tbuckley/cabot-search huggingface dataset:
RIP Links TLR4 to Akt and Is Essential for Cell Survival in Response to LPS Stimulation
Authors: Marina S. Vivarelli, Douglas McDonald, Mendy Miller, Nicole Cusson, Michelle Kelliher, Raif S. Geha
Journal: The Journal of Experimental Medicine (2004)

Receptor-interacting protein (RIP) has been reported to associate with tumor necrosis–associated factor (TRAF)2 and TRAF6. Since TRAF2 and TRAF6 play important roles in CD40 signaling and TRAF6 plays an important role in TLR4 signaling, we examined the role of RIP in signaling via CD40 and TLR4. Splenocytes from RIP−/− mice proliferated and underwent isotype switching normally in response to anti-CD40–IL-4 but completely failed to do so in response to LPS–IL-4. However, they normally up-regulated TNF-α and IL-6 gene expression and CD54 and CD86 surface expression after LPS stimulation. RIP−/− splenocytes exhibited increased apoptosis and impaired Akt phosphorylation after LPS stimulation. These results suggest that RIP is essential for cell survival after TLR4 signaling and links TLR4 to the phosphatidylinositol 3 kinase–Akt pathway.
Phase III Trial of Casopitant, a Novel Neurokinin-1 Receptor Antagonist, for the Prevention of Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy
Authors: Jørn Herrstedt, Wichit Apornwirat, Ahmed Shaharyar, Zeba Aziz, Fausto Roila, Simon Van Belle, Mark W. Russo, Jeremey Levin, Salabha Ranganathan, Mary Guckert, Steven M. Grunberg
Journal: Journal of Clinical Oncology (2009)

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.
Migration patterns of dendritic cells in the mouse. Homing to T cell-dependent areas of spleen, and binding within marginal zone.
Authors: J M Austyn, J W Kupiec-Weglinski, D F Hankins, P J Morris
Journal: The Journal of Experimental Medicine (1988)

Using quantitative techniques we have shown elsewhere that dendritic cells (DC) migrate from blood into the spleen, under the control of T cells. Here we traced the localization of DC within the spleen and sought to explain the means by which they entered. DC were labeled with a fluorochrome, Hoescht 33342, and injected intravenously. Spleens were removed 3 or 24 h later and DC were visualized within particular areas that were defined by mAbs and FITC anti-Igs. At 3 h most DC were in the red pulp, whereas by 24 h the majority had homed to T-dependent areas of the white pulp and may have become interdigitating cells. Lymphoid DC, isolated from spleen and perhaps normally present in blood, may thus be a migratory stage distinct from the relatively fixed interdigitating cells. We also developed a frozen section assay to investigate the interaction of DC with various lymphoid elements. When DC were incubated on sections of spleen, at 37 degrees C but not at 4 degrees C they attached specifically within the marginal zone and did not bind to T areas; in contrast, macrophages attached only to red pulp and T cells did not bind specifically. However, DC did not bind to sections of mesenteric lymph node, whereas T cells localized in particular regions at 4 degrees C but not at 37 degrees C, probably the high endothelial venules. DC may thus express "homing receptors," similar to those of T cells, for certain endothelia. We propose that T cells can modify the vascular endothelium in certain areas to allow egress of DC from the bloodstream.
Evaluation of the Quality of Prognosis Studies in Systematic Reviews
Authors: Jill A. Hayden, Pierre Côté, Claire Bombardier
Journal: Annals of Internal Medicine (2006)

