tbuckley/cabot-search huggingface dataset:
IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden
Authors: Marten van der Zee, Andrea Sacchetti, Medine Cansoy, Rosalie Joosten, Miriam Teeuwssen, Claudia Heijmans-Antonissen, Patricia C. Ewing-Graham, Curt W. Burger, Leen J. Blok, Riccardo Fodde
Journal: Cancer Research (2015)

Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH(hi)) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDH(hi) cells in immunodeficient mice. ALDH(hi) cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDH(lo) cells. Notably, the number of ALDH(hi) cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDH(hi) endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer.
Surgical Palliative Care Consultations Over Time in Relationship to Systemwide Frailty Screening
Authors: Katherine F. Ernst, Daniel E. Hall, Kendra K. Schmid, Georgia Seever, Pierre Lavedan, Thomas G. Lynch, Jason Michael Johanning
Journal: JAMA Surgery (2014)

The need for integrating palliative care into surgical services has been established within the surgical literature. The ability to effectively screen, obtain an appropriately timed consultation, and determine the effect of consultation remains problematic.To examine surgical palliative care consultations over time and their relationship to the initiation and implementation of a systemwide frailty-screening program.We reviewed all surgical palliative care consultations performed between January 1, 2006, and August 31, 2013, and abstracted the referring service (medicine/surgery), date of surgery (if any), date of death (if any), and all variables required to calculate a frailty score using the risk analysis index. We examined changes in mortality and referral patterns before and after implementation of the frailty-screening program using multivariable logistic regression.Surgical palliative care consultations, including frailty screening.The primary study outcomes were 30-, 180-, and 360-day mortality.From 2006 to 2013, a total of 310 palliative care consultations were ordered for surgical patients: 160 before initiation of frailty screening (January 1, 2011) and 150 after initiation of the program. The groups had similar demographics, comorbidities, and frailty scores. After initiation, we observed dramatically decreased mortality at 30, 180, and 360 days (21.3% vs 31.9%, 44.0% vs 70.6%, and 66.0% vs 78.8%, respectively; all P < .05). This coincided with an increased rate of palliative care consultations from 32 per year to 56 per year. After initiation of the program, consultations were more likely to be requested by surgeons (56.7% vs 24.4%; P < .05) and were more likely to occur before the index operation (52.0% vs 26.3%; P < .05). Implementation of the screening program was associated with a 33% reduction in 180-day mortality (odds ratio [OR], 0.37; 95% CI, 0.22-0.62; P < .001) even after controlling for age, frailty, and whether the patients had surgery. Modeled mortality was also reduced when the palliative care consultation was ordered by a surgeon (OR, 0.50; CI, 0.30-0.83; P = .007) or ordered before the operation (OR, 0.52; CI, 0.30-0.90; P = .02).Our data suggest that a systematic frailty-screening program effectively identifies at-risk surgical patients and is associated with a significant reduction in mortality for patients undergoing palliative care consultation. Analysis also suggests that preoperative palliative care consultations ordered by surgeons are associated with reduced mortality rates.
16 Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on endothelial cells in bronchial asthma: role of macrophage-derived tumor necrosis factor α
Authors: P LASSALLE, P GOSSET, Y DELNESTE, A TSICOPOULOS, M JOSEPH, A TONNEL, A CAPRON
Journal: Journal of Allergy and Clinical Immunology (1991)
Compliance with physical activity guidelines in rural, black South Africans in the Limpopo Province: an energy expenditure approach
Authors: Ian Cook, Marianne Alberts, Estelle V Lambert
Journal: British Journal of Sports Medicine (2011)

