tbuckley/cabot-search huggingface dataset:
T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion
Authors: James P. Hindley, Emma Jones, Kathryn Smart, Hayley Bridgeman, Sarah N. Lauder, Beatrice Ondondo, Scott Cutting, Kristin Ladell, Katherine K. Wynn, David Withers, David A. Price, Ann Ager, Andrew J. Godkin, Awen M. Gallimore
Journal: Cancer Research (2012)

Abstract The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T-cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. Cancer Res; 72(21); 5473–82. ©2012 AACR.
Opposing Roles of Murine Duffy Antigen Receptor for Chemokine and Murine CXC Chemokine Receptor-2 Receptors in Murine Melanoma Tumor Growth
Authors: Linda W. Horton, Yingchun Yu, Snjezana Zaja-Milatovic, Robert M. Strieter, Ann Richmond
Journal: Cancer Research (2007)

Abstract The Duffy antigen receptor for chemokines (DARC) has been classified as a “silent” receptor, as it can bind CXC and CC chemokines to undergo ligand-induced receptor internalization, but is not coupled to trimeric G proteins required for the classic G protein–coupled receptor–mediated signaling. CXC chemokine receptor-2 (CXCR2) has been shown to play a major role in tumor angiogenesis. To test the hypothesis that these two chemokine receptors might play opposing roles in the growth of melanoma tumors, we developed a transgenic mouse model, where the preproendothelin promoter/enhancer (PPEP) is used to drive expression of either murine DARC (mDARC) or murine CXCR2 (mCXCR2) in endothelial cells. We show herein that the growth of melanoma tumor xenografts, established from s.c. injection of immortalized murine melanocytes overexpressing macrophage inflammatory protein-2, was inhibited or enhanced in the PPEP-mDARC and PPEP-mCXCR2 transgenic mice, respectively, compared with control mice. The early tumors formed in mDARC transgenic mice exhibited a significantly higher number of infiltrating leukocytes compared with either the control or mCXCR2 transgenic mice, suggesting a potential role for DARC expressed on endothelial cells in leukocyte migration. In addition, the tumor-associated angiogenesis in mDARC transgenic mice was reduced when compared with the control. Conversely, tumor angiogenesis was significantly increased in mCXCR2 transgenic mice. Results indicate that endothelial cell overexpression of mDARC increased leukocyte trafficking to the tumor, reduced the growth of blood vessels into the tumor, and reduced the growth rate of the tumor, whereas endothelial cell overexpression of mCXCR2 had the reverse effect on tumor angiogenesis and growth. [Cancer Res 2007;67(20):9791–9]
Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge
Authors: F.-R. E. Curry, R. H. Adamson
Journal: Cardiovascular Research (2010)

Multiple processes modulate net blood-to-tissue exchange in a microvascular unit in normal and pathophysiological conditions. These include mechanisms that control the number and type of microvessels perfused, the balance of adhesion and contractile forces that determine the conductance of the spaces between endothelial cells to water and solutes, the pressure and chemical potential gradients determining the driving forces through these conductive pathways, and the organization of barriers to macromolecules in the endothelial glycocalyx. Powerful methods are available to investigate these mechanisms at the levels of cultured endothelial monolayers, isolated microvessels, and the microvascular units within intact organs. Here we focus on current problems that limit the integration of our knowledge of mechanisms investigated in detail at the cellular level into a more complete understanding of modulation of blood-to-tissue exchange in whole organs when the endothelial barrier is exposed to acute and more long-term inflammatory conditions. First, we review updated methods, applicable in mouse models of vascular permeability regulation, to investigate both acute and long-term changes in permeability. Methods to distinguish tracer accumulation due to change in perfusion from real increases in extravascular accumulation are emphasized. The second part of the review compares normal and increased permeability in individually perfused venular microvessels and endothelial cell monolayers. The heterogeneity of endothelial cell phenotypes in the baseline state and after exposure to injury and inflammatory conditions is emphasized. Lastly, we review new approaches to investigation of the glycocalyx barrier properties in cultured endothelial monolayers and in whole-body investigations.
Regulation of the Cl−/HCO3 − Exchanger AE2 in Rat Thick Ascending Limb of Henle’s Loop in Response to Changes in Acid-Base and Sodium Balance
Authors: Fabienne Quentin, Dominique Eladari, Sebastian Frische, Michèle Cambillau, Søren Nielsen, Seth L Alper, Michel Paillard, Régine Chambrey
Journal: Journal of the American Society of Nephrology (2004)