Background: To provide valid assessments of answers to prognostic questions, systematic reviews must appraise the quality of the available evidence. However, no standard quality assessment method is currently available. Purpose: To appraise how authors assess the quality of individual studies in systematic reviews about prognosis and to propose recommendations for these quality assessments. Data Sources: English-language publications listed in MEDLINE from 1966 to October 2005 and review of cited references. Study Selection: 163 systematic reviews about prognosis that included assessments of the quality of studies. Data Extraction: A total of 882 distinct quality items were extracted from the assessments that were reported in the various reviews. Using an iterative process, 2 independent reviewers grouped the items into 25 domains. The authors then specifically identified domains necessary to assess potential biases of studies and evaluated how often those domains had been addressed in each review. Data Synthesis: Fourteen of the domains addressed 6 sources of bias related to study participation, study attrition, measurement of prognostic factors, measurement of and controlling for confounding variables, measurement of outcomes, and analysis approaches. Reviews assessed a median of 2 of the 6 potential biases; only 2 (1%) included criteria aimed at appraising all potential sources of bias. Few reviews adequately assessed the impact of confounding (12%), although more than half (59%) appraised the methods used to measure the prognostic factors of interest. Limitations: Reviews may have been missed by the search or misclassified because of incomplete reporting. Validity and reliability testing of the authors' recommendations are required. Conclusions: Quality appraisal, a necessary step in systematic reviews, is incomplete in most reviews of prognosis studies. Adequate quality assessment should include judgments about 6 areas of potential study biases. Authors should incorporate these quality assessments into their synthesis of evidence about prognosis.
Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells
Authors: Hyun-Soo Cho, Takehiro Suzuki, Naoshi Dohmae, Shinya Hayami, Motoko Unoki, Masanori Yoshimatsu, Gouji Toyokawa, Masashi Takawa, Taiping Chen, Julia K. Kurash, Helen I. Field, Bruce A.J. Ponder, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2010)

Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.
Effect of Upper Respiratory Tract Infection in Patients with Neuromuscular Disease
Authors: JANET M. POPONICK, I. JACOBS, GERALD SUPINSKI, ANTHONY F. DiMARCO
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Respiratory muscle strength during acute upper respiratory tract infection (URI) was assessed in patients with various forms of neuromuscular disease. Vital capacity (VC), oxygen saturation, end-tidal PCO2, maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were determined in 25 stable patients with various forms of neuromuscular disease. Thirteen episodes of URI developed in 10 patients. Respiratory parameters were reassessed within 24-36 h following the onset of symptoms in each patient. In patients with URI, mean baseline VC, MIP, and MEP were 1.16 L +/- 0.14, 49.2 cm H2O +/- 6.8, and 35.5 cm H2O +/- 3.8 and fell to 1.01 L +/- 0.15, 37.1 cm H2O +/- 6.2, and 25.5 cm H2O +/- 3.0 during URI (p < 0.05 for each), respectively. Mean baseline PCO2 and oxygen saturation were 39.1 mm Hg +/- 1.1 and 95.1% +/- 1.0, and during URI, 43.9 mm Hg +/- 2.1 (p < 0.05) and 95.0% +/- 1.0 (NS), respectively. Five episodes of significant hypercapnia were observed in 4 patients. All parameters returned to near baseline values following recovery. We conclude that patients with various forms of neuromuscular disease develop reductions in respiratory muscle strength in association with URI. Unlike normal subjects, however, these decrements in respiratory muscle function may result in symptoms of shortness of breath, reductions in vital capacity, and acute hypercapnia in this patient population.
Aldo-Keto Reductases and Bioactivation/Detoxication
Authors: Yi Jin, Trevor M. Penning
Journal: The Annual Review of Pharmacology and Toxicology (2006)

Aldo-keto reductases (AKRs) are soluble NAD(P)(H) oxidoreductases that primarily reduce aldehydes and ketones to primary and secondary alcohols, respectively. The ten known human AKR enzymes can turnover a vast range of substrates, including drugs, carcinogens, and reactive aldehydes. They play central roles in the metabolism of these agents, and this can lead to either their bioactivation or detoxication. AKRs are Phase I drug metabolizing enzymes for a variety of carbonyl-containing drugs and are implicated in cancer chemotherapeutic drug resistance. They are involved in tobacco-carcinogenesis because they activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active o-quinones, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. They also detoxify reactive aldehydes formed from exogenous toxicants, e.g., aflatoxin, endogenous toxicants, and those formed from the breakdown of lipid peroxides. AKRs are stress-regulated genes and play a central role in the cellular response to osmotic, electrophilic, and oxidative stress.
Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer
Authors: M. Zweifel, G.C. Jayson, N.S. Reed, R. Osborne, B. Hassan, J. Ledermann, G. Shreeves, L. Poupard, S.-P. Lu, J. Balkissoon, D.J. Chaplin, G.J.S. Rustin
Journal: Annals of Oncology (2011)
Factors Influencing Cerebral Blood Flow and Metabolism
Authors: PERITZ SCHEINBERG, HAROLD W. JAYNE
Journal: Circulation (1952)

