tbuckley/cabot-search huggingface dataset:
Expression of muscarinic receptors by human macrophages
Authors: A. Koarai, S. L. Traves, P. S. Fenwick, S. M. Brown, K. K. Chana, R. E. K. Russell, A. G. Nicholson, P. J. Barnes, L. E. Donnelly
Journal: European Respiratory Journal (2011)

Macrophages increase in number and are highly activated in chronic obstructive pulmonary disease (COPD). Muscarinic receptor antagonists inhibit acetylcholine-stimulated release of neutrophilic chemoattractants, suggesting that acetylcholine may regulate macrophage responses. Therefore, expression and function of components of the non-neuronal cholinergic system in monocyte-macrophage cells was investigated. RNA was isolated from monocytes, monocyte-derived macrophages (MDMs), lung and alveolar macrophages from nonsmokers, smokers and COPD patients, and expression of the high-affinity choline transporter, choline acetyltransferase, vesicular acetylcholine transporter and muscarinic receptors (M<sub>1</sub>–M<sub>5</sub>) ascertained using real-time PCR. M<sub>2</sub> and M<sub>3</sub> receptor expression was confirmed using immunocytochemistry. Release of interleukin (IL)-8, IL-6 and leukotriene (LT)B<sub>4</sub> were measured by ELISA or EIA. All monocyte-macrophage cells expressed mRNA for components of the non-neuronal cholinergic system. Lung macrophages expressed significantly more M<sub>1</sub> mRNA compared with monocytes, and both lung macrophages and alveolar macrophages expressed the highest levels of M<sub>3</sub> mRNA. Expression of M<sub>2</sub> and M<sub>3</sub> protein was confirmed in MDMs and lung macrophages. Carbachol stimulated release of LTB<sub>4</sub> from lung macrophages (buffer 222.3±75.1 <i>versus</i> carbachol 1,118±622.4 pg·mL<sup>−1</sup>; n=15, p&lt;0.05) but not IL-6 or IL-8. LTB<sub>4</sub> release was attenuated by the M<sub>3</sub> antagonist, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; half maximal effective concentration 5.2±2.2 nM; n=9). Stimulation of macrophage M<sub>3</sub> receptors promotes release of LTB<sub>4</sub>, suggesting that anti-muscarinic agents may be anti-inflammatory.
Experimental Evaluation of Vitellogenin as a Predictive Biomarker for Reproductive Disruption
Authors: Ann Oliver Cheek, Thea Hoexum Brouwer, Suzanne Carroll, Steve Manning, John A. McLachlan, Marius Brouwer
Journal: Environmental Health Perspectives (2001)

Vitellogenin (VTG) synthesis in male oviparous vertebrates is used as an indicator of environmental estrogen exposure, but the relationship between elevated VTG levels and the effects of environmental estrogens on reproductive success are poorly understood. To examine whether altered VTG expression predicts reproductive impairment, we exposed medaka (Oryzias latipes) for 2 or 8 weeks posthatch to 0, 0.5, 1.0, 2.5, and 7.5 ppb of the environmental estrogen o,p'-DDT. Fish were sampled 2, 4, and 8 weeks after hatch to examine VTG expression and gonad development. After exposure, fish were transferred to clean water, grown to sexual maturity, and placed in mating pairs. We collected eggs for 7 days and scored them for fecundity (number of eggs), fertility (percent fertilized), and hatching success (percent hatched). DDT had no effect on VTG expression after a 2-week exposure, whereas all doses induced VTG after 8 weeks. At both exposure durations, the highest doses of DDT caused a female-skewed sex ratio in adults. Gonadal feminization appeared to be progressive: some ovotestes were observed after 2- or 4-week exposure to the two highest doses, but the proportion of ovaries increased after 8 weeks. Both 2- and 8-week exposures significantly reduced fertility and hatching success at all doses, with lower doses having a greater effect after longer exposure. Fertility and hatching success were more sensitive to estrogenic disruption than were gonad differentiation and vitellogenin expression. We suggest that VTG expression may be interpreted as a warning of reproductive consequences, but absence of expression cannot be interpreted as absence of consequences.
Loss of Elastic Fiber Integrity and Reduction of Vascular Smooth Muscle Contraction Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in the Thoracic Aortic Aneurysm in Marfan Syndrome
Authors: Ada W.Y. Chung, Karen Au Yeung, George G.S. Sandor, Daniel P. Judge, Harry C. Dietz, Cornelis van Breemen
Journal: Circulation Research (2007)

Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn 1 allele encoding a cysteine substitution in fibrillin-1 ( Fbn1 C1039G/+ , designated as “Marfan” mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1 +/+ served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of α-smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.
Antibodies to laminin in Chagas' disease.
Authors: A Szarfman, V P Terranova, S I Rennard, J M Foidart, M de Fatima Lima, J I Scheinman, G R Martin
Journal: The Journal of Experimental Medicine (1982)

We have found that sera from humans with Chagas' disease and Rhesus monkeys infected with Trypanosoma cruzi contain IgM and IgG antibodies, which react with structures in a variety of connective tissues. These antibodies react with laminin but not with various other purified connective tissue components like collagen types I, III, IV, and V, fibronectin, heparan sulfate (BM-1) proteoglycan, or chondronectin. The tissue-reacting antibodies were isolated by absorption to a laminin-Sepharose column. The bound fraction contained all the tissue-reacting antibodies. These antibodies strongly stained trypomastigotes and amastigotes, but weakly stained epimastigotes. These studies show that sera from T. cruzi-infected primates contain antilaminin antibodies, which may be produced by those host in response to a laminin-like molecule present in the parasite.
TCR repertoire divergence reflects micro-environmental immune phenotypes in glioma
Authors: Jennifer Sims, Boris Grinshpun, Yaping Feng, Justin Neira, Jorge Samanamud, Peter Canoll, Peter Sims, Yufeng Shen, Jeffrey Bruce
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Glioblastoma (GBM) remains prognostically dismal, with only modest gains in mean survival time with chemo- and radiotherapy motivating research into reversing its characteristic local and systemic immunosuppression with precision in this high-risk tissue. While whole-repertoire
Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity
Authors: Andrea Sottoriva, Joost J.C. Verhoeff, Tijana Borovski, Shannon K. McWeeney, Lev Naumov, Jan Paul Medema, Peter M.A. Sloot, Louis Vermeulen
Journal: Cancer Research (2010)

Abstract The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46–56
Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis
Authors: Laurence M. Howard, Amy J. Miga, Carol L. Vanderlugt, Mauro C. Dal Canto, Jon D. Laman, Randolph J. Noelle, Stephen D. Miller
Journal: Journal of Clinical Investigation (1999)

Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS pathology. We asked whether blockade of the CD40–CD154 (CD40L) costimulatory pathway could suppress relapses in mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin (IL)-2, IL-4, IL-5, and IL-10 were normal, antibody treatment severely inhibited interferon-γ production, myelin peptide–specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154 antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells, suggesting that CD40–CD154 interactions may be involved in directing the CNS migration of these cells and/or in their effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154–CD40 interactions is a promising immunotherapeutic strategy for treatment of ongoing T cell–mediated autoimmune diseases.
MYOCARDIAL STEATOSIS AND LEFT VENTRICULAR STRAIN AND STRAIN RATE IMAGING IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Authors: Arnold C. Ng, Victoria Delgado, Matteo Bertini, See Hooi Ewe, Rutger W. van der Meer, Luuk J. Rijzewijk, Hans-Marc Siebelink, Johannes WA Smit, Michaela Diamant, Johannes A. Romijn, Albert de Roos, Dominic Y. Leung, Hildo J. Lamb, Jeroen J. Bax
Journal: Journal of the American College of Cardiology (2010)
Function and expression of a novel rat salt-tolerant protein
Authors: E Tsuji, Y Tsuji, M Sasaguri, K Arakawa
Journal: Journal of the American Society of Nephrology (1998)

