tbuckley/cabot-search huggingface dataset:
Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2
Authors: Chen Wang, Lingfeng Qin, Thomas D. Manes, Nancy C. Kirkiles-Smith, George Tellides, Jordan S. Pober
Journal: The Journal of Experimental Medicine (2014)

Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells (ECs). Here we report that rapamycin pretreatment reduced the ability of TNF-treated ECs to capture T cells under conditions of venular flow. This functional change was caused by inhibition of TNF-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and could be mimicked by knockdown of mammalian target of rapamycin (mTOR) or rictor, but not raptor, implicating mTORC2 as the target of rapamycin for this effect. Mechanistically, mTORC2 acts through Akt to repress Raf1-MEK1/2-ERK1/2 signaling, and inhibition of mTORC2 consequently results in hyperactivation of ERK1/2. Increased ERK1/2 activity antagonizes VCAM-1 expression by repressing TNF induction of the transcription factor IRF-1. Preventing activation of ERK1/2 reduced the ability of rapamycin to inhibit TNF-induced VCAM-1 expression. In vivo, rapamycin inhibited mTORC2 activity and potentiated activation of ERK1/2. These changes correlated with reduced endothelial expression of TNF-induced VCAM-1, which was restored via pharmacological inhibition of ERK1/2. Functionally, rapamycin reduced infiltration of leukocytes into renal glomeruli, an effect which was partially reversed by inhibition of ERK1/2. These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target.
Important Role of Erythropoietin Receptor to Promote VEGF Expression and Angiogenesis in Peripheral Ischemia in Mice
Authors: Makoto Nakano, Kimio Satoh, Yoshihiro Fukumoto, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa
Journal: Circulation Research (2007)

We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR(-/-)-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR(-/-)-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR(-/-)-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR(-/-)-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR(-/-)-rescued mice that had been transplanted with WT-BM or EpoR(-/-)-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR(-/-)-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
THE BEHAVIOR OF ELASTIC TISSUE IN THE POSTFETAL OCCLUSION AND OBLITERATION OF THE DUCTUS ARTERIOSUS (BOTALLI) IN SUS SCROFA
Authors: J. Parsons Schaeffer
Journal: The Journal of Experimental Medicine (1914)

A study of the histogenesis of elastic tissue in the embryonic ductus arteriosus of Sus scrofa is in accord with the theory that elastic fibrils are directly differentiated in the outlying portion of the protoplasm of the early connective tissue cell. In the occlusion of the postfetal ductus arteriosus of Sus scrofa there is early a hypertrophy of the internal elastic membrane. Subsequently there takes place a marked delamination of the thickened internal elastic membrane in the production of new and independent elastic fibers and lamellae. The formation of new elastic fibers from preformed elastic tissue is most abundant where the postfetal contraction of the ductus arteriosus is least marked. These new elastic fibers play an important part in the occlusion of the lumen of the postfetal ductus. Aside from the extensive formation of elastic fibers from preformed elastic tissue, in the occlusion of the lumen of the postfetal ductus arteriosus of Sus scrofa, there are also some elastic fibrils formed from non-elastic elements, apparently from connective tissue cells. In some recent preliminary work on ligations of the common carotid artery there was found, after an interval of from eight to twelve days, at some points between the ligatures, a slight but obvious cellular thickening of the so-called subendothelial stratum. Some of these connective tissue cells may have wandered from the other coats of the vessel, through the inner elastic membrane into the subendothelial stratum; others may have proliferated from cells in situ. Specific stains revealed near the periphery of some of these cells, i. e., in the outlying portion of the exoplasm, very delicate elastic fibrils, apparently the product of protoplasmic activity.
THE ASSOCIATION OF LUPUS ERYTHEMATOSUS AND PORPHYRIA
Authors: G. W. HETHERINGTON, R. L. JETTON, JOH. M KNOX
Journal: British Journal of Dermatology (1970)

