass, perhaps through remodeling (recruitment of smaller fat cells) and redistribution of adipose tissue. We assessed the effects of pioglitazone versus diet and exercise on fat distribution and the relationship between fat distribution and insulin sensitivity in upper body obesity. RESEARCH DESIGN AND METHODS—Thirty-nine upper body obese, insulin-resistant, nondiabetic men and premenopausal women were randomly assigned to receive either 30 mg/day pioglitazone or a diet and exercise program for 20 weeks. Before and after the intervention, insulin sensitivity, body composition, body fat distribution (waist-to-hip ratio [WHR], computed tomography abdomen, and dual-energy X-ray absorptiometry), and abdominal and femoral fat cell size were assessed. RESULTS—Diet and exercise resulted in an 11.8 ± 1.1 kg weight loss. Both diet and exercise and pioglitazone improved insulin sensitivity, but only the former was associated with loss of intra-abdominal fat. Pioglitazone increased total body fat, which preferentially accumulated in the lower body depot in both men and women. WHRs decreased in both groups. Abdominal fat cell size decreased (P = 0.06) after diet and exercise. No statistically significant changes in fat cell size were observed in pioglitazone-treated volunteers. CONCLUSIONS—In nondiabetic upper body obese subjects, increasing insulin sensitivity via diet and exercise accompanies reductions in visceral fat. Pioglitazone treatment also improves insulin sensitivity and lowers WHR, but this is due to a selective increase in lower body fat. This confirms a site-specific responsiveness of adipose tissue to TZD and suggests that improvements in insulin sensitivity by pioglitazone are achieved independent of changes in intra-abdominal fat.
Induction of IL-8 production in human alveolar macrophages and human bronchial epithelial cells in vitro by swine dust
Authors: L. Palmberg, B.-M. Larsson, P. Malmberg, K. Larsson
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Exposure to swine dust causes an intense airway inflammation with increased levels of interleukin 8 (IL-8) and predominantly neutrophils in the nasal and bronchoalveolar lavage fluids of healthy human subjects. It is not clear which components in the swine house environment are responsible for the airway reaction. The aim of the present study was to evaluate and compare the effect in vitro of swine dust components on human alveolar macrophages and bronchial epithelial cells. <h3>METHODS</h3> Normal human bronchial epithelial cells (NHBE), human pulmonary epithelial carcinoma cell line (A549), and human alveolar macrophages were stimulated with swine dust, lipopolysaccharides (LPS; present in Gram negative bacteria), grain dust (swine feed components), and glucans (a structural component of fungi) in a dose response manner (1–100 μg/ml). <h3>RESULTS</h3> Swine dust at a concentration of 100 μg/ml increased IL-8 production 20 fold in NHBE cells, 28 fold in A549 cells, and 15 fold in macrophages. LPS (100 μg/ml) stimulated all three cell types significantly, in macrophages to the same extent as swine dust, but in NHBE and A549 cells swine dust was 5–8 times as potent. Grain dust (100 μg/ml) had no effect in A549 cells but stimulated NHBE cells and macrophages. Glucans (100 μg/ml) stimulated A549 cells and macrophages but not NHBE cells. Both glucans and grain dust were weaker stimuli than swine dust and LPS. The LPS content of swine dust solution was 2.16 (0.2) ng/100 μg and of grain dust was 0.53 (0.04) ng/100 μg. <h3>CONCLUSIONS</h3> Swine dust is a strong stimulus for IL-8 production in both bronchial epithelial cells and human alveolar macrophages, whereas LPS has different potency in these cells.
Phase II Trial of Sorafenib Combined With Concurrent Transarterial Chemoembolization With Drug-Eluting Beads for Hepatocellular Carcinoma
Authors: Timothy M. Pawlik, Diane K. Reyes, David Cosgrove, Ihab R. Kamel, Nikhil Bhagat, Jean-Francois H. Geschwind
Journal: Journal of Clinical Oncology (2011)