Higher dietary salt intake in humans is associated with higher BP, but the BP response to NaCl, so-called salt sensitivity, is heterogeneous among individuals. It has been postulated that modifications in cellular cation metabolism may be related to salt sensitivity in mammalian hypertension. The authors have isolated a novel rat complementary DNA, called salt-tolerant protein (STP), that can functionally complement Saccharomyces cervisiae HAL1, which improves salt tolerance by modulating the cation transport system. On high-salt (8% NaCl) diets, both Dahl salt-sensitive and salt-resistant rats displayed an elevated BP and increased STP mRNA expression. Immunohistochemistry using an anti-rat STP antibody demonstrated the presence of STP immunoreactivity in the proximal tubules. In cells that transiently expressed STP, the intracellular [Na+]/[K+] ratio was higher than that in control cells. STP contains predicted coiled-coil and Src homology 3 domains, and shows a partially high degree of nucleotide identity to human thyroid-hormone receptor interacting protein. These results suggest that STP may play an important role in salt sensitivity through cellular sodium metabolism by mediating signal transduction and a hormone-dependent transcription mechanism.
The Football Association medical research programme: an audit of injuries in academy youth football
Authors: R J Price, R D Hawkins, M A Hulse, A Hodson
Journal: British Journal of Sports Medicine (2004)

To undertake a prospective epidemiological study of the injuries sustained in English youth academy football over two competitive seasons.Player injuries were annotated by medical staff at 38 English football club youth academies. A specific injury audit questionnaire was used together with a weekly return form that documented each club's current injury status.A total of 3805 injuries were reported over two complete seasons (June to May) with an average injury rate of 0.40 per player per season. The mean (SD) number of days absent for each injury was 21.9 (33.63), with an average of 2.31 (3.66) games missed per injury. The total amount of time absent through injury equated to about 6% of the player's development time. Players in the higher age groups (17-19 years) were more likely to receive an injury than those in the younger age groups (9-16 years). Injury incidence varied throughout the season, with training injuries peaking in January (p<0.05) and competition injuries peaking in October (p<0.05). Competition injuries accounted for 50.4% of the total, with 36% of these occurring in the last third of each half. Strains (31%) and sprains (20%) were the main injury types, predominantly affecting the lower limb, with a similar proportion of injuries affecting the thigh (19%), ankle (19%), and knee (18%). Growth related conditions, including Sever's disease and Osgood-Schlatter's disease, accounted for 5% of total injuries, peaking in the under 13 age group for Osgood-Schlatter's disease and the under 11 age group for Sever's disease. The rate of re-injury of exactly the same anatomical structure was 3%.Footballers are at high risk of injury and there is a need to investigate ways of reducing this risk. Injury incidence at academy level is approximately half that of the professional game. Academy players probably have much less exposure to injury than their full time counterparts. Areas that warrant further attention include the link between musculoskeletal development and the onset of youth related conditions such as Sever's disease and Osgood-Schlatter's disease, the significant number of non-contact injuries that occur in academy football, and the increased rates of injury during preseason training and after the mid season break. This study has highlighted the nature and severity of injuries that occur at academy level, and the third part of the audit process now needs to be undertaken: the implementation of strategies to reduce the number of injuries encountered at this level.
Impact of TASK-1 in Human Pulmonary Artery Smooth Muscle Cells
Authors: Andrea Olschewski, Yingji Li, Bi Tang, Jörg Hanze, Bastian Eul, Rainer M. Bohle, Jochen Wilhelm, Rory E. Morty, Michael E. Brau, E. Kenneth Weir, Grazyna Kwapiszewska, Walter Klepetko, Werner Seeger, Horst Olschewski
Journal: Circulation Research (2006)

