tbuckley/cabot-search huggingface dataset:
Endothelin-1 mRNA is widely expressed in porcine and human tissues.
Authors: D J Nunez, M J Brown, A P Davenport, C B Neylon, J P Schofield, R K Wyse
Journal: Journal of Clinical Investigation (1990)

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide isolated from porcine endothelial cells. We have previously demonstrated widespread binding sites for ET-1 in blood vessels, heart, kidney, adrenal, lung, and brain in a distribution that paralleled that of endothelial cells. To determine whether these cells are capable of synthesizing ET-1 in close proximity to its binding sites, amplification of cDNA using the polymerase chain reaction and in situ hybridization were used to study the distribution of ET-1 mRNA. We have found widespread transcription of ET-1 mRNA in human and porcine tissues. The identity of the transcripts was confirmed by prediction of restriction fragment lengths or sequencing. In situ hybridization in the kidney showed that the regional expression of these transcripts is localized, probably to small blood vessels, but the failure to visualize ET-1 mRNA in the capillaries may reflect absence of expression or insufficient sensitivity of the technique. These results should permit investigation of the role of ET-1 as a local factor in vascular pathophysiology.
Extracellular Matrix–Bound Angiopoietin-Like 4 Inhibits Endothelial Cell Adhesion, Migration, and Sprouting and Alters Actin Cytoskeleton
Authors: Aurélie Cazes, Ariane Galaup, Clémence Chomel, Marine Bignon, Nicolas Bréchot, Sébastien Le Jan, Holger Weber, Pierre Corvol, Laurent Muller, Stéphane Germain, Catherine Monnot
Journal: Circulation Research (2006)

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of angptl4 by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.
Maternal Modification of Antigen Recognition in the Ova-Transfer Substrain RIIIeB
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1972)

The ova-transfer substrain RIIIeB differs from the parental strain in its radiation sensitivity in the midlethal range and in its ability to produce a lethal graft-versus-host reaction in lethally irradiated (C57BL × RIII)F1 recipients. This maternal modification was established during embryonic development in the strain of the foster mother (C57BL) and has been vertically transmitted for more than 20 generations. The evidence that this modification involved the antigen recognition system was derived from the fact that RIII was able to recognize the qualitative difference in antigenicity between reciprocal hybrids (C57BL × RIII)F1 and (RIII × C57BL)F1, whereas RIIIeB was unresponsive to both hybrids. However, both RIII and RIIIeB recognized the quantitative reduction in antigenicity (gene dosage effect) between C57BL and (C57BL × RIII)F1. Although C57BL did not recognize different degrees of antigenicity in reciprocal hybrids, it was able to recognize quantitative differences in antigenicity between the RIII and (RIII × C57BL)F1 recipients.
ACUTE HYPERGLYCEMIA IN NONDIABETIC WOMEN REDUCES CORONARY FLOW RESERVE: NOVEL OBSERVATIONS DURING NONINVASIVE ASSESSMENT OF MYOCARDIAL PERFUSION USING RAPID-ACQUISITION BEDSIDE CONTRAST ECHOCARDIOGRAPHY
Authors: Sahar S. Abdelmoneim, Ananda Basu, Rita Basu, Mary Hagan, Edward Mendrick, Vishwanath Pattan, Barbara Norby, Tamara Roberson, Troy Szydel, Sharon L. Mulvagh
Journal: Journal of the American College of Cardiology (2011)
Randomized, Double-Blind, Controlled Trial of Mitoxantrone/Prednisone and Clodronate Versus Mitoxantrone/Prednisone and Placebo in Patients With Hormone-Refractory Prostate Cancer and Pain
Authors: D.S. Ernst, I.F. Tannock, E.W. Winquist, P.M. Venner, L. Reyno, M.J. Moore, K. Chi, K. Ding, C. Elliott, W. Parulekar
Journal: Journal of Clinical Oncology (2003)