The Cl(-)/HCO(3)(-) exchanger AE2 is believed to be involved in transcellular bicarbonate reabsorption that occurs in the thick ascending limb of Henle's loop (TAL). The purpose of this study was to test whether chronic changes in acid-base status and sodium intake regulate AE2 polypeptide abundance in the TAL of the rat. Rats were subjected to 6 d of loading with NaCl, NH(4)Cl, NaHCO(3), KCl, or KHCO(3). AE2 protein abundance was estimated by semiquantitative immunoblotting in renal membrane fractions isolated from the cortex and the outer medulla of treated and control rats. In the renal cortex, AE2 abundance was markedly increased in response to oral loading with NH(4)Cl or with NaCl. In contrast, AE2 abundance was unchanged in response to loading with KCl or with NaHCO(3) and was decreased by loading with KHCO(3). The response of AE2 in the outer medulla differed from that in the cortex in that HCO(3)(-) loading increased AE2 abundance when administered with Na(+) but had no effect when administered with K(+). Immunohistochemistry revealed that NaCl loading increased AE2 abundance in the basolateral membrane of both the cortical and the medullary TAL. In contrast, NH(4)Cl loading increased AE2 abundance only in the cortical TAL but not in the medullary TAL. These results suggest that regulation of the basolateral Cl(-)/HCO(3)(-) exchanger AE2 plays an important role in the adaptation of bicarbonate absorption in the TAL during chronic acid-base disturbances and high sodium intake. The present study also emphasizes the contribution of cortical TAL adaptation in the renal regulation of acid-base status.
FGF-2 modulates human airway smooth muscle contractile protein expression and cell stiffness
Authors: Michael Schuliga, Trudi Harris, Yuxiu Xia, Zhexing Wang, Xuehua Zhang, Peter Lee, Alastair Stewart
Journal: European Respiratory Journal (2013)

In asthma, fibroblast growth factor-2 (FGF-2) has an important (patho)physiological role. We have investigated the effect of FGF-2 on airway smooth muscle (ASM) differentiation in vitro by measuring increases in contractile protein expression and cell stiffness. Differentiation of human ASM cells was assessed following incubation with TGF-β (100pM) for 48h, in the absence or presence of FGF-2 (300pM) and the TGF-β-R kinase (Alk-5) inhibitor, SB431542 (10μM). Differentiation was measured by changes in levels of mRNA of the contractile proteins, SM22 and calponin, using real time PCR. Changes in cell stiffness were assessed by micropipette aspiration. FGF-2 inhibited TGF-β-stimulated increases in SM22 and calponin gene expression (n=15, P 0.05). The addition of FGF-2 24h after TGF-β still reduced contractile protein expression, even when the TGF-β-receptor kinase inhibitor, SB431542 (10μM), was added 1h before FGF-2. These data suggests that FGF-2 is able to reduce contractile protein gene expression in ASM cells in a manner that occurs independently of concurrent TGF-β-signaling. A better understanding the mechanism of action of FGF-2 is necessary to develop a strategy for therapeutic exploitation in the treatment of asthma.
Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro. Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors.
Authors: H A Chapman, O L Stone
Journal: Journal of Clinical Investigation (1984)