PURPOSE To evaluate safety and efficacy of combined transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS A prospective single-center phase II study was undertaken involving patients with unresectable HCC. The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE. Safety and response were assessed. Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients: mean age, 63 years; Child's A, 89%; Barcelona Clinic Liver Cancer stage C, 64%; Eastern Cooperative Oncology Group performance status of 0 and 1, 46% and 54%, respectively; and mean index tumor size, 7.7 cm (standard deviation, ± 4.2 cm). Patients underwent 128 cycles of therapy (sorafenib plus DEB-TACE, 60 cycles; sorafenib alone, 68 cycles). Median number of cycles per patient was two (range, one to five cycles); median number of days treated with sorafenib was 71 (range, 4 to 620 days). The most common toxicities during cycle one were fatigue (94%), anorexia (67%), alterations in liver enzymes (64%), and dermatologic adverse effects (48%). Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% v grade 3 to 4, 17%). Toxicity during cycle two was decreased. Over the course of the study, there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions. Sorafenib plus DEB-TACE was associated with a disease control rate of 95% (Response Evaluation Criteria in Solid Tumors Group)/100% (European Association for the Study of the Liver [EASL]), with an objective response of 58% (EASL). CONCLUSION The combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. Toxicity is manageable with dose adjustment of sorafenib. Preliminary efficacy data are promising.
Fcγ Receptor–Mediated Phagocytosis in Macrophages Lacking the Src Family Tyrosine Kinases Hck, Fgr, and Lyn
Authors: Cheryl J. Fitzer-Attas, Malcolm Lowry, Mary T. Crowley, Alexander J. Finn, Fanying Meng, Anthony L. DeFranco, Clifford A. Lowell
Journal: The Journal of Experimental Medicine (2000)

Macrophage Fcγ receptors (FcγRs) mediate the uptake and destruction of antibody-coated viruses, bacteria, and parasites. We examined FcγR signaling and phagocytic function in bone marrow–derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn. Many FcγR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal–regulated kinases 1 and 2. Significant reduction of IgG-dependent phagocytosis was not seen in hck−/−fgr−/− or lyn−/− cells, although the single mutant lyn−/− macrophages did manifest signaling defects. Thus, Src family kinases clearly have roles in two events leading to FcγR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization. Since FcγR-mediated phagocytosis did occur at modest levels in a delayed fashion in triple mutant macrophages, these Src family kinases are not absolutely required for uptake of IgG-opsonized particles.
Regulation of lutropin circulatory half-life by the mannose/N-acetylgalactosamine-4-SO4 receptor is critical for implantation in vivo
Authors: Yiling Mi, Steven D. Shapiro, Jacques U. Baenziger
Journal: Journal of Clinical Investigation (2002)

Lutropin (LH) directs ovulation and implantation by regulating the production of estrogen and progesterone. We have shown that the circulatory half-life of LH is controlled by the Man/GalNAc-4-SO4 receptor, which binds GalNAc-4-SO4 on LH oligosaccharides. The short half-life in conjunction with episodic release of LH from the pituitary accounts for the pulsatile rise and fall in circulating LH. Complete genetic ablation of the Man/GalNAc-4-SO4 receptor results in death in utero. Heterozygous female mice clear LH from the circulation more slowly and have smaller litters due to a reduction in the rate of implantation. This reduction is fully correctable by exogenous progesterone and estrogen, indicating that the rate of LH clearance is critical for the production of sufficient progesterone and estrogen for implantation. Thus, the Man/GalNAc-4-SO4 receptor regulates the endocrinological status of the female and is essential for an early event in embryonic development.
Night Shift Work, Light at Night, and Risk of Breast Cancer
Authors: S Davis, D K Mirick, R G Stevens
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Exposure to light at night may increase the risk of breast cancer by suppressing the normal nocturnal production of melatonin by the pineal gland, which, in turn, could increase the release of estrogen by the ovaries. This study investigated whether such exposure is associated with an increased risk of breast cancer in women. Methods: Case patients (n = 813), aged 20–74 years, were diagnosed from November 1992 through March 1995; control subjects (n = 793) were identified by random-digit dialing and were frequency matched according to 5-year age groups. An in-person interview was used to gather information on sleep habits and bedroom lighting environment in the 10 years before diagnosis and lifetime occupational history. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of conditional logistic regression, with adjustment for other potential risk factors. Results: Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when melatonin levels are typically at their highest (OR = 1.14 for each night per week; 95% CI = 1.01 to 1.28). Risk did not increase with interrupted sleep accompanied by turning on a light. There was an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk (OR = 1.6; 95% CI = 1.0 to 2.5), with a trend of increased risk with increasing years and with more hours per week of graveyard shiftwork (P = .02, Wald chi-squared test). Conclusion: The results of this study provide evidence that indicators of exposure to light at night may be associated with the risk of developing breast cancer.
The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation
Authors: Nicole Salazar, Daniel Muñoz, Georgios Kallifatidis, Rajendra K Singh, Mercè Jordà, Bal L Lokeshwar
Journal: Molecular Cancer (2014)