To compare the incidence of palliative response in patients with hormone-resistant prostate cancer (HRPC) treated with mitoxantrone and prednisone (MP) plus clodronate with that of patients treated with MP plus placebo.Men with HRPC, bone metastases, and bone pain were randomly assigned to receive clodronate 1,500 mg administered intravenously (IV) or placebo every 3 weeks, in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid. Patients completed the present pain intensity (PPI) index and Prostate Cancer-Specific Quality-of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis. The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50% in analgesic intake, without increase in either.The study accrued 209 eligible patients over 44 months. One hundred sixty patients (77%) had mild PPI scores (1 or 2), and 49 (24%) had moderate PPI scores (3 or 4). The primary end point of palliative response was achieved in 46 (46%) of 104 patients on the clodronate arm and in 41 (39%) of 105 patients on the placebo arm (P =.54). The median duration of response, symptomatic disease progression-free survival, overall survival, and overall quality of life were similar between the arms. Subgroup analysis suggested possible benefit in patients with more severe pain.MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.
Post-mortem lung volumes.
Authors: W M Thurlbeck
Journal: Thorax (1979)

The volumes of 78 adult human lungs at necropsy after fixation with intrabronchial 10% formaldehyde at a transpulmonary pressure of 25 cm of water (VL) were similar to their total lung capacity (TLC) as assessed radiologically (VX). Corrected for stature, VL and VX did not increase with age in non-emphsematous lungs, nor did the radio of VL to VX (VL/VX) change with age. VL and VX relative to body length increased with emphysema, and the increase even occurred in lungs from men with trivial or equivocal amounts of emphysema. Thus alteration of the mechanical properties of the lung may precede the appearance of obvious emphysema. VL/VX was not affected by the presence or severity of emphysema. The right lung formed 53% of VL with a range of 49-58% in apparently normal lungs. The amount of air in 13 human lungs at necropsy averaged 61% of TLC with a wide variation, indicating that this is not a useful point at which to measure lung dimensions. It is concluded that the volume of lungs fixed with formaldehyde at a transpulmonary pressure of 25 cmH2O closely approximates to total lung capacity.
Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study)
Authors: Jeffrey Kaine, Geoffrey Gladstein, Ingrid Strusberg, Manuel Robles, Ingrid Louw, Sheila Gujrathi, Ramesh Pappu, Ingrid Delaet, Miranda Pans, Charles Ludivico
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. Methods Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. Results Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. Conclusions Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop–start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. ClinicalTrials gov Identifier NCT00533897
PERFORMANCE OF LEFT VENTRICULAR EJECTION FRACTION ON PATIENTS WITH STABLE MULTIVESSEL CORONARY DISEASE SUBMITTED TO MEDICINE, ANGIOPLASTY OR SURGERY: 10 YEARS FOLLOW-UPFROM MASS II TRIAL
Authors: Cibele L. Garzillo, Whady Hueb, Eduardo Gomes Lima, Paulo Cury Rezende, Desiderio Favarato, Paulo Soares, Alexandre Ciappina Hueb, Noedir AG Stolf, Jose Ramires, Roberto Kalil-Filho
Journal: Journal of the American College of Cardiology (2012)
Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity
Authors: Jun Yamagami, Aimee S. Payne, Stephen Kacir, Ken Ishii, Don L. Siegel, John R. Stanley
Journal: Journal of Clinical Investigation (2010)

Pemphigus is a life-threatening autoimmune disease in which antibodies specific for desmogleins (Dsgs) cause loss of keratinocyte cell adhesion and blisters. In order to understand how antibodies cause pathogenicity and whether there are commonalities among antibodies in different patients that could ultimately be used to target specific therapy against these antibodies, we characterized Dsg-specific mAbs cloned by phage display from 3 patients with pemphigus vulgaris and 2 with pemphigus foliaceus. Variable heavy chain gene usage was restricted, but similar genes were used for both pathogenic and nonpathogenic mAbs. However, the heavy chain complementarity-determining region 3 (H-CDR3) of most pathogenic, but not nonpathogenic, mAbs shared an amino acid consensus sequence. Randomization of the H-CDR3 and site-directed mutagenesis indicated that changes in this sequence could block pathogenicity but not necessarily binding. In addition, for 2 antibodies with longer H-CDR3s, a tryptophan was critical for pathogenicity but not binding, a result that is consistent with blocking the tryptophan acceptor site that is thought to be necessary for Dsg-mediated adhesion. These studies indicate that H-CDR3 is critical for pathogenicity of a human autoantibody, that a small region (even 1 amino acid) can mediate pathogenicity, and that pathogenicity can be uncoupled from binding in these antibodies.
A Pathogenetic Role for Mast Cells in Experimental Crescentic Glomerulonephritis
Authors: Jennifer R. Timoshanko, Richard Kitching, Timothy J. Semple, Peter G. Tipping, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2005)