Elastin is an extracellular matrix protein critical to the normal structure and function of human lung. Recently reported data indicate that live human alveolar macrophages can degrade purified elastin in vitro. In this study, we directly compared the elastolytic activity of alveolar macrophages with that of human neutrophils. In the absence of proteinase inhibitors, human neutrophils degrade much more elastin than do human alveolar macrophages. However, macrophages cultured in 10% human serum and in contact with purified 3H-elastin degraded 4.7 micrograms elastin/10(6) cells per 24 h, as compared to less than 1 microgram/10(6) cells/24 h for neutrophils. We observed a similar pattern when the two cells were cultured in human alveolar fluid. We determined that the relative resistance of macrophage elastolytic activity to serum or alveolar proteinase inhibitors was not simply due to phagocytosis of substrate by the larger macrophages. Live macrophages as well as neutrophils degrade 125I-elastin coupled to noningestible sepharose beads. Again in serum-free media, neutrophils degraded eight-fold more elastin than macrophages but only macrophages degraded sepharose-coupled elastin in the presence of 10% serum. Because of these findings, we compared the enzymatic mechanisms of elastin breakdown by macrophages with that of neutrophils. Macrophage elastolytic activity is largely (65-80%) due to a cysteine proteinase(s), at least part of which is Cathepsin B. Approximately half of the cysteine proteinase activity appeared to be expressed at or near the cell surface. These experiments defined two enzymatically distinct pathways of elastin breakdown by human inflammatory cells: the classic, neutrophil derived soluble elastase(s) that is sensitive to serum and alveolar proteinase inhibitors, and a macrophage-mediated pathway that is largely cell associated and relatively resistant to inhibitors. The function of the two pathways depends on the relative excess or deficiency of soluble inhibitors. At inflammatory sites rich in proteinase inhibitors, tissue macrophages may degrade more extracellular matrix elastin than neutrophils. In smokers without antiproteinase deficiency, pulmonary macrophages, which are known to be increased in number, may be the more important cause of elastin breakdown and emphysema.
Local Drug Delivery via a Coronary Stent With Programmable Release Pharmacokinetics
Authors: Ariel Finkelstein, Dougal McClean, Saibal Kar, Kaname Takizawa, Kiron Varghese, Namjin Baek, Kinam Park, Michael C. Fishbein, Raj Makkar, Frank Litvack, Neal L. Eigler
Journal: Circulation (2003)

Fixed drug release kinetics and vessel wall partitioning may limit the effectiveness of drug-eluting stents. We report preliminary experience using a new coronary stent with programmable pharmacokinetics.A newly designed metallic stent contains honeycombed strut elements with inlaid stacked layers of drug and polymer. In vitro studies evaluated recipes for loading paclitaxel to establish the parameters for controlling drug release. Manipulation of the layers of biodegradable polymer and drug allowed varying of the initial 24-hour burst release of paclitaxel from 69% to 8.6% (P<0.0001). Late release of drug could be adjusted dependently or independently of early burst release. A biphasic release profile was created by the addition of blank layers of polymer within the stack. In the 30-day porcine coronary model (n=17 pigs), there was a 70% reduction in late loss (0.3+/-0.5 versus 1.0+/-0.5 mm, P=0.04), a 28% increase in luminal volume (132+/-12 versus 103+/-21 mm(3), P=0.02), and a 50% decrease in histological neointimal area (2.0+/-0.5 versus 4.0+/-1.6 mm(2); P<0.001) compared with bare metal controls. Temporal and regional variations in vascular healing were seen histologically.Layered polymer/drug inlay stent technology permits flexible and controllable pharmacokinetic profiles. Programmable, complex chemotherapy using this approach may be feasible for the treatment of cardiovascular disease.
Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis
Authors: Suetonia C Palmer, Dimitris Mavridis, Eliano Navarese, Jonathan C Craig, Marcello Tonelli, Georgia Salanti, Natasha Wiebe, Marinella Ruospo, David C Wheeler, Giovanni F M Strippoli
Journal: The Lancet (2015)
Racial Differences in Risk of Oral and Pharyngeal Cancer: Alcohol, Tobacco, and Other Determinants
Authors: G. L. Day, W. J. Blot, D. F. Austin, L. Bernstein, R. S. Greenberg, S. Preston-Martin, J. B. Schoenberg, D. M. Winn, J. K. McLaughlin, J. F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1993)

