tbuckley/cabot-search huggingface dataset:
Endothelial function, vascular reactivity and gender differences in the cardiovascular system
Authors: M Sader
Journal: Cardiovascular Research (2002)

Time for primary review 40 days. 

A marked gender difference exists in the prevalence and severity of cardiovascular disease, even after adjustment for traditional vascular risk factors, which are more prevalent in males [1]. This has led to an interest in the role of sex steroids themselves in the promotion or inhibition of atherogenic events. As endothelial dysfunction is an early and important event in atherogenesis [2] and appears to predict adverse coronary outcomes [3], gender differences in endothelial function and the effects of hormonal therapy on vascular function have been the focus of considerable research interest.

The normal vascular endothelium regulates arterial tone, platelet and leukocyte interactions, coagulation, fibrinolysis and vascular growth [4]. Measurement of endothelial function in the systemic arteries has become established as an important method for the detection of early (pre-symptomatic) arterial abnormalities in humans [5]. Ultrasound-detected endothelial dysfunction in peripheral arteries correlates significantly with coronary endothelial dysfunction [6], as well as with the extent and severity of coronary atherosclerosis [7]. The availability of a non-invasive method for the reproducible measurement of endothelium-dependent dilatation has facilitated the study of the interactions between sex hormones and arterial function, in both males and females.

The normal vascular endothelium is only one cell layer thick, separating the blood and vascular smooth muscle. The endothelium responds to physical and chemical stimuli via the synthesis and/or release of regulatory substances affecting vascular tone and growth, thrombosis and thrombolysis and platelet and leukocyte interactions with the endothelium. Substances released by the endothelium include nitric oxide (NO), prostacyclin, endothelins, interleukins, endothelial growth factors, adhesion molecules, plasminogen inhibitors and von Willebrand factor [4,8–10].

The pivotal role of the endothelium in regulating vascular smooth muscle tone has only recently been appreciated [11]. The existence of an endothelium-derived … 

* Corresponding author. Tel.: +61-2-9515-6519; fax: +61-2-9550-6262 davidc{at}card.rpa.cs.nsw.gov.au
The energy cost of an 80 km run.
Authors: W. S. Myles
Journal: British Journal of Sports Medicine (1979)

Data was collected from two men who attempted an 80 km run. Measurements of aerobic power (VO2 max) and determinations of heart rate (HR) and submaximal oxygen consumption (VO2) during treadmill running were carried out one week before the run. Throughout the 80 km run, HR was recorded by telemetry and used together with the laboratory data to estimate VO2 as a percentage of VO2 max. One subject completed the 80 km distance at 58% of VO2 max, the other subject, operating at 74% of VO2 max, was obliged to retired after 55 km. The data in this and other studies indicate that the high energy costs reported for the marathon (70-85% of VO2 max) cannot be sustained over the 80 km distance but that about 60% of VO2 max can be continued for seven hours and longer.
The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response
Authors: Gabriella Pagnan, Daniela Di Paolo, Roberta Carosio, Fabio Pastorino, Danilo Marimpietri, Chiara Brignole, Annalisa Pezzolo, Monica Loi, Luis J.V. Galietta, Federica Piccardi, Michele Cilli, Beatrice Nico, Domenico Ribatti, Vito Pistoia, Mirco Ponzoni
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma. Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezomib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.
Soluble Adenylyl Cyclase Reveals the Significance of cAMP Compartmentation on Pulmonary Microvascular Endothelial Cell Barrier
Authors: Sarah L. Sayner, Mikhail Alexeyev, Carmen W. Dessauer, Troy Stevens
Journal: Circulation Research (2006)

Subtle elevations in cAMP localized to the plasma membrane intensely strengthen endothelial barrier function. Paradoxically, pathogenic bacteria insert adenylyl cyclases (ACs) into eukaryotic cells generating a time-dependent cytosolic cAMP-increase that disrupts rather than strengthens the endothelial barrier. These findings bring into question whether membrane versus cytosolic AC activity dominates in control of cell adhesion. To address this problem, a mammalian forskolin-sensitive soluble AC (sACI/II) was expressed in pulmonary microvascular endothelial cells. Forskolin stimulated this sACI/II construct generating a small cytosolic cAMP-pool that was not regulated by phosphodiesterases or Galphas. Whereas forskolin simultaneously activated the sACI/II construct and endogenous transmembrane ACs, the modest sACI/II activity overwhelmed the barrier protective effects of plasma membrane activity to induce endothelial gap formation. Retargeting sACI/II to the plasma membrane retained AC activity but protected the endothelial cell barrier. These findings demonstrate for the first time that the intracellular location of cAMP synthesis critically determines its physiological outcome.
Influence of cardiopulmonary vagal afferent activity on carotid chemoreceptor and baroreceptor reflexes in the dog.
Authors: H Koike, A L Mark, D D Heistad, P G Schmid
Journal: Circulation Research (1975)