SUMMARY.— Two cases of chronic discoid lupus erythematosus associated with porphyria cutanea tarda are described and the literature on this association is reviewed. The coexistence of these 2 conditions may be fortuitous or may be determined by some unknown mechanism. Since both conditions may present clinically as photosensitivity, one may conceal the presence of the other if their possible association is not considered.
Epigenetic Inactivation of microRNA-34b/c Predicts Poor Disease-Free Survival in Early-Stage Lung Adenocarcinoma
Authors: Ernest Nadal, Guoan Chen, Marc Gallegos, Lin Lin, Daysha Ferrer-Torres, Anna Truini, Zhuwen Wang, Jules Lin, Rishindra M. Reddy, Roger Llatjos, Ignacio Escobar, Juan Moya, Andrew C. Chang, Felipe Cardenal, Gabriel Capellà, David G. Beer
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The microRNA-34b/c (miR-34b/c) is considered a tumor suppressor in different tumor types and a transcriptional target of TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in patients with early-stage lung adenocarcinoma and to determine the functional role of miR-34b/c re-expression in lung adenocarcinoma cell lines. Experimental Design: Aberrant methylation and expression of miR-34b/c were assessed in 15 lung adenocarcinoma cell lines and a cohort of 140 early-stage lung adenocarcinoma. Lung adenocarcinoma cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion, and apoptosis were investigated. Results: Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung adenocarcinoma cell lines and 64 of 140 (46%) primary lung adenocarcinoma. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially with TP53 mutations. Patients with increased miR-34b/c methylation had significantly shorter disease-free and overall survival as compared to patients with unmethylated or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung adenocarcinoma cell lines decreased cell proliferation, migration, and invasion. Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in patients with early-stage lung adenocarcinoma. Reexpression of miR-34b/c leads to a less aggressive phenotype in lung adenocarcinoma cell lines. Clin Cancer Res; 19(24); 6842–52. ©2013 AACR.
Successful Treatment of Postchemotherapy Azoospermia With Microsurgical Testicular Sperm Extraction: The Weill Cornell Experience
Authors: Wayland Hsiao, Peter J. Stahl, E. Charles Osterberg, Edward Nejat, Gianpiero D. Palermo, Zev Rosenwaks, Peter N. Schlegel
Journal: Journal of Clinical Oncology (2011)

Purpose Advances in chemotherapy have led to greater longevity and paternity may be an important consideration for postchemotherapy survivors of childhood cancers. While traditionally considered sterile, men who are azoospermic after chemotherapy can be treated with microdissection testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). Patients and Methods Oncologic data, pretreatment hormone profiles, testicular histology, and outcomes of microdissection TESE-ICSI were reviewed. ICSI was performed in a programmed in vitro fertilization cycle using fresh spermatozoa. Embryos were transferred into the uterine cavity on the third day after microinjection. Results Eighty-four microdissection TESE procedures were performed in 73 patients. The mean time elapsed since chemotherapy was 18.6 years (range, 1 to 34 years). Spermatozoa were retrieved in 37% of patients and in 42.9% of overall procedures. A 57.1% fertilization rate (per injected oocyte) was achieved with ICSI allowing a 50% clinical pregnancy rate with a live birth rate of 42% overall. There were 15 deliveries, with a total of 20 children born. Hypospermatogenesis seen on preoperative biopsy was associated with 100% sperm retrieval while exposure to alkylating agents resulted in a significantly lower sperm retrieval rate. Patients with testicular cancer had the highest sperm retrieval rates while patients previously treated for sarcoma had the lowest retrieval rates. Conclusion To our knowledge, this represents the largest series of postchemotherapy microdissection TESE-ICSI to date. Sperm were retrieved in 37% of patients despite a prevalence of Sertoli cell–only pattern on preoperative biopsy. Although prechemotherapy sperm cryopreservation is recommended, treatment with microdissection TESE and ICSI are effective treatment options for many azoospermic men after chemotherapy.
Cigarette smoke extract reduces VEGF in primary human airway epithelial cells
Authors: J. V. Thaikoottathil, R. J. Martin, J. Zdunek, A. Weinberger, J. G. Rino, H. W. Chu
Journal: European Respiratory Journal (2009)