In the United States, Blacks have increasingly higher rates of oral and pharyngeal cancer (oral cancer) than Whites, but determinants of the racial disparity have not been clear.The purpose of this study was to explore reasons for the higher incidence of oral cancer among Blacks than Whites.We used data from a large, population-based case-control study of oral cancer risk factors conducted in four areas of the United States. On the basis of interviews that ascertained characteristics of 1065 oral cancer patients (871 Whites and 194 Blacks) and 1182 controls (979 Whites and 203 Blacks), we examined racial differences in exposure prevalences and relative risks for a number of known etiologic factors, including tobacco and alcohol consumption, diet, and socioeconomic and other variables. To evaluate the extent to which the major risk factors explained the excess risk of oral cancer among Blacks, population-attributable risks were calculated.Differences with respect to alcohol consumption, especially among current smokers, emerged as the most important explanatory variables. After adjusting for smoking, heavy drinking (> or = 30 drinks/week) resulted in a 17-fold increased risk among Blacks and a ninefold increase among Whites. Among drinkers, Blacks tended to drink more than Whites. Also, a higher (P = .01) percentage of Blacks (37%) than Whites (28%) were current smokers, although there were little or no racial differences in relative risks or patterns of use for other smoking variables, including number of cigarettes smoked per day, years of smoking, and age started smoking. From population-attributable risk calculations, we estimated that differences in alcohol and tobacco use account for the bulk of the higher incidence of oral cancer among Blacks in the United States and that, in the absence of alcohol and tobacco, the rates of this cancer according to race (Black, White) and gender would be nearly equal. With regard to other potential etiologic factors, protective effects provided by higher dietary intake of fruits and vitamin C were more pronounced for Whites, while Blacks more often tended to be in sociodemographic and medical or dental health categories associated with increased risk.These analyses provide evidence that various environmental or lifestyle determinants of oral cancer may contribute to the higher oral cancer rates in Blacks than in Whites in the United States, but that patterns and risks associated with alcohol consumption, particularly among current smokers, are the most important contributors to the excess risk in Blacks.These findings suggest that the key to prevention of oral and pharyngeal cancers among both Blacks and Whites is reduced intake of alcoholic beverages and, because of strong interactive effects, the cessation of smoking.
Primary Hyperoxaluria with Normal Alpha-Ketoglutarate:Glyoxylate Carboligase Activity
Authors: E. BOURKE
Journal: Annals of Internal Medicine (1972)

A 10-year-old girl with primary hyperoxaluria, calcium oxalate nephrolithiasis, and normal blood urea was studied. Despite high urinary oxalate and glycolate excretion, normal activity of α-ketoglutarate:glyoxylate carboligase was observed in both mitochondria-containing and soluble cytoplasmic fractions of striated muscle tissue. No effect on the urinary excretion of oxalate or glycolate was observed with the administration of pyridoxine, allopurinol, or calcium carbimide. A 40% reduction in urinary oxalate excretion was produced by isocarboxazid therapy. Further studies are necessary to elucidate the role of monoamine oxidase inhibitors in the treatment of primary hyperoxaluria.
Broccoli, PTEN deletion and prostate cancer: where is the link ?
Authors: Giovanni Appendino, Alberto Bardelli
Journal: Molecular Cancer (2010)