The results of studies utilizing the nitrous oxide technic for measuring cerebral blood flow have been reviewed and divided into three groups: (1) those in which cerebral blood flow and metabolism were normal, (2) those in which cerebral blood flow was increased, and (3) those in which cerebral blood flow and metabolism were decreased. The factors which apparently regulate and control cerebral blood flow and metabolism are reviewed and discussed.
Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme
Authors: Amparo Wolf, Sameer Agnihotri, Johann Micallef, Joydeep Mukherjee, Nesrin Sabha, Rob Cairns, Cynthia Hawkins, Abhijit Guha
Journal: The Journal of Experimental Medicine (2011)

Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the “Warburg effect.” Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1α and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs.
Mixtures of Estrogenic Chemicals Enhance Vitellogenic Response in Sea Bass
Authors: Ana D. Correia, Sandro Freitas, Martin Scholze, José F. Goncalves, Petra Booij, Marja H. Lamoree, Evaristo Mañanós, Maria A. Reis-Henriques
Journal: Environmental Health Perspectives (2007)

The potential impact of natural and synthetic estrogens on aquatic ecosystems has attracted considerable attention because it is currently accepted that their joint effects are more severe when they are present in mixtures. Although it is well-known that they occur as mixtures in the marine environment, there is little information about the combined effects of estrogenic chemicals on marine biota.In 14-day tests with juvenile sea bass, we analyzed singly and in combination the estrogenic activity of estradiol (E(2)), ethynylestradiol (EE(2)), and bisphenol A (BPA) using vitellogenin induction as an end point.Fish were exposed to each compound, and on the basis of these concentration-response data, we predicted mixture effects by applying the model of concentration addition. The mixtures were tested using a fixed-ratio design, and the resulting mixture effects were compared to the predictions.EE(2) was the most potent steroid, with an EC(50) (median effective concentration) of 0.029 microg/L, 3.6 times more potent than E(2) (EC(50) = 0.104 microg/L); BPA was the least potent chemical, with an EC(50) of 77.94 microg/L. The comparative assessment yielded a good agreement between observed and predicted mixture effects.This study demonstrates the potential hazard of these compounds to seawater life by their ability to act together in an additive manner. It provides evidence that concentration addition can be used as a predictive tool for assessing the combined effects of estrogenic chemicals in marine ecosystems.
Chaperone-mediated autophagy: roles in neurodegeneration
Authors: Gang Wang, Zixu Mao
Journal: Translational Neurodegeneration (2014)

Chaperone-mediated autophagy (CMA) selectively delivers cytosolic proteins with an exposed CMA-targeting motif to lysosomes for degradation and plays an important role in protein quality control and cellular homeostasis. A growing body of evidence supports the hypothesis that CMA dysfunction may be involved in the pathogenic process of neurodegenerative diseases. Both down-regulation and compensatory up-regulation in CMA activities have been observed in association with neurodegenerative conditions. Recent studies have revealed several new mechanisms by which CMA function may be involved in the regulation of factors critical for neuronal viability and homeostasis. Here, we summarize these recent advances in the understanding of the relationship between CMA dysfunction and neurodegeneration and discuss the therapeutic potential of targeting CMA in the treatment of neurodegenerative diseases.
Night cough in a population-based sample of children: characteristics, relation to symptoms and associations with measures of asthma severity
Authors: AM Brooke, PC Lambert, PR Burton, C Clarke, DK Luyt, H Simpson
Journal: European Respiratory Journal (1996)

Nocturnal cough in asthma is a common but poorly understood phenomenon. The aims of this study were to determine the relationship between recorded night cough, reported night cough and current wheeze in a population-based sample of children previously identified as wheezy, and to examine the relationship of nocturnal cough to current symptoms, markers of asthma severity and environmental exposure. Children were reassessed in the early school years by measuring current symptoms, ventilatory function, bronchial reactivity, peak flow variability, respiratory symptom diaries and home monitoring of overnight cough, transcutaneous arterial oxygen saturation, room temperature and humidity. Night studies were performed on 59 asymptomatic children and 41 children with current wheeze. Cough occurred more frequently in current wheezers compared to asymptomatic children (16 out of 41 (39%) vs 11 out of 59 (19%)), and more cough episodes were recorded (median 3.5 vs 2.0). Night cough was not associated with bronchial reactivity, peak flow variability, degree of morning dip, mean overnight arterial oxygen saturation, ventilatory function, maternal smoking or treatment of asthma. However, it was associated with lower overnight air temperature. Although night cough is more common in current wheezers, there is poor agreement between recorded and reported night cough. Objective tests of asthma severity are of little use in predicting its presence in this age group. The sleeping environment deserves further study.
Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi.
Authors: A J Ammit, S S Bekir, P R Johnson, J M Hughes, C L Armour, J L Black
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The aim of this study was to examine the process underlying the increase in responsiveness of human bronchus related to sensitization status by examining inflammatory cells in sensitized and nonsensitized tissue. Sensitization status was determined in tissue from 26 subjects by detecting the presence or absence of contraction of bronchial rings to common Australian allergens. Serial sections (6-micron) of bronchial tissue were stained for mast cells, T lymphocytes, and eosinophils. There was no significant difference between the total number of inflammatory cells present in all locations (to a depth of 0.5 mm) of nonsensitized (n = 14) and sensitized (n = 12) bronchi. Similar numbers of cells were present in the two patient groups in epithelium, lamina propria, and adventitia. In contrast, there were significantly (p = 0.03) more inflammatory cells present within the smooth muscle of sensitized bronchi. A significantly (p = 0.04) greater number of mast cells in sensitized (9 [2-14]) versus nonsensitized (2[0-8]) tissue was found in this location (data are median with first and third quartile range). In addition there was a trend toward a greater area of smooth muscle in sensitized tissue. There results suggest that an interaction between smooth muscle and inflammatory cells, especially mast cells, may play a role in bronchial hyperresponsiveness in vitro.
Contrasting short-term effects of nifedipine on glomerular and tubular functions in glomerulonephritic patients.
Authors: A Hartmann, K Lund, H Holdaas, P Fauchald, A Reisaeter, K J Berg
Journal: Journal of the American Society of Nephrology (1994)

The short-term effects of nifedipine on glomerular hemodynamics, sieving function, and renal tubular function were assessed in 10 patients suffering from biopsy-verified chronic glomerulonephritis. Three weeks of nifedipine treatment after 2 wk of placebo significantly reduced the blood pressure from 153 +/- 6/90 +/- 3 to 139 +/- 6/84 +/- 4 mm Hg (mean +/- SE; P < 0.05). Renal vascular resistance was reduced from 0.54 +/- 0.10 to 0.46 +/- 0.08 mm Hg/mL per minute. However, GFR (44.3 +/- 7 mL/min), effective RPF (265 +/- 37 mL/min), and filtration fraction (0.17 +/- 0.01) remained unchanged. The excretion of albumin of 1,318 +/- 395 micrograms/min was not affected by nifedipine. The glomerular sieving estimated by use of the fractional dextran clearance technique revealed no significant change by nifedipine compared with placebo in the range of 30 to 60 A of hydrodynamic dextran radius. Fractional proximal reabsorption (lithium clearance method) was reduced by nifedipine from 53 +/- 5 to 46 +/- 4% (P < 0.05). Also, the excretion of beta 2-microglobulin and N-acetyl-beta-glucosaminidase increased from 10.98 +/- 4.62 to 11.86 +/- 4.74 mg/24 h (P < 0.05) and from 19.7 +/- 4.2 to 25.3 +/- 7.0 nmol/h per micromoles of creatinine (P = 0.05), respectively. It was concluded that nifedipine treatment acutely represses proximal tubular function but is without significant effect on glomerular sieving and albuminuria in these patients.
Levetiracetam improves verbal memory in high-grade glioma patients
Authors: Marjolein de Groot, Linda Douw, Eefje M. Sizoo, Ingeborg Bosma, Femke E. Froklage, Jan J. Heimans, Tjeerd J. Postma, Martin Klein, Jaap C. Reijneveld
Journal: Neuro-Oncology (2012)

Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of older and newer AEDs on cognitive performance in postoperative HGG patients. We selected HGG patients from 3 separate cohorts for use of older, newer, or no AEDs, as they represented distinct treatment eras and provided the opportunity to compare older and newer AEDs. In all 3 cohorts, patients were included within 6 weeks following neurosurgery before the start of postoperative treatment. Cognitive functioning was evaluated by an extensive neuropsychological assessment, executed in 6 cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed). One hundred seventeen patients met the inclusion criteria; 44 patients used no AED, 35 were on monotherapy with a newer AED (all levetiracetam), and 38 were on monotherapy with an older AED (valproic acid or phenytoin). Patients on older and newer AEDs performed equally well as patients not on an AED, and patients on levetiracetam performed even better on verbal memory tests than patients not on an AED. Post-hoc analyses revealed that within the group using older AEDs, patients on valproic acid performed better than patients on phenytoin. Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients.