tbuckley/cabot-search huggingface dataset:
Post–Heart Transplant Survival Is Inferior at Low-Volume Centers Across All Risk Strata
Authors: Mark J. Russo, Alexander Iribarne, Rachel Easterwood, Ali N. Ibrahimiye, Ryan Davies, Kimberly N. Hong, Deborah D. Ascheim, Annetine C. Gelijns, Yoshifumi Naka
Journal: Circulation (2010)

Previous studies have demonstrated a relationship between increasing center volume and cardiac transplant outcomes. The purpose of this study was to confirm a relationship between post-heart transplant outcomes and center experience and to determine whether this relationship persists among low- and high-risk heart transplant recipient-donor pairs.The United Network for Organ Sharing (UNOS) provided deidentified patient-level data. Analysis included 8029 heart transplant recipients aged ≥18 years and transplanted between January 1, 2001 and December 31, 2006 with follow-up available through February 3, 2009. The primary outcome was observed 1-year posttransplant graft survival. Multivariable logistic regression was used to calculate expected 1-year survival for recipients. Threshold analysis identified 3 discrete risk groups of transplant recipients: high-risk, moderate-risk, and low-risk. Three discrete risk strata for center volume: low (<10.5 recipients/yr), intermediate (10.5 to 47 recipients/yr), and high (>47 recipients/yr) were also identified. χ(2) test was used to compare 1-year survival at low- and intermediate- with high-volume centers. In multivariable logistic regression analysis, annual center volume was significantly associated with posttransplant graft survival at 1 year (odds ratio [OR]=0.995, 0.992 to 0.999; P=0.010) and primary graft failure (OR=0.985, 0.972 to 0.997; P=0.015), but not stroke (OR=0.996, 0.990 to 1.003; P=0.295), infection (OR=1.001, 0.998 to 1.003; P=0.613), or dialysis (OR=1.001, 0.997 to 1.005; P=0.522). Log-rank test demonstrated significant difference in survival between volume groups with respect to high-risk (P=0.0032) and low-risk (P=0.00415), but not moderate-risk (P=0.128) patients.A direct relationship existed between increasing center volume and improved graft survival. Across all recipient-donor pair risk strata, posttransplant graft survival at 1 year was significantly lower at low-volume centers. The volume-outcomes relationship was strongest in the highest-risk recipient-donor category.
Nocturnal Continuous Positive Airway Pressure Decreases Daytime Sympathetic Traffic in Obstructive Sleep Apnea
Authors: Krzysztof Narkiewicz, Masahiko Kato, Bradley G. Phillips, Catherine A. Pesek, Diane E. Davison, Virend K. Somers
Journal: Circulation (1999)

Patients with obstructive sleep apnea (OSA) have high levels of muscle sympathetic nerve activity (MSNA). We tested the hypothesis that long-term continuous positive airway pressure (CPAP) treatment will decrease MSNA in OSA patients.We measured blood pressure, heart rate, and MSNA in 11 normotensive, otherwise healthy patients with OSA who were treated with CPAP. The measurements were obtained at baseline and after 1 month, 6 months, and 1 year of CPAP treatment. These measurements were compared with those recorded in 9 otherwise healthy OSA patients who were not treated with CPAP for 1 year. In both untreated and treated patients, blood pressure and heart rate did not change over time. MSNA was similar during repeated measurements in the untreated group. By contrast, MSNA decreased significantly over time in patients treated with CPAP. This decrease was evident after both 6 months and 1 year of CPAP treatment (P=0.02 for both).CPAP treatment decreases muscle sympathetic traffic in patients with OSA. This effect of CPAP is evident only after an extended duration of therapy.
Lipid phosphate phosphatase 3 enables efficient thymic egress
Authors: Béatrice Bréart, Willy D. Ramos-Perez, Alejandra Mendoza, Abdelghaffar K. Salous, Michael Gobert, Yong Huang, Ralf H. Adams, Juan J. Lafaille, Diana Escalante-Alcalde, Andrew J. Morris, Susan R. Schwab
Journal: The Journal of Experimental Medicine (2011)