Reduced vascular endothelial growth factor (VEGF) has been reported in bronchoalveolar lavage fluid and lungs of severe emphysema patients. Airway epithelial cells (AEC) are exposed to various environmental insults like cigarette smoke and bacterial infections, but their direct effect on VEGF production in well-differentiated primary human AEC remains unclear. The current authors determined the effect of cigarette smoke extract (CSE) alone and in combination with Mycoplasma pneumoniae (Mp) on VEGF production in well-differentiated primary normal human bronchial epithelial (NHBE) and small airway epithelial cells (SAEC) in air-liquid interface cultures. Secretion and expression of VEGF were determined by ELISA and real-time RT-PCR, respectively. Cell growth, apoptosis, extracellular signal-regulated kinase (ERK)1/2 and protein kinase (PK)C signalling pathways were evaluated to further dissect VEGF regulation under CSE treatment. CSE significantly reduced VEGF secretion in NHBE and SAEC. In SAEC, Mp alone significantly increased the VEGF, while the presence of CSE attenuated Mp-induced VEGF production. While ERK inhibitor reduced VEGF secretion only in NHBE, a PKC inhibitor significantly decreased VEGF secretion in both NHBE and SAEC. In conclusion, direct cigarette smoke extract exposure significantly reduced vascular endothelial growth factor production in well-differentiated primary human airway epithelial cells, in part through modifying extracellular signal-regulated kinase 1/2 and protein kinase C signalling pathways.
Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women
Authors: T P Ng
Journal: Thorax (2001)

Previous studies have not found a consistent association between exposure to domestic cooking using gas appliances and exacerbation of asthma. We investigated the immediate airflow response to acute exposure from single episodes of gas cooking, and peak airflow variability from continued exposure to repeated episodes of gas cooking in a group of non-smoking asthmatic women.Sixteen adult non-smoking women with mild to severe persistent asthma were studied. The acute short term level of nitrogen dioxide (NO2) during gas cooking episodes and the mean exposure to NO2 from repeated gas cooking episodes were measured over a 2 week period, as well as proxy measures of frequency of cooking on each day and the length of time spent cooking each day. Their asthma status was monitored using peak expiratory flow rates (PEFR) before and after cooking, 2 week self-recorded serial readings of PEFR, respiratory symptom severity score, and use of rescue bronchodilators for acute asthma attacks.Cooking was significantly associated with an immediate mean fall in PEFR of 3.4% (p=0.015, paired t test). The acute short term NO2 level during cooking was significantly correlated with the fall in PEFR (r=-0.579; p=0.019). The frequency of cooking over a 2 week period was positively correlated with the mean exposure to NO2 (r=0.529; p=0.042). Continued exposure to NO2 over a 2 week period was associated significantly with increased frequency of rescue bronchodilator usage for asthma attacks (r=0.597; p=0.031). However, it was negatively associated with PEFR variability (r=-0.512; p=0.051) and respiratory symptom severity score (r= -0.567; p=0.043), probably due to the masking effects of bronchodilator treatment.Acute short term exposure to NO2 from single episodes of gas cooking is associated with immediate airflow limitation. Continued exposure from repeated episodes of gas cooking in asthmatic women is associated with greater use of rescue bronchodilators.
COMPLEMENT-DEPENDENT PLATELET INJURY BY STAPHYLOCOCCAL PROTEIN A
Authors: Jacek Hawiger, Samuel R. Marney, Daniel G. Colley, Roger M. Des Prez
Journal: The Journal of Experimental Medicine (1972)

A new example of complement-mediated platelet injury has been described. Staphylococcal protein A (SPA) causes rabbit platelet injury as manifested by release of platelet 5-hydroxytryptamine (5HT). This reaction is complement-dependent and occurs over a very small range of SPA concentration, larger amounts being inhibitory. Complement fixation by SPA demonstrates the same narrow SPA concentration requirement whereas precipitation of IgG by SPA is roughly proportional to SPA concentration over a wide concentration range. The reaction can be separated into a sensitization step which requires SPA and plasma but not complement, and a release step which does require complement. Complement-mediated platelet damage induced by SPA is a new biologic property of this common component of the cell wall of pathogenic staphylococci which may contribute to the development of inflammatory and thromboembolic reactions complicating intravascular staphylococcal infection.
Effects of prostaglandins E1, E2, and F2 alpha on mucin secretion from human bronchi in vitro.
Authors: B Rich, A C Peatfield, I P Williams, P S Richardson
Journal: Thorax (1984)