Recent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. The CXC chemokine receptor-7 (CXCR7) is the latest chemokine receptor implicated in cancer. Although over expressed in breast cancer cell lines and tumor tissues, its mechanism of action in breast cancer (BrCa) growth and metastasis is unclear. Studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The present study was initiated to examine the pattern of CXCR7 expression and its role in regulation of growth signaling in breast cancer.The contribution of CXCR7 in BrCa cell proliferation was investigated in representative cell lines using real time quantitative PCR (q-PCR), proliferation assays, immunohistochemistry and immunoblotting. Phenotypic changes were examined after CXCR7 specific cDNA and siRNA transfection and expression levels were monitored by q-PCR. Further, the association of CXCR7 with epidermal growth factor receptor (EGFR) and modulation of its activity were investigated by western blotting, immunofluorescence, and in-situ proximity ligation assays in human BrCa cells and tissues.CXCR7 was expressed in both, estrogen receptor (ER) positive and negative BrCa cell lines. CXCR7 was also expressed unevenly in normal breast tissues and to a much higher extent in ER + cancer tissues. Depletion of CXCR7 in MCF7 BrCa cells by RNA interference decreased proliferation and caused cell cycle arrest. Further, proximity ligation assay (PLA) revealed colocalization of CXCR7 with EGFR in cancer tissues and cancer cell lines. CXCR7 depletion reduced levels of phospho-EGFR at Tyrosine1110 after EGF-stimulation and also reduced phosphorylation of ERK1/2, indicating a potentially direct impact on mitogenic signaling in MCF7 cells. Using siRNA to knockdown β-arrestin2 in cells with EGFR over expression we were able to nearly deplete the CXCR7-EGFR colocalization events, suggesting that β-arrestin2 acts as a scaffold to enhance CXCR7 dependent activation of EGFR after EGF stimulation.These results demonstrate coupling of CXCR7 with EGFR to regulate proliferation of BrCa cells and suggest an important ligand-independent role of CXCR7 in BrCa growth. Thus, the CXCR7-EGFR axis is a promising target for breast cancer therapy.
Chronic lactic acidosis in a patient with acquired immunodeficiency syndrome and mitochondrial myopathy
Authors: R Gopinath, M Hutcheon, S Cheema-Dhadli, M Halperin
Journal: Journal of the American Society of Nephrology (1992)

A 30-yr-old man with acquired immunodeficiency syndrome treated with zidovudine developed biopsy-proven mitochondrial myopathy. Chronic lactic acidosis (lactate, 10 +/- 1 mmol/L) persisted for more than 5 wk. Liver function tests were normal, but the concentration of lactose rose to 16.1 mmol/L when 500 mmol of ethanol was infused. The concentration of lactose rose by only 1.5 mmol/L with maximally tolerated exercise. If this mitochondrial lesion compromised flux through the electron transport system, increased turnover of ATP with exercise should have exacerbated the degree of lactic acidosis because of increased need to regenerate ATP via glycolysis. Two possible explanations will be discussed: first, there was both a rapid rate of production of lactic acid in affected muscles in conjunction and an equally rapid rate of removal by uninvolved organs. Second, there was a low net rate of production of lactic acid in involved muscles despite the exercise.
THE INHERITANCE OF THE PROTEIN AND NUCLEIC ACID CHARACTERISTICS OF T2 AND T6 BACTERIOPHAGE
Authors: Margeris A. Jesaitis
Journal: The Journal of Experimental Medicine (1965)