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance.
A randomized, double-blind, active-controlled, parallel-group pilot study to compare the efficacy and sedative effects of desloratadine 5 mg with levocetirizine 5 mg in the treatment of chronic idiopathic urticaria
Authors: Jin-Bon Hong, Hsing-Chuan Lee, Fu-Chang Hu, Chia-Yu Chu
Journal: Journal of the American Academy of Dermatology (2010)
Changes in priorities for improvement in patients with rheumatoid arthritis during 1 year of anti-tumour necrosis factor treatment
Authors: P. M ten Klooster, M. M Veehof, E. Taal, P. L C M van Riel, M. A F J van de Laar
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> To examine priorities for health status improvement in patients with active rheumatoid arthritis (RA) during anti-tumour necrosis factor (TNF) treatment. <h3>Methods:</h3> Data were used from 173 patients with RA starting treatment with TNF-blocking agents. Outcome measures included assessment of health status with the Arthritis Impact Measurement Scales 2 (AIMS2) at baseline and after 3 and 12 months. The AIMS2 contains a priority list from which patients are asked to select from 12 areas of health the 3 in which they would most like to see improvement. <h3>Results:</h3> After 1 year of treatment, 10 out of 12 areas of health on the AIMS2 were significantly improved. The most commonly selected priorities for improvement at baseline were pain (88%), hand and finger function (57%), walking and bending (42%), mobility (33%), and work (29%). At group level, this priority ranking remained largely unchanged during treatment. After adjustment for multiple comparisons, only pain was selected significantly less often at 3 and 12 months (71% at both assessments). Within individual patients, however, priorities often changed. Changes in the priority of pain were related to the achieved level of patient-perceived pain and disease activity. <h3>Conclusions:</h3> This study shows that, at the group level, patients' priorities for improvement are fairly stable during 12 months of anti-TNF therapy, despite major improvements in health status. Although pain reduction becomes somewhat less important, it remains the most commonly selected priority. In contrast, individual patient priorities are not stable over the course of treatment and appear to be associated with differences in disease state.
Identification of androgen-coregulated protein networks from the microsomes of human prostate cancer cells
Authors: Michael E Wright, Jimmy Eng, James Sherman, David M Hockenbery, Peter S Nelson, Timothy Galitski, Ruedi Aebersold
Journal: Genome biology (2003)

Androgens play a critical role in the development of prostate cancer-dysregulation of androgen-regulated growth pathways can led to hormone-refractory prostate cancer. A comprehensive understanding of androgen-regulated cellular processes has not been achieved to date. To this end, we have applied a large-scale proteomic approach to define cellular processes that are responsive to androgen treatment in LNCaP prostate cancer cells.Using isotope-coded affinity tags and mass spectrometry we identified and quantified the relative abundance levels of 1,064 proteins and found that distinct cellular processes were coregulated by androgen while others were essentially unaffected. Subsequent pharmacological perturbation of the cellular process for energy generation confirmed that androgen starvation had a profound effect on this pathway.Our results provide evidence for the role of androgenic hormones in coordinating the expression of critical components involved in distinct cellular processes and further establish a foundation for the comprehensive reconstruction of androgen-regulated protein networks and pathways in prostate cancer cells.
Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases
Authors: Hong Zhao, Guangxu Jin, Kemi Cui, Ding Ren, Timothy Liu, Peikai Chen, Solomon Wong, Fuhai Li, Yubo Fan, Angel Rodriguez, Jenny Chang, Stephen TC Wong
Journal: Cancer Research (2013)

A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.
Caste- and development-associated gene expression in a lower termite
Authors: Michael E Scharf, Dancia Wu-Scharf, Barry R Pittendrigh, Gary W Bennett
Journal: Genome biology (2003)

Social insects such as termites express dramatic polyphenism (the occurrence of multiple forms in a species on the basis of differential gene expression) both in association with caste differentiation and between castes after differentiation. We have used cDNA macroarrays to compare gene expression between polyphenic castes and intermediary developmental stages of the termite Reticulitermes flavipes. We identified differentially expressed genes from nine ontogenic categories. Quantitative PCR was used to quantify precise differences in gene expression between castes and between intermediary developmental stages. We found worker and nymph-biased expression of transcripts encoding termite and endosymbiont cellulases; presoldier-biased expression of transcripts encoding the storage/hormone-binding protein vitellogenin; and soldier-biased expression of gene transcripts encoding two transcription/translation factors, two signal transduction factors and four cytoskeletal/muscle proteins. The two transcription/translation factors showed significant homology to the bicaudal and bric-a-brac developmental genes of Drosophila. Our results show differential expression of regulatory, structural and enzyme-coding genes in association with termite castes and their developmental precursor stages. They also provide the first glimpse into how insect endosymbiont cellulase gene expression can vary in association with the caste of a host. These findings shed light on molecular processes associated with termite biology, polyphenism, caste differentiation and development and highlight potentially interesting variations in developmental themes between termites, other insects, and higher animals.
Attenuated Expression of Profilin-1 Confers Protection From Atherosclerosis in the LDL Receptor–Null Mouse
Authors: Giulio R. Romeo, Karen S. Moulton, Andrius Kazlauskas
Journal: Circulation Research (2007)