The effects of three prostaglandins on the output of 35S labelled mucus glycoproteins (mucins), from explants of human bronchial tissue suspended in Ussing chambers, have been investigated. Prostaglandin F2 alpha, added to the Krebs-Henseleit solution bathing both luminal and submucosal sides of the tissue, significantly increased mucin output at concentrations of 0.1 and 1.0 micrograms/ml (0.28 and 2.8 microM), 11 preparations being used for each dose. Since prostaglandin F2 alpha has been shown to be released from human airways challenged by antigen, it may be important in the regulation of mucus secretion in these circumstances. Prostaglandins E1 and E2 had no significant effects on mucin output even at the highest concentration (1.0 micrograms/ml), though in half the tissues tested PGE2 stimulated secretion consistently. These results contrast with the findings in a previous study, which showed an inhibition of mucin output by PGE2.
The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice
Authors: Beichu Guo, Elmer Y. Chang, Genhong Cheng
Journal: Journal of Clinical Investigation (2008)

IFN-beta, a type I IFN, is widely used for the treatment of MS. However, the mechanisms behind its therapeutic efficacy are not well understood. Using a murine model of MS, EAE, we demonstrate that the Th17-mediated development of autoimmune disease is constrained by Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta-dependent (TRIF-dependent) type I IFN production and its downstream signaling pathway. Mice with defects in TRIF or type I IFN receptor (IFNAR) developed more severe EAE. Notably, these mice exhibited marked CNS inflammation, as manifested by increased IL-17 production. In addition, IFNAR-dependent signaling events were essential for negatively regulating Th17 development. Finally, IFN-beta-mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-beta in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-beta in MS but also demonstrate a regulatory role for type I IFN induction and its downstream signaling pathways in limiting Th17 development and autoimmune inflammation.
Ventilator-associated Lung Injury Decreases Lung Ability to Clear Edema in Rats
Authors: E. LECUONA, F. SALDÍAS, A. COMELLAS, K. RIDGE, C. GUERRERO, J. I. SZNAJDER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Ventilator-associated lung injury (VALI) is caused by high tidal volume (Vt) excursions producing microvascular leakage and pulmonary edema. However, the effects of VALI on lung edema clearance and alveolar epithelial cells' Na,K-ATPase function have not been elucidated. We studied lung edema clearance in the isolated–perfused rat lung model after ventilation for 25, 40, and 60 min with high Vt (peak airway opening pressure [Pao] of approximately 35 cm H2O) and compared them with low Vt ventilation (Pao ∼ 8 cm H2O), moderate Vt ventilation (Pao ∼ 20 cm H2O), and nonventilated rats. Lung edema clearance in control rats was 0.50 ± 0.02 ml/h and decreased after 40 and 60 min of high Vt to 0.26 ± 0.03 and 0.11 ± 0.08 ml/h, respectively (p < 0.01), but did not change after low Vt and moderate Vt ventilation at any time point. Lung permeability to small (22Na+, [3H]mannitol) and large solutes (fluorescein isothiocyanate–tagged albumin [FITC–albumin]) increased significantly in rats ventilated for 60 min with high Vt, compared with low Vt, moderate Vt, and control rats (p < 0.01). Paralleling the impairment in lung edema clearance we found a decrease in Na,K-ATPase activity in alveolar type II (ATII) cells isolated from rats ventilated with moderate Vt and high Vt for 40 min without changes in α 1 Na,K-ATPase mRNA. We reason that VALI decreases lung ability to clear edema by inhibiting active sodium transport and Na,K-ATPase function in the alveolar epithelium.
Evidence for the existence of inositol tetrakisphosphate in mammalian heart. Effect of alpha 1-adrenoceptor stimulation.
Authors: C Kohl, W Schmitz, H Scholz, J Scholz
Journal: Circulation Research (1990)