The goal of this study was to determine if physiological levels of cardiopulmonary vagal afferent activity modulate carotid chemoreceptor and baroreceptor reflexes. In anesthetized, ventilated dogs, the aortic nerves and the cervical sympathetic trunks were cut, and atropine was administered so that vagotomy would interrupt only cardiopulmonary afferent impulses. Reflex vascular responses were observed in perfused gracilis muscle and hindpaw. Carotid chemoreceptors were activated with nicotine or hypoxic, hypercapnic blood; carotid baroreceptors were stimulated by changes in carotid pressure. Interruption of vaga afferents augmented reflex vascular responses during changes incarotid pressure from 75 to 125 mm Hg. Interruption of cardiopulmonary vagal afferents potentiated reflex vasoconstrictor (muscle), vasodilator (paw), and vasopressor responses to activation of the carotid chemoreceptors. The potentiation of the chemoreceptor reflex frequently occurred in the absence of increases in base-line vascular resistance. Vagotomy also potentiated ventilatory responses to stimulation of the carotid chemoreceptors in spontaneously breathing dogs. The results indicate that interruption of cardiopulmonary afferents potentiates the vascular and ventilatory responses to activation of the carotid chemoreceptors and augments the gain of the carotid baroreceptor reflex at low carotid pressures. These findings suggest that physiological levels of cardiopulmonary vagal afferent impulses suppress carotid baroreceptor and chemoreceptor reflexes through an interaction in the central nervous system. The suppressive effect on the chemoreceptor reflex may be distinct from tonic restraint of the vasomotor center by vagal afferents, since it involves sympathetic vasodilator as well as vasoconstrictor responses and may occur without suppression of base-line adrenergic constrictor tone.
Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer
Authors: Alex A. Adjei, Julian R. Molina, Sumithra J. Mandrekar, Randolph Marks, Joel R. Reid, Gary Croghan, Lorelei J. Hanson, James R. Jett, Chenghua Xia, Chetan Lathia, Ronit Simantov
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non–small cell lung cancer. Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib Cmax (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease ≥4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non–small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
<i>MicroRNA-148a</i> Suppresses Tumor Cell Invasion and Metastasis by Downregulating <i>ROCK1</i> in Gastric Cancer
Authors: Biqiang Zheng, Linhui Liang, Chunmeng Wang, Shenglin Huang, Xi Cao, Ruopeng Zha, Li Liu, Deshui Jia, Qi Tian, Jianghong Wu, Yanwei Ye, Qifeng Wang, Ziwen Long, Ye Zhou, Chunyan Du, Xianghuo He, Yingqiang Shi
Journal: Clinical Cancer Research (2011)

Abstract Purpose: MicroRNAs (miRNA) have been documented playing a critical role in cancer development and progression. In this study, we investigate the role of miR-148a in gastric cancer metastasis. Experimental Design: We examined miR-148a levels in 90 gastric cancer samples by qRT-PCR and analyzed the clinicopathologic significance of miR-148a expression. The gastric cancer cells stably expressing miRNA-148a were analyzed for migration and invasion assays in vitro and metastasis assays in vivo; the target genes of miR-148a were further explored. Results: We found that miR-148a expression was suppressed by more than 4-fold in gastric cancer compared with their corresponding nontumorous tissues, and the downregulated miR-148a was significantly associated with tumor-node-metastasis (TNM) stage and lymph node-metastasis. Functional assays showed that overexpression of miR-148a suppressed gastric cancer cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, overexpression of miR-148a in GC cells could reduce the mRNA and protein levels of ROCK1, whereas miR-148a silencing significantly increased ROCK1 expression. Luciferase assays confirmed that miR-148a could directly bind to the 2 sites of 3′ untranslated region of ROCK1. Moreover, in gastric cancer tissues, we observed an inverse correlation between miR-148a and ROCK1 expression. Knockdown of ROCK1 significantly inhibited gastric cancer cell migration and invasion resembling that of miR-148a overexpression. We further found that ROCK1 was involved in miR-148a–induced suppression of gastric cancer cell migration and invasion. Conclusions: miR-148a functions as a tumor metastasis suppressor in gastric cancer, and downregulation of miR-148a contributes to gastric cancer lymph node-metastasis and progression. miR-148a may have a therapeutic potential to suppress gastric cancer metastasis. Clin Cancer Res; 17(24); 7574–83. ©2011 AACR.
Relationship between left ventricular hypertrophy and plasma renin activity in chronic hemodialysis patients.
Authors: D V Vlahakos, G Hahalis, P Vassilakos, K P Marathias, S Geroulanos
Journal: Journal of the American Society of Nephrology (1997)