Atherosclerosis-related events are a major cause of morbidity and death worldwide, but the mechanisms underlying atherogenesis are not fully understood. We showed in previous studies that the actin-binding protein profilin-1 (pfn) was upregulated in atherosclerotic plaques and in endothelial cells (ECs) treated with oxidized low-density lipoproteins (oxLDL). The present study addressed the role of pfn in atheroma formation. To this end, mice with heterozygous deficiency of pfn, Pfn +/− , were crossed with Ldlr −/− mice. After 2 months under a 1.25% cholesterol atherogenic diet, Pfn +/− Ldlr −/− (PfnHet) exhibited a significant reduction in lesion burden compared with Ldlr −/− control mice (PfnWT), whereas total cholesterol and triglyceride levels were similar in the 2 groups. Relevant atheroprotective changes were identified in PfnHet. When compared with PfnWT, aortas from PfnHet mice showed preserved endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO)-dependent signaling, and reduced vascular cell adhesion molecule (VCAM)-1 expression and macrophage accumulation at lesion-prone sites. Similarly, knockdown of pfn in cultured aortic ECs was protective against endothelial dysfunction triggered by oxLDL. Finally, bone marrow–derived macrophages from PfnHet showed blunted internalization of oxLDL and oxLDL-induced inflammation. These studies demonstrate that pfn levels modulate processes critical for early atheroma formation and suggest that pfn heterozygosity confers atheroprotection through combined endothelial- and macrophage-dependent mechanisms.
Pulmonary B-cell non-Hodgkin's lymphoma associated with autoimmune disorders: a clinicopathological review of six cases
Authors: AG Nicholson, AC Wotherspoon, AL Jones, MN Sheppard, PG Isaacson, B Corrin
Journal: European Respiratory Journal (1996)

Because pulmonary B-cell non-Hodgkin's lymphomas are now thought to arise in bronchial mucosa-associated lymphoid tissue (MALT), 45 patients with pulmonary B-cell lymphomas were reviewed to look for aetiological factors in the lung. It was found that six of the 45 lymphomas arose in patients with systemic autoimmune disease, which in three patients involved the lung. These three patients all had cryptogenic fibrosing alveolitis treated with long-term immunosuppressive therapy. Five of the six lymphomas were high grade and one was low grade. The association of pulmonary lymphomas with autoimmune interstitial lung disease is consistent with associations between autoimmune diseases and lymphomas presenting at other mucosal sites, and lends weight to the hypothesis that formation of bronchial mucosa-associated lymphoid tissue precedes the development of lymphoma.
Superoxide Mediates the Actions of Angiotensin II in the Central Nervous System
Authors: Matthew C. Zimmerman, Eric Lazartigues, Julie A. Lang, Puspha Sinnayah, Iman M. Ahmad, Douglas R. Spitz, Robin L. Davisson
Journal: Circulation Research (2002)

Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II-mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector-mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.
Effect of the 21-aminosteroid U-74006F on antigen-induced bronchoconstriction and bronchoalveolar eosinophilia in allergic sheep
Authors: K Fujimoto, K Kubo, K Okada, T Kobayashi, M Sekiguchi, A Sakai
Journal: European Respiratory Journal (1996)

U-74006F, a non-glucocorticoid 21-aminosteroid, has been developed as an inhibitor of iron-dependent lipid peroxidation. This class of compounds has been shown to prevent antigen-induced eosinophil accumulation in the lungs. In this study, Ascaris-sensitive, "dual-respondent" sheep (showing both immediate (IAR) and late (LAR) asthmatic response) (n = 6) were used to assess the effect of U-74006F on antigen-induced bronchoconstriction and airway inflammation and reactivity 8 h after antigen challenge. Antigen provocation induced dual-phase bronchoconstriction, bronchoalveolar eosinophilia and airway hyperreactivity (AHR) to methacholine. Throughout the experiment, intravenous administration of the drug significantly reduced the IAR and inhibited the LAR along with the inhibition of eosinophil influx, but did not inhibit the increase in airway reactivity observed 8 h after antigen challenge. Post-antigen challenge treatment with U-74006 from 3 h after antigen challenge also significantly reduced the LAR and bronchoalveolar eosinophilia, although the degree of inhibitory effect was milder. The development of the LAR appeared to be dependent on eosinophil recruitment into the lungs. These findings suggest that lipid peroxidation is involved in antigen-induced bronchoconstriction and eosinophil recruitment into the lungs, and that the inhibitor U-74006F may be an effective drug for the treatment of bronchoconstriction and airway inflammation characterized by eosinophil infiltration in asthmatics.
Basophil Histamine Release by RNA, DNA and Aggregated IgG Examined in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Authors: Henrik Permin, Per Stahl Skov, Svend Norn, Frede Juhl
Journal: Allergy (1978)