The authors used an energy expenditure-based approach to determine the non-compliance and compliance with public health physical activity (PA) guidelines in rural, black South Africans.The authors analysed 7-day objectively measured PA data (NL-2000 pedometer) in 508 females and 267 males. Compliance was defined for the American College of Sports Medicine guideline (ACSM: ≥7.5 to <21 kcal/kg/week and ≥1.5 kcal/kg/day for ≥5 days/week) and the Institute of Medicine guideline (IOM: ≥21 kcal/kg/week and ≥3 kcal/kg/day for 7 days/week).The age- and sex-adjusted prevalence for non-compliance, ACSM compliance and IOM compliance in the sample was 7.8%, 55.0% and 37.2%, respectively. Complying with IOM guidelines required substantially more ambulation (14 522 steps/day) than ACSM guidelines (10 837 steps/day) and non-compliance (6420 steps/day) (p<0.0001). Approximately 95% of IOM-compliant subjects and 51% of ACSM-compliant subjects achieved ≥10 000 steps/day on 4-7 days. Compliance with IOM or ACSM guideline was associated with an 87% (p<0.0001) and a 49% (p=0.0647) reduced risk of obesity, respectively. Partial and full IOM compliance was associated with a significantly reduced risk of obesity (OR=0.58 to 0.16, p<0.04).The 10 000 steps/day guideline concurs with the ACSM guideline, whereas IOM compliance required higher ambulation levels. Compared with ACSM compliance, IOM compliance was associated with a lower risk of obesity.
Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen
Authors: Debra L. Laskin, Carol R. Gardner, Veronica F. Price, David J. Jollow
Journal: Hepatology (1995)

Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophenmercapturic acid. LPS treatment of rats caused a general depression of acetaminophen metabolism involving all of the known pathways of metabolic clearance, resulting in a decrease in the blood half-life of the drug. However, the fraction of the dose converted to the toxic metabolite (NAPQI) was not different from that observed in rats given acetaminophen alone. Collectively, these data indicate that the protection afforded the animals by pretreatment with macrophage modulators was not due to suppression of the formation of NAPQI and hence support the hypothesis that macrophages may contribute directly to acetaminophen hepatotoxicity by an independent mechanism. (Hepatology 1995; 21:1045-1050.)
Human T cell leukemia virus-I-associated T-suppressor cell inhibition of erythropoiesis in a patient with pure red cell aplasia and chronic T gamma-lymphoproliferative disease.
Authors: L J Levitt, G R Reyes, D K Moonka, K Bensch, R A Miller, E G Engleman
Journal: Journal of Clinical Investigation (1988)

Human retroviruses have recently been linked with T cell lymphoproliferative disorders and with the acquired immune deficiency syndrome. We investigated the mechanisms for acquired pure red cell aplasia and cutaneous anergy in a patient with the chronic T gamma-lymphoproliferative disease (T gamma-LPD) syndrome. Patient marrow erythroid progenitors (BFU-E) were 17 +/- 9% of control and were selectively increased to 88-102% of control after marrow T cell depletion. Patient Leu 2+ suppressor T cells spontaneously produced high titers of human gamma-interferon and resulted in a concentration-dependent selective inhibition (74-91%) of BFU-E when co-cultured with autologous or allogeneic marrow. Conditioned media (CM) derived from patient Leu 2+ T cells similarly inhibited growth of autologous or allogeneic marrow BFU-E. The inhibitory factor derived from patient CM was acid-labile (pH 2) and sensitive to trypsin; prior treatment of patient T cells with anti-HLA-DR monoclonal antibody plus complement abrogated the suppressive effect of T cell-derived CM. Patient peripheral blood mononuclear cells (PBMC) were unable to support growth of cultured interleukin 2 (IL 2)-dependent T cells, but responded to exogenous IL 2 in vitro with a 16-21-fold augmentation, relative to control, in mitogen-induced proliferation. Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24. Patient cultured PBMC demonstrated integrated HTLV-I genomic sequences by the Southern technique and expressed both specific HTLV-I genomic sequences by RNA dot blot plus reverse transcriptase activity. Utilizing a cloned DNA probe for the beta chain of the T cell receptor gene, patient PMBC demonstrated gene rearrangements providing presumptive evidence for clonality. The presence in serum of HTLV-I p19 and p24 antibodies, the expression of p19 and p24 core antigens on patient mononuclear cells, the evidence of HTLV-I proviral integration sequences and the expression of HTLV-I genomic sequences in patient cells, indicates infection with HTLV-I and raises the possibility of an etiologic link between human retrovirus infection and some instances of large granular lymphocytic leukemia (T gamma-LPD).
Myosin Light Chain Phosphatase
Authors: R. John Solaro
Journal: Circulation Research (2000)