A study of the immunological properties of phage strains derived from T2 x T6 crosses revealed that the majority of the progeny differ serologically from the parental viruses. Some hybrids were found to contain head membranes having the serological specificity of both T2 and T6 phages, while others contained tail sheaths of the former and the tail fibers of the latter. Since the immunological properties of all hybrids were heritable, it has been concluded that the serological specificity of the head proteins of T2 and T6 is controlled by at least two genetic determinants, and that the specificities of the fiber and sheath proteins may be governed by single genes. Furthermore it was found that nucleic acids of hybrids had similar proportions of unsubstituted, mono- and diglucosylated hydroxymethylcytosine nucleotides to the nucleic acid of either T2 or T6 phage. Since the parental and hybrid viruses having chemically similar nucleic acids contained in some instances serologically different proteins, it has also been concluded that the extent of glucosylation of the hydroxymethylcytosine component of viral nucleic acids and the immunological properties of viral proteins are independently heritable traits of T2 and T6 bacteriophages.
Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia
Authors: Mahboobeh Mahdavinia, Lydia A. Suh, Roderick G. Carter, Whitney W. Stevens, James E. Norton, Atsushi Kato, Bruce K. Tan, Robert C. Kern, David B. Conley, Rakesh Chandra, Jennifer Lavin, Anju T. Peters, Leslie C. Grammer, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2014)
Auricular chondritis in NOD.DQ8.Aβo (Ag7–/–) transgenic mice resembles human relapsing polychondritis
Authors: Veena Taneja, Marie Griffiths, Marshall Behrens, Harvinder S. Luthra, Chella S. David
Journal: Journal of Clinical Investigation (2003)

Relapsing polychondritis is a multisystem autoimmune disease involving cartilage destruction but no known causative antigen. HLA-DQ8 has been associated with various autoimmune diseases in humans. To study the role of DQ8 in autoimmune diseases, we have generated transgenic mice expressing DQ8 (DQA1*0301, DQB1*0302) in a NOD background lacking endogenous class II molecules (Aβo). Upon immunization with type II collagen (CII), 85% of NOD.DQ8 mice develop severe experimental polychondritis, auricular chondritis, and polyarthritis, with clinical and histological similarities to relapsing polychondritis (RP) in humans. CII-immunized mice mount a T cell response and produce Ab's to type IX collagen (CIX) and self-CII. Transgene-negative littermates do not develop any serological and clinical manifestations following immunization. B10.DQ8 transgenic mice develop polyarthritis and Ab's to CII only. The susceptibility to auricular chondritis in NOD.DQ8 mice can be attributed to response to CIX. A higher number of activated cells, CD4+CD44hiCD62Llo, and lower regulatory cells CD4+CD152+CD25+ were observed in NOD.DQ8 mice compared with B10.DQ8 mice. The NOD.DQ8 mice provide a model of RP with a high disease incidence and multiple organ involvement to investigate putative autoantigen and regulatory cells involved in disease pathogenesis. An experimental model restricted by the human class II molecule will be valuable when studying the role of various collagens in immunologic and pathologic responses in human RP.
Importance of the Stress Kinase p38α in Mediating the Direct Cytotoxic Effects of the Thalidomide Analogue, CPS49, in Cancer Cells and Endothelial Cells
Authors: Noel A. Warfel, Erin R. Lepper, Chunyu Zhang, William D. Figg, Phillip A. Dennis
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Thalidomide has gained renewed interest as a cancer therapeutic due to its potential antiangiogenic effects. The thalidomide analogues CPS11 and CPS49 are active in preclinical angiogenesis assays and xenograft model systems, but the biochemical basis for these observations is unclear. Experimental Design: To address this question, we assessed the toxicity of these thalidomide analogues in cancer cells, endothelial cells, and genetically modified cells using assays that measure apoptotic and nonapoptotic cell death. Phosphospecific and native antibodies were used in immunoblotting and immunohistochemical experiments to assess the activation states of kinases that control cellular survival in vitro and in vivo. Results: CPS49 predominantly induced nonapoptotic cell death in lung cancer cells, prostate cancer cells, and endothelial cells in a dose-dependent manner, whereas CPS11 was not cytotoxic. CPS49 did not inhibit kinases that promote survival, such as Akt or extracellular signal-regulated kinase, but rather rapidly activated the stress kinase p38 pathway in both cancer cells and endothelial cells. CPS49 activated p38 in tumor xenografts. Using p38α−/− cells or an inhibitor of p38, we show that the presence and activation of p38α is important for cytotoxicity in all cell types examined. Conclusions: Our studies identify a unifying mechanism of action for cytotoxicity of the tetraflourinated thalidomide analogue, CPS49, and suggest that activation of p38 could serve as a biomarker in clinical trials with CPS49.
Beclometasone–formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial
Authors: Alberto Papi, Massimo Corradi, Catherine Pigeon-Francisco, Roberta Baronio, Zenon Siergiejko, Stefano Petruzzelli, Leonardo M Fabbri, Klaus F Rabe
Journal: The Lancet Respiratory Medicine (2013)