tbuckley/cabot-search huggingface dataset:
Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma
Authors: Deborah JL Wong, Lidia Robert, Mohammad S Atefi, Amanda Lassen, Geetha Avarappatt, Michael Cerniglia, Earl Avramis, Jennifer Tsoi, David Foulad, Thomas G Graeber, Begonya Comin-Anduix, Ahmed Samatar, Roger S Lo, Antoni Ribas
Journal: Molecular Cancer (2014)

In melanoma, dysregulation of the MAPK pathway, usually via BRAF V600 or NRAS Q61 somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF V600 , NRAS mutant, or wild-type melanoma. The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined. Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF V600 mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis. Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.
888 ASSOCIATION BETWEEN NAIVE REGULATORY T (TREG) CELLS AND HCV-SPECIFIC IMMUNE RESPONSES IN PATIENTS WITH CHRONIC HEPATITIS C
Authors: N. Rallón, V. Soriano, J. García-Samaniego, M. Lopez, M. Romero, C. Restrepo, S. Lozano, A. Peris, J.M. Benito
Journal: Journal of Hepatology (2009)
EXPERIMENTAL RICKETS IN RATS
Authors: A. M. Pappenheimer, G. F. McCann, T. F. Zucker
Journal: The Journal of Experimental Medicine (1922)

1. Casein phosphorus does not completely prevent the development of rickets when substituted in Diet 84 in amount equivalent to a protective dose of basic potassium phosphate. 2. The protection given by lecithin is equivalent to its phosphorus content. 3. The protection given by yeast is at least proportional to its phosphorus content. An amount carrying sufficient vitamine B to promote growth, but insufficient to provide adequate phosphorus, does not prevent rickets. 4. Vitamine A, in the form of butter or butter fat to the amount of 10 per cent of the diet, neither prevents nor cures rickets. 5. The substitution of 10 per cent of egg albumin in Diet 84 improves the nutrition, but does not prevent rickets. 6. The addition of meat to Diet 84, thereby supplying an abundance of phosphorus, promotes normal growth and normal bone formation. A diet consisting solely of meat and flour is inadequate for proper growth, and leads to changes in the bones comparable with those observed on a diet low in calcium, but rich in phosphorus. 7. A diet has been found which contains the necessary food elements for approximately normal growth, and in which the only known deficiency is phosphorus. This leads regularly to the production of rickets.
The requirement for proteasome activity class I major histocompatibility complex antigen presentation is dictated by the length of preprocessed antigen.
Authors: B Yang, Y S Hahn, C S Hahn, T J Braciale
Journal: The Journal of Experimental Medicine (1996)

Accumulating evidence has implicated the proteasome in the processing of protein along the major histocompatibility complex (MHC) class I presentation pathway. The availability of potent proteasome inhibitors provides an opportunity to examine the role of proteasome function in antigen presentation by MHC class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). We have investigated the processing and presenting of antigenic epitopes from influenza hemagglutinin in target cells treated with the inhibitor of proteasome activity MG132. In the absence of proteasome activity, the processing and presentation of the full-length hemagglutinin was abolished, suggesting the requirement for proteasome function in the processing and presentation of the hemagglutinin glycoprotein. Epitope-containing translation products as short as 21 amino acids when expressed in target cells required proteasome activity for processing and presentation of the hemagglutin epitope to CTLs. However, when endogenous peptides of 17 amino acids or shorter were expressed in target cells, the processing and presentation of epitopes contained in these peptides were insensitive to the proteasome inhibitor. Our results support the hypothesis that proteasome activity is required for the generation of peptides presented by MHC class I molecules and that the requirement for proteasome activity is dependent on the size of the translation product expressed in the target cell. The implications of these findings are discussed.
Iron Regulatory Protein 1 Sustains Mitochondrial Iron Loading and Function in Frataxin Deficiency
Authors: Alain Martelli, Stéphane Schmucker, Laurence Reutenauer, Jacques R.R. Mathieu, Carole Peyssonnaux, Zoubida Karim, Hervé Puy, Bruno Galy, Matthias W. Hentze, Hélène Puccio
Journal: Cell Metabolism (2015)