lthough several myofilament proteins are modified by protein phosphorylation, the 18-kDa myosin light chain 2 (MLC2) has special significance.In striated muscle, after some experimental struggles, MLC2 phosphorylation was shown to modulate myofilament activation by Ca 2ϩ . 1 However, in the case of smooth muscle, phosphorylation of the MLC2 by a Ca 2ϩ calmodulin-dependent kinase triggers contraction. 2The state of MLC2 phosphorylation in smooth muscle determines whether crossbridges are turned off, cycling, or in a latch or catch-like state.Understandably, the initial focus of experiments was on Ca 2ϩ and the regulation of MLC2 kinase (MLCK) activity.It was always understood that control of the level of MLC phosphorylation requires some balance of activities and separation of powers between an MLCK and MLC2 phosphatase (MLCP), 3 yet little attention was given to the possibility that the activity of MLCP could be modulated.Now MLCP seems to be the Cinderella of phosphoryl group transfer enzymes.This mindset concerning regulation of MLC2 phosphorylation changed dramatically with two observations.One was evidence that addition of GTP-␥-S to permeable preparations of smooth muscle was able to sensitize the myofilaments to Ca 2ϩ and slow down relaxation, alterations suggesting modulation of MLCP. 4 A second was the elucidation of the functional domains of MLCP, 5 which consist of a 37-kDa catalytic subunit, a 20-kDa subunit of unknown function, and a 110-to 130-kDa subunit that targets MLCP to myosin.This targeting domain of MLCP, which is termed myosin binding site (MBS) or myosin phosphatase targeting peptide, binds to myosin or MLC2 and promotes catalytic activity of the 37-kDa domain.MBS was also shown to contain Ser and Thr residues, which, when phosphorylated, inhibit the ability of MBS to activate the catalytic domain, thereby reducing activity of the MLCP holoenzyme. 5A significant pathway for modulation of MLCP activity is by a signaling cascade involving the small G protein Rho and its activation of Rho-kinase, which phosphorylates MBS. 6 -
P377Late sodium current as a promising drug target for treatment of atrial fibrillation?
Authors: C Poulet, L Fabritz, U Ravens
Journal: Cardiovascular Research (2014)

Background: Slowly inactivating Na+channels conducting “late” Na+currents (INa, late) contribute to ventricular arrhythmogenesis under pathological conditions. It was recently suggested that INa, late also plays a role in chronic atrial fibrillation (AF). In the present study, we investigated the presence of late Na+ currents in atrial myocytes from patients in sinus rhythm (SR) and AF, and their potential influence on action potential (AP) shape. Methods & Results: We validated 2 voltage-clamp protocols for the detection of late Na+ currents using ΔKPQ mice (LQT3), which were previoulsy shown to have increased INa,late in cardiomyocytes. In both protocols, Na+ channels were activated by a rectangular test pulse to -30 mV and we found that 250 ms after Na+ channel activation, current amplitude was significantly reduced upon application of 10 μM tetrodotoxin (TTX). We measured the amplitude of TTX-sensitive currents to estimate the density of INa,late and found 0.27 ± 0.06 pA/pF in ventricular cells and 0.18 ± 0.05 pA/pF in atrial myocytes. In human, TTX significantly reduced current amplitude, 50 and 250 ms after Na+ channel activation, only in cardiomyocytes from AF patients. In those cells, INa,late amplitude amounted to 0.16 ± 0.02 pA/pF versus 0.01 ± 0.01 pA/pF in SR myocytes (p < 0.001). Similar resuts were obtained when 30 μM ranolazine was used to block Na+ currents. In AF cells, INa,late amplitude averaged at 0.14 ± 0.02 pA/pF versus 0.04 ± 0.03 pA/pF in SR myocytes (p < 0.05). At 37°C, We detected INa,late only 50 ms after Na+ channel activation, suggesting a faster inactivation of the current at physiological temperature. Action potentials (APs) were further recorded in intact trabeculae from SR and AF patients. We found that 30 μM ranolazine significantly reduced the plateau potential in AF preparations, in line with the block of a small depolarizing current during the first 100 ms of the AP. This was not observed in SR trabeculae. Conclusions: Taken together, these results suggest the existence of a small lNa,late in atrial myocytes from patients with AF, which might participate in altering the AP shape.
Comments Regarding “My Thyroid Story”
Authors: David L. Keller
Journal: JAMA Internal Medicine (2014)

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Inhibition of the T790M Gatekeeper Mutant of the Epidermal Growth Factor Receptor by EXEL-7647
Authors: Steven B. Gendreau, Richard Ventura, Paul Keast, A. Douglas Laird, F. Michael Yakes, Wentao Zhang, Frauke Bentzien, Belinda Cancilla, Jeffery Lutman, Felix Chu, Lisa Jackman, Yongchang Shi, Peiwen Yu, Jing Wang, Dana T. Aftab, Christopher T. Jaeger, Stephanie M. Meyer, Anushka De Costa, Kelly Engell, Jason Chen, Jean-Francois Martini, Alison H. Joly
Journal: Clinical Cancer Research (2007)

Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.
Erythropoiesis Abnormalities Contribute to Early-Onset Anemia in Patients with Septic Shock
Authors: Yann-Erick Claessens, Michaëla Fontenay, Frédéric Pene, Jean-Daniel Chiche, Martine Guesnu, Cyrla Hababou, Nicole Casadevall, Jean-Francçois Dhainaut, Jean-Paul Mira, Alain Cariou
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

The intimate mechanisms of early onset anemia observed in critically ill patients with septic shock remain unclear.We investigated erythropoiesis abnormalities in this setting by studying morphologic, functional, and biochemical patterns of erythroid lineage.Erythroid lineage in the bone marrow from patients with septic shock who developed early-onset anemia was compared with that of healthy control subjects. Survival and proliferation capacities were quantified in both groups. Biochemical and flow cytometry patterns of apoptosis were dissected by exploring antiapoptotic (erythropoietin [Epo] receptor-dependent) and proapoptotic (death receptor-dependent) pathways.Erythroid lineage was morphologically similar in both groups. Apoptosis of glycophorin-A-positive erythroid precursors was increased in patients versus control subjects as assessed by labeling with annexin V (26.1 +/- 8.8 vs. 3.1 +/- 2.9%, p < 0.05) or 3-3'-dihexyloxacarbocyanine iodide (55.9 +/- 10.5 vs. 19.1 +/- 5.4%, p < 0.05), respectively. This was associated with significant overexpression of Fas on erythroid precursors and higher tumor necrosis factor-alpha plasma levels in patients with septic shock vs. control subjects. Moreover, growth capacities of late erythroid progenitors of burst-forming unit erythroids (BFU-Es) at Day 10 were impaired in the presence of serum from patients with septic shock as compared with the effect of serum from control subjects (27 +/- 12 vs. 109 +/- 27 per 10(5) seeded cells, respectively; p < 0.001). Saturating concentrations of recombinant human Epo (rHuEpo) restored growth capacity of patients' BFU-Es (72 +/- 14 per 10(5) seeded cells) in autologous conditions of serum.Early-onset anemia that may be observed in patients with septic shock is associated with defective erythropoiesis related to an excess of apoptosis that can be counterbalanced in vitro by rHuEpo.
British urologists provide a cost effective service
Authors: G M. Flannigan
Journal: BMJ (1996)

British urologists provide a cost effective service EDrrOR,-The juxtaposition of Linda Beecham's article on NHS doctors' pay' and Charles-Gene McDaniel's article on American doctors' income2 leads to comparisons of the earning capacity of different doctors.It would be fair, however, also to compare the work that each of the two groups does, and I have considered urol- ogy on the two sides ofthe Atlantic.For a current maximum annual salary in Britain of £52 440 and an average American salary of £100 000, the two groups of urologists do quite different aver- age amounts of work.The ratio ofpopulation to consultants in urology in the United States is roughly 200 million to 9000,