Left ventricular hypertrophy (LVH) is very common in uremic patients. It was shown previously that hemodialysis patients are chronically exposed to the extremes of plasma renin activity due to differences in the original renal disease. Because nonhemodynamic factors seem to play a fundamental role in the development of LVH, the present study was undertaken to investigate the relationship between the predialysis renin level and the echocardiographically determined cardiac structure in stable hemodialysis patients, matched for other parameters known to participate in the development of LVH, such as age; gender; body mass index; interdialytic weight gain; heart rate; systolic, diastolic, and mean arterial BP; hematologic and biochemical profile; vascular access; adequacy of dialysis; nutritional status; and period of follow-up. Thirty-three such patients were stratified in three groups according to predialysis renin levels: group A (n = 11), with renin levels < or = 1 ng.ml-1.h-1; group B (n = 9), with renin levels between 1 and 4 ng.ml-1.h-1; and group C (n = 13), with renin levels > or = 4 ng.ml-1.h-1. LVH with disproportionate septal thickening was directly related to the degree of renin-angiotensin system activation, and values for interventricular septum thickness, posterior wall thickness, interventricular septum thickness/posterior wall thickness ratio, left ventricular mass, and left ventricular mass index were all significantly correlated with predialysis renin levels. Because angiotensin II promotes growth in both fibroblasts and cardiac myocytes, these relationships suggest that elevated renin levels may be causally associated with the development of LVH in chronic hemodialysis patients.
Idiotype-recognizing T helper cells that are not idiotype specific.
Authors: M McNamara, H Kohler
Journal: The Journal of Experimental Medicine (1983)

In this study T helper cells that recognize idiotypes as carriers for a hapten-specific B cell response were analyzed under limiting dilution conditions. T helper cells, induced by phosphorylcholine-hemocyanin (PC-Hy) priming, recognize trinitrophenylated TEPC-15 and MOPC-167 (TNP-T15, TNP-167) equally well. Limiting dilution analysis indicates identical frequencies of helper cells for TNP-T15 and TNP-167. Double immunization protocols using TNP-T15 and TNP-167 fail to demonstrate additive effects. Inhibition of carrier recognition in vitro using free hapten, PC, and unconjugated T15 or M167 indicates identical specificities of helper cells for T15 and M167. Collectively, these results provide strong evidence that PC-Hy priming induces only one population of idiotype-recognizing helper cells that are unable to distinguish between the T15 and the M167 idiotopes. The helper cell induction circuit was further analyzed. PC-Hy priming induces T15/167-specific helper T cells in X-linked immune defect-expressing F1 mice. This indicates that a B cell response to PC is not required to induce idiotype-recognizing T cells. Adoptive cotransfer of B cells from PC-Hy-primed mice together with normal T cells fails to induce idiotype-recognizing T cells. These results indicate the existence of a T helper1-T helper2 induction loop. In this scheme, the T helper1 cell carries T15-like receptors and the T helper2 cells, anti-T15-like receptors. Monoclonal antiidiotypic antibodies specific for T15 also induce a T15/167-recognizing T helper cell population. This finding demonstrates that idiotope-specific priming induces non-idiotype-specific T cells. Evidently, the idiotypic T cell network is based on a different selection of idiotope determinants than the selection of the B cell idiotype network.
Development, reliability, and validity of a novel Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI)
Authors: Clement C.H. Loh, Jaehwan Kim, John C. Su, Benjamin S. Daniel, Supriya S. Venugopal, Lesley M. Rhodes, Lizbeth R.A. Intong, Matthew G. Law, Dedee F. Murrell
Journal: Journal of the American Academy of Dermatology (2013)
Rare serotype adenoviral vectors for HIV vaccine development
Authors: Nelson L. Michael
Journal: Journal of Clinical Investigation (2011)