Mast cells infiltrate kidneys of humans with crescentic glomerulonephritis (GN), and the degree of infiltrate correlates with outcome. However, a functional role for mast cells in the pathogenesis of GN remains speculative. GN was induced by intravenous administration of sheep anti-mouse glomerular basement membrane globulin. After 21 d, systemic immune responses and disease severity were analyzed in wild-type, mast cell-deficient (W/Wv), and bone marrow-derived mast cell-reconstituted W/Wv mice (BMMC-->W/Wv). There were no significant differences in the humoral response toward the nephritogenic antigen or in memory T cell number among the three groups; however, antigen-stimulated T cell IFN-gamma production was significantly elevated in BMMC-->W/Wv mice. Dermal delayed-type hypersensitivity in W/Wv mice was reduced compared with wild-type and BMMC-->W/Wv mice. No mast cells were detected in kidneys of W/Wv mice with GN, whereas in BMMC-->W/Wv mice, the numbers of renal mast cells were similar to wild-type mice with GN. W/Wv mice were protected from the development of crescentic GN, exhibiting reduced crescent formation (10 +/- 1% c.f. 36 +/- 2% in wild type), glomerular influx of T cells/macrophages, and interstitial infiltrate compared with wild-type mice. In contrast, BMMC-->W/Wv demonstrated a similar severity of GN as wild-type mice (35 +/- 2% crescentic glomeruli), accompanied by a prominent inflammatory cell infiltrate into glomeruli and interstitial areas. Glomerular expression of intercellular adhesion molecule-1 and P-selectin were reduced in W/Wv mice but restored to wild-type levels in BMMC-->W/Wv mice. These findings suggest that renal mast cells mediate crescentic GN by facilitating effector cell recruitment into glomeruli via augmentation of adhesion molecule expression.
A patient request for some “deprescribing”:
Authors: David Unwin, Simon Tobin
Journal: BMJ (2015)

A 52 year old man with a history of type 2 diabetes for 14 years and hypertension for nine years presented to his general practitioner. He was a non-smoker with an alcohol intake of eight units a week. He had been experiencing bloating, abdominal pains, and erratic motions for more than a year. Because he drove about 12 000 miles a year for his job he found the loose motions "a real worry." He wondered whether any of his problems might be caused by his drugs and asked if he could cut down on any if they weren't all needed. He admitted to being afraid that his diabetic control might deteriorate and that he might need insulin, like some of his relatives who also had diabetes. He was taking aspirin 75 mg once daily, metformin 500 mg three times daily, perindopril 4 mg daily, and simvastatin 40 mg at night. On examination his weight was 108.8 kg (steady at this for 10 years), body mass index was 34.4, waist circumference was 113 cm, and his blood pressure was 130/80 mm Hg (steady at this level for some years). His abdominal examination was normal, except that he had central obesity. Glycated haemoglobin (HbA1c) was 52 mmol/mol (reference range 0-41), bilirubin was 7 µmol/L (0-20), alanine aminotransferase was 53 U/L (5-37), and γ-glutamyl transferase (GGT) was 59 U/L (0-50). In addition, his estimated glomerular filtration rate was 100 mL/min/1.73m2 (90-120), total cholesterol was 3.7 mmol/L (desirable ≤4.0), high density lipoprotein-cholesterol was 1.3 mmol/L (>1.0), and triglycerides were 1.3 mmol/L (<1.7).
Too Many Cooks? Intrinsic and Synaptic Homeostatic Mechanisms in Cortical Circuit Refinement
Authors: Gina Turrigiano
Journal: Annual Review of Neuroscience (2011)

Maintaining the proper balance between excitation and inhibition is critical for the normal function of cortical circuits. This balance is thought to be maintained by an array of homeostatic mechanisms that regulate neuronal and circuit excitability, including mechanisms that target excitatory and inhibitory synapses, and mechanisms that target intrinsic neuronal excitability. In this review, I discuss where and when these mechanisms are used in complex microcircuits, what is currently known about the signaling pathways that underlie them, and how these different ways of achieving network stability cooperate and/or compete. An important challenge for the field of homeostatic plasticity is to assemble our understanding of these individual mechanisms into a coherent view of how microcircuit stability is maintained during experience-dependent circuit refinement.
Infrequent Transitions between Saline and Fresh Waters in One of the Most Abundant Microbial Lineages (SAR11)
Authors: R. Logares, J. Brate, F. Heinrich, K. Shalchian-Tabrizi, S. Bertilsson
Journal: Molecular Biology and Evolution (2009)