The concept that vegetables and fruits are relevant sources of cancer-preventive substances is strongly supported by population studies. Among others, cruciferous vegetables like broccoli, cabbage, cauliflower and Brussels sprouts are thought to affect the development of various types of cancers and especially prostate tumors. Yet, the identification of the molecular mechanisms by which the 'active' compounds contained in these vegetables mediate their anticancer activity has historically lagged behind. Accordingly, direct laboratory evidence of how individual nutrients affect cancer genes and the pathways they control remains the major obstacle to progress in this research field. Here we review a recent report investigating the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, and expression of the PTEN tumor suppressor gene in pre malignant prostate tissue.
Role of the autonomic nervous system in the pressor response to calcium in conscious dogs
Authors: L. D HORWITZ, M. D LIFSCHITZ
Journal: Cardiovascular Research (1980)

Journal Article Role of the autonomic nervous system in the pressor response to calcium in conscious dogs Get access LAWRENCE D HORWITZ, LAWRENCE D HORWITZ * From Denver VA Hospital and University of Colorado Health Sciences Center, Denver, Colorado† *Address for reprints: Professor L D Horwitz, University of Colorado Health Science Centre 4200 East Ninth Avenue, Denver, Colorado 80262, USA. Search for other works by this author on: Oxford Academic PubMed Google Scholar MEYER D LIFSCHITZ MEYER D LIFSCHITZ From Denver VA Hospital and University of Colorado Health Sciences Center, Denver, Colorado† Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 14, Issue 9, September 1980, Pages 522–529, https://doi.org/10.1093/cvr/14.9.522 Published: 01 September 1980
Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation
Authors: Fanjun Meng, Dongdong Yao, Yang Shi, Jonathan Kabakoff, Wei Wu, Joshua Reicher, Yuliang Ma, Bernd Moosmann, Eliezer Masliah, Stuart A Lipton, Zezong Gu
Journal: Molecular Neurodegeneration (2011)

Abstract Background Accumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emerging evidence suggests that oxidative/nitrosative stress compromises the precisely-regulated network of ubiquitination in PD, particularly affecting parkin E3 ligase activity, and contributes to the accumulation of toxic proteins and neuronal cell death. Results To gain insight into the mechanism whereby cell stress alters parkin-mediated ubiquitination and LB formation, we investigated the effect of oxidative stress. We found significant increases in oxidation (sulfonation) and subsequent aggregation of parkin in SH-SY5Y cells exposed to the mitochondrial complex I inhibitor 1-methyl-4-phenlypyridinium (MPP + ), representing an in vitro cell-based PD model. Exposure of these cells to direct oxidation via pathological doses of H 2 O 2 induced a vicious cycle of increased followed by decreased parkin E3 ligase activity, similar to that previously reported following S-nitrosylation of parkin. Pre-incubation with catalase attenuated H 2 O 2 accumulation, parkin sulfonation, and parkin aggregation. Mass spectrometry (MS) analysis revealed that H 2 O 2 reacted with specific cysteine residues of parkin, resulting in sulfination/sulfonation in regions of the protein similar to those affected by parkin mutations in hereditary forms of PD. Immunohistochemistry or gel electrophoresis revealed an increase in aggregated parkin in rats and primates exposed to mitochondrial complex I inhibitors, as well as in postmortem human brain from patients with PD with LBs. Conclusion These findings show that oxidative stress alters parkin E3 ligase activity, leading to dysfunction of the ubiquitin-proteasome system and potentially contributing to LB formation.
Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes.
Authors: K Whaley
Journal: The Journal of Experimental Medicine (1980)

Short-term cultures of human peripheral blood monocytes were shown to synthesize the alternative pathway complement components C3, factors B (B) and D (D), and properdin, the regulatory proteins C3b inactivator (C3bINA) and beta 1H, in addition to C2, C4, and C5. B, D, properdin, C3bINA, and C2 were detected by functional assays, whereas beta 1H, C4, C3, and C5 could only be detected using immunochemical procedures. Immunoperoxidase localization studies showed that all the cells in each culture contained each component, so it is possible that all monocytes synthesize each component. It is concluded that cells of the monocyte-macrophage series form a mobile source of complement components and regulatory proteins which can be concentrated at sites of inflammation.