The time course of the effects of phenylephrine (10 mumol/l) on force of contraction and on inositol phosphates in electrically driven left auricles from rat hearts labeled with [3H]inositol was studied. All experiments were performed in the presence of propranolol (1 mumol/l) and LiCl (10 mmol/l). Products measured after separation with high-performance liquid chromatography were inositol 1-phosphate (1-IP1), inositol 1,4-bisphosphate (1,4-IP2), inositol 1,3,4-trisphosphate (1,3,4,-IP3), inositol 1,4,5-trisphosphate (1,4,5-IP3), and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4). All inositol phosphates increased after stimulation with phenylephrine. 1,4,5-IP3 was the first compound to rise maximally within 30 seconds; this rise was followed by an increase in 1,3,4,5-IP4 and 1,4-IP2 beginning within 2 minutes. The increase in 1,3,4-IP3 and 1-IP1 was slower and did not reach steady state within 15 minutes. The positive inotropic effect of phenylephrine was maximal after 5 minutes. It is concluded that the increase in the presumed second messengers 1,4,5-IP3 and 1,3,4,5-IP4 coincides with the positive inotropic effect after alpha 1-adrenoceptor stimulation. Since the increase in 1,4,5-IP3 precedes the increase in force of contraction, 1,4,5-IP3 may initiate the positive inotropic effect of alpha 1-adrenoceptor agonists and 1,3,4,5-IP4 maintains the increase in force of contraction.
Functional and molecular aspects of renal prostaglandin receptors.
Authors: M D Breyer, H R Jacobson, R M Breyer
Journal: Journal of the American Society of Nephrology (1996)

The diverse intrarenal effects of the prostaglandins (PG) are mediated by distinct guanine nucleotide regulatory protein (G-protein)-coupled receptors. The cDNA for these receptors have been cloned, their signal transduction mechanisms determined, and their intrarenal distribution mapped. PGE2, the major intrarenal prostaglandin, interacts with at least three distinct E-prostanoid (EP) receptors that are highly expressed in specific regions of the kidney. Each EP receptor not only selectively binds PGE2, but also preferentially couples to different signal transduction pathways, including: stimulation of cAMP generation, via Gq (EP2 and EP4 receptors); inhibition of cAMP generation, via Gi (EP3 receptors); and activation of phosphatidylinositol hydrolysis (EP1 receptor), via one of the Gq family members. Activation of each these EP receptors is responsible for a distinct renal effect of PGE2, including its well-described renal hemodynamic and transport effects along the nephron. Other intrarenal prostanoid receptors include the PGF2 alpha receptor (FP), the thromboxane A2 receptor (TP) and the prostacyclin receptor (IP). Knowledge about localization of these receptors and their affinities for receptor-selective agonists and antagonists should aid in the understanding of renal disease and the development of therapeutic strategies for the use of these prostaglandin analogs in select renal diseases.
Activation of the human beta-globin promoter in K562 cells by DNA sequences 5' to the fetal gamma- or embryonic zeta-globin genes.
Authors: H J Lin, N P Anagnou, T R Rutherford, T Shimada, A W Nienhuis
Journal: Journal of Clinical Investigation (1987)

Regulatory sequences of the human fetal gamma-globin gene were studied by constructing composite gamma/beta globin promoters and comparing their function to that of intact beta promoters in human K562 cells. The beta-globin gene with either 1,600 or 127 basepairs of beta promoter sequence was not expressed after stable introduction into K562 cells, consistent with the known inactivity of the beta-globin gene in these cells. In contrast, a gamma/beta promoter composed of a gamma fragment spanning positions -408 to -137 joined to the 127-bp beta promoter was able to drive the beta-globin gene. The gene appeared to be inducible with hemin. A zeta-globin 5' flanking fragment also activated the beta promoter. The function of a series of composite gamma/beta promoters was then assessed by their ability to drive directly the neomycin resistance gene, again in stably transformed cells. The -408 to -137 gamma fragment activated the beta promoter in an orientation-specific manner in this assay. Deletion analysis showed that regulatory sequences were present between positions -259 and -137 of the fetal gamma-globin gene flanking region.