The aquatic bacterial group SAR11 is one of the most abundant organisms on Earth, with an estimated global population size of 2.4 × 1028 cells in the oceans. Members of SAR11 have also been detected in brackish and fresh waters, but the evolutionary relationships between the species present in the different environments have been ambiguous. In particular, it was not clear how frequently this lineage has crossed the saline–freshwater boundary during its evolutionary diversification. Due to the huge population size of SAR11 and the potential of microbes for long-distance dispersal, we hypothesized that environmental transitions could have occurred repeatedly during the evolutionary diversification of this group. Here, we have constructed extensive 16S rDNA–based molecular phylogenies and undertaken metagenomic data analyses to assess the frequency of saline–freshwater transitions in SAR11 and to investigate the evolutionary implications of this process. Our analyses indicated that very few saline–freshwater transitions occurred during the evolutionary diversification of SAR11, generating genetically distinct saline and freshwater lineages that do not appear to exchange genes extensively via horizontal gene transfer. In contrast to lineages from saline environments, extant freshwater taxa from diverse, and sometimes distant, geographic locations were very closely related. This points to a rapid diversification and dispersal in fresh waters or to slower evolutionary rates in fresh water SAR11 when compared with marine counterparts. In addition, the colonization of both saline and fresh waters appears to have occurred early in the evolution of SAR11. We conclude that the different biogeochemical conditions that prevail in saline and fresh waters have likely prevented the environmental transitions in SAR11, promoting the evolution of clearly distinct lineages in each environment.
Measurement of Blood Flow in the Femoral Artery in Man at Rest and during Exercise by Local Thermodilution
Authors: V. GANZ, A. HLAVOVÁ, A. FRONĚK, J. LINHART, I. PŘEROVSKÝ
Journal: Circulation (1964)

A new method is described for measuring blood flow in the femoral artery in man, based on local thermodilution. The method makes it possible to take 3 or 4 measurements per minute at rest and during muscular exercise of the investigated limb. The average blood flow in eight subjects at rest was 635.9±223.1 ml./min., or 6.0±2.3 ml./100 ml. limb volume/min. Changes during graded and increased work loads were also measured in 5-minute periods (150, 200, and 250 Kg./min.). The rate of flow rise was faster at the start of a given period than in the latter half of the same period. After the end of the work load, the rate of return of blood flow to the baseline fell off rapidly with time, but by 30 minutes later baseline values had still not been attained.
Variability in the Recurrence Rate at First Follow-up Cystoscopy after TUR in Stage Ta T1 Transitional Cell Carcinoma of the Bladder: A Combined Analysis of Seven EORTC Studies
Authors: Maurizio Brausi, Laurence Collette, Karlheinz Kurth, Adrian P. van der Meijden, Wim Oosterlinck, J.A. Witjes, Donald Newling, Christian Bouffioux, Richard J. Sylvester
Journal: European Urology (2002)
Cisplatin and ultra-violet-C synergistically down-regulate receptor tyrosine kinases in human colorectal cancer cells
Authors: Junji Kawaguchi, Seiji Adachi, Ichiro Yasuda, Takahiro Yamauchi, Masanori Nakashima, Tomohiko Ohno, Masahito Shimizu, Takashi Yoshioka, Masahiko Itani, Osamu Kozawa, Hisataka Moriwaki
Journal: Molecular Cancer (2012)

Abstract Background Platinum-containing anti-cancer drugs such as cisplatin are widely used for patients with various types of cancers, however, resistance to cisplatin is observed in some cases. Whereas we have recently reported that high dose UV-C (200 J/m²) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 μM) and low dose UV-C (10 J/m²) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116. Results The combination inhibited cell cycle and colony formation, while either cisplatin or UV-C alone had little effect. The combination also induced apoptosis in these cells. In addition, the combination caused the downregulation of EGFR and HER2. Moreover, UV-C alone caused the transient internalization of the EGFR, but with time EGFR recycled back to the cell surface, while cisplatin did not affect its localization. Surprisingly, the combination caused persistent internalization of the EGFR, which results in the lasting downregulation of the EGFR. Conclusions The combination of low dose cisplatin and low dose UV-C synergistically exerted anti-cancer effect by down-regulating RTK, such as EGFR and HER2. These findings may provide a novel strategy for the treatment of patients with colorectal cancer.