The excitability of pulmonary artery smooth muscle cells (PASMC) is regulated by potassium (K+) conductances. Although studies suggest that background K+ currents carried by 2-pore domain K+ channels are important regulators of resting membrane potential in PASMC, their role in human PASMC is unknown. Our study tested the hypothesis that TASK-1 leak K+ channels contribute to the K+ current and resting membrane potential in human PASMC. We used the whole-cell patch-clamp technique and TASK-1 small interfering RNA (siRNA). Noninactivating K+ current performed by TASK-1 K+ channels were identified by current characteristics and inhibition by anandamide and acidosis (pH 6.3), each resulting in significant membrane depolarization. Moreover, we showed that TASK-1 is blocked by moderate hypoxia and activated by treprostinil at clinically relevant concentrations. This is mediated via protein kinase A (PKA)-dependent phosphorylation of TASK-1. To further confirm the role of TASK-1 channels in regulation of resting membrane potential, we knocked down TASK-1 expression using TASK-1 siRNA. The knockdown of TASK-1 was reflected by a significant depolarization of resting membrane potential. Treatment of human PASMC with TASK-1 siRNA resulted in loss of sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. These results suggest that (1) TASK-1 is expressed in human PASMC; (2) TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K+ channels in the regulation of pulmonary vascular tone; and (3) treprostinil activates TASK-1 at clinically relevant concentrations via PKA, which might represent an important mechanism underlying the vasorelaxing properties of prostanoids and their beneficial effect in vivo.
CHEMICAL INVESTIGATIONS ON THE ACTIVE PRINCIPLES OF THE PHENOMENON OF LOCAL SKIN REACTIVITY TO BACTERIAL FILTRATES
Authors: Gregory Shwartzman, S. A. Morell
Journal: The Journal of Experimental Medicine (1938)

Several physicochemical properties of the active principles of the phenomenon of local skin reactivity to bacterial filtrates have been investigated. Ultrafiltration through Zsigmondy filters of graded porosities has shown that the active substances are retained by membranes finer than 100 to 120 seconds, whereas coarser ones readily permit their passage. The average porosity of this filtration end-point represents a particle size of about 50 to 100 mmicro. When fractionally precipitated with ammonium sulfate, most of the activity of a culture filtrate was concentrated in the two-thirds saturated portion. Isoelectric properties were studied by means of capillary analysis and cataphoresis. At pH 3.0 and below, the substances suspended in the culture filtrates migrated to the cathode; activity in this chamber, however, could not be demonstrated. At pH 4.0 and above, reversal to the anode occurred, as the active materials became negatively charged and readily migrated to this chamber. The isoelectric point, therefore, was considered to be between pH 3.0 and 4.0. Preliminary experiments on adsorption, extraction, and pH stability have been described.
Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies
Authors: Quincy Siu-Chung Chu, Lisa A. Hammond, Garry Schwartz, Leonel Ochoa, Sun-Young Rha, Louis Denis, Kathleen Molpus, Brian Roedig, Stephen P. Letrent, Bharat Damle, Arthur P. DeCillis, Eric K. Rowinsky
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized. Results: Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m2/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT. Conclusions: The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m2/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.
Interpretation of Low to Moderate Relative Risks in Environmental Epidemiologic Studies
Authors: John F. Acquavella, Barry R. Friedlander, Belinda K. Ireland
Journal: Annual Review of Public Health (1994)

In recent decades, there has been remarkable growth in scientific research examining the multiple ways in which racism can adversely affect health. This interest has been driven in part by the striking persistence of racial/ethnic inequities in health and ...Read More
miRNA-708 Control of CD44+ Prostate Cancer–Initiating Cells
Authors: Sharanjot Saini, Shahana Majid, Varahram Shahryari, Sumit Arora, Soichiro Yamamura, Inik Chang, Mohd Saif Zaman, Guoren Deng, Yuichiro Tanaka, Rajvir Dahiya
Journal: Cancer Research (2012)

Abstract Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44+ cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44+ prostate cancer cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44− population of prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer. Cancer Res; 72(14); 3618–30. ©2012 AACR.