Basophils from patients with rheumatoid arthritis (RA) respond to RNA, DNA and immune complexes (aggregated IgG) with histamine release. The RNA response was well correlated to the clinical activity of the disease, since histamine liberation was found in all patients with severe activity, whereas no liberation was observed in patients with moderate or quiescent activity. A less significant correlation was obtained with DNA and aggregated IgG. In contrast, no response was obtained with RNA, DNA and aggregated IgG in patients with systemic lupus erythematosus (SLE) or in controls. In the RA and the SLE groups no significant correlation was found between the response of RNA, DNA and aggregated IgG and the serum titres of anti-DNA and antinuclear antibodies. No difference in basophil cell count in peripheral blood and basophil histamine content was found between RA, SLE and controls. Our results point to an involvement of an autoimmune type I reaction in the pathogenesis of RA directed against the nuclear components RNA and DNA and against immune complexes.
Severe hepatic injury in interleukin 18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo
Authors: S Finotto
Journal: Gut (2004)

<b>Background:</b> Interleukin 18 (IL-18) is a cytokine with pleiotropic activity that augments T helper 1 responses and cytotoxic activity of natural killer cells. <b>Methods:</b> To assess the function of IL-18 in vivo, we generated IL-18 transgenic (IL-18 Tg) mice under the control of a CD2 promoter/enhancer construct. <b>Results:</b> Macroscopically, IL-18 Tg mice showed reduced relative liver weight compared with wild-type littermates. TUNEL assays demonstrated increased hepatocyte apoptosis, and primary hepatocytes isolated from IL-18 Tg mice exhibited an increased spontaneous apoptosis rate. Furthermore, cross linking of Fas increased significantly the apoptosis rate in hepatocytes isolated from wild- type mice but to a much lesser extent in IL-18 Tg mice, suggesting spontaneous activation of the Fas pathway in the latter mice. In fact, in vivo blockade of Fas signal transduction by an adenovirus overexpressing the dominant negative form of the Fas associated death domain rescued hepatocytes from undergoing apoptosis. Finally, adoptive transfer of CD4<sup>+</sup> T cells from IL-18 Tg mice but not from wild-type littermates in SCID mice resulted in severe liver failure with massive periportal fibrosis due to hepatocyte apoptosis. <b>Conclusion:</b> IL-18 plays a fundamental role in regulating hepatocyte apoptosis. Furthermore, our transgenic model provides a novel tool to study the mechanisms of IL-18 dependent liver injury in vivo.
Stimulation of microsomal prostaglandin synthesis by a blood plasma constituent which augments autoregulation and maintenance of vascular tone in isolated rabbit hearts.
Authors: R L Moretti, S Abraham
Journal: Circulation Research (1978)

Infusion of small amounts of plasma (1-2%) into isolated hearts perfused with Tyrode's solution causes vasoconstriction and augments regulation of coronary flow in response to changes in perfusion pressure (autoregulation).When plasma infusion is stopped, the vasoconstrictor effect dissipates within 5 minutes, whereas the autoregnlatory response remains for about 15 minutes.Thus the plasma-augmented autoregubtory response is not dependent on plasma-Induced vasoconstriction.Indomethadn (10 ftg/ml), an inhibitor of prostaglandin synthetase, causes coronary vasodflation and also abolishes the lingering autoregulatory response.These effects of indomethacin are counteracted by the addition of 1.5% plasma to the perfusate.Purification procedures led to the extraction of an active material from plasma which migrates as a single substance in thin layer chromatograms.This substance causes coronary vasoconstriction, augments autoregulation, and counteracts the effects of indometbacin in isolated rabbit hearts as effectively as plasma.The purified vasoactive substance stimulates a 2-fold increase in cardiac microsomal prostaglandin synthesis and a 5-fold increase using renal microsomal preparations.This substance counteracts indomethadn-induced inhibition of prostaglandin synthesis in microsomal preparations.These results provide convincing evidence that the effects of this pbtma constituent on the coronary vasculature are mediated by stimulation of prostaglandin synthesis.Thus it appears that prostaglandin synthesis plays an integral role In both the maintenance of coronary vascular tone and the autoregulatory response in isolated rabbit hearts.