Human adenoviral vectors are being developed for use in candidate vaccines for HIV-1 and other pathogens. However, this approach suffered a setback when an HIV-1 vaccine using an adenovirus type 5 (Ad5) vector failed to reduce, and might even have increased, the rate of HIV infection in men who were uncircumcised and who had preexisting antibodies specific for Ad5. This increased interest in the evaluation of serologically distinct adenoviral vectors. In this issue of the JCI, Frahm and coworkers report evidence that preexisting cellular immune responses directed toward Ad5 reduce the immunogenicity of antigens expressed in Ad5-vectored vaccines and have cross-reacting potential with non-Ad5 adenoviral vectors. The implications of this observation need to be carefully evaluated in future clinical trials of all serotypes of adenovirus-vectored vaccines.
Sorting Nexin 1 Down-Regulation Promotes Colon Tumorigenesis
Authors: Lananh N. Nguyen, Matthew S. Holdren, Anthony P. Nguyen, Momoko H. Furuya, Michele Bianchini, Estrella Levy, José Mordoh, Annie Liu, Gabriela D. Guncay, Jean S. Campbell, W. Tony Parks
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Colon cancer is one of the most common human malignancies, yet studies have only begun to identify the multiple mechanisms that underlie the development of this tumor. In this study, we have identified a novel mechanism, dysregulation of endocytic sorting, which promotes colon cancer development. Experimental Design: Immunohistochemical and microarray analyses were done on human colon cancer tissue specimens to determine the levels of one endocytic protein, sorting nexin 1 (SNX1). SW480 cells, a human colon cancer cell line that retains a relatively high level of SNX1 expression, were used to assess the effects of down-regulating this protein by small hairpin RNA. Activation of signal transduction cascades was evaluated in these cells using Western blotting, and multiple functional assays were done. Results: We determined by immunohistochemistry that the level of SNX1 was significantly down-regulated in 75% of human colon cancers. In corroborative studies using microarray analysis, SNX1 message was significantly decreased (log2 ratio less than −1) for 8 of 19 colon carcinomas. Cell lines with reduced SNX1 levels showed increased proliferation, decreased apoptosis, and decreased susceptibility to anoikis. They also showed increased activation of epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 in response to epidermal growth factor. This increased activation was abolished by inhibition of endocytosis. Conclusions: These data suggest that loss of SNX1 may play a significant role in the development and aggressiveness of human colon cancer, at least partially through the mechanism of increased signaling from endosomes. Further, these findings suggest that dysregulation of endocytic proteins may represent a new paradigm in the process of carcinogenesis.
Insights into snoRNA biogenesis and processing from PAR-CLIP of snoRNA core proteins and small RNA sequencing
Authors: Shivendra Kishore, Andreas R Gruber, Dominik J Jedlinski, Afzal P Syed, Hadi Jorjani, Mihaela Zavolan
Journal: Genome biology (2013)

Abstract Background In recent years, a variety of small RNAs derived from other RNAs with well-known functions such as tRNAs and snoRNAs, have been identified. The functional relevance of these RNAs is largely unknown. To gain insight into the complexity of snoRNA processing and the functional relevance of snoRNA-derived small RNAs, we sequence long and short RNAs, small RNAs that co-precipitate with the Argonaute 2 protein and RNA fragments obtained in photoreactive nucleotide-enhanced crosslinking and immunoprecipitation (PAR-CLIP) of core snoRNA-associated proteins. Results Analysis of these data sets reveals that many loci in the human genome reproducibly give rise to C/D box-like snoRNAs, whose expression and evolutionary conservation are typically less pronounced relative to the snoRNAs that are currently cataloged. We further find that virtually all C/D box snoRNAs are specifically processed inside the regions of terminal complementarity, retaining in the mature form only 4-5 nucleotides upstream of the C box and 2-5 nucleotides downstream of the D box. Sequencing of the total and Argonaute 2-associated populations of small RNAs reveals that despite their cellular abundance, C/D box-derived small RNAs are not efficiently incorporated into the Ago2 protein. Conclusions We conclude that the human genome encodes a large number of snoRNAs that are processed along the canonical pathway and expressed at relatively low levels. Generation of snoRNA-derived processing products with alternative, particularly miRNA-like, functions appears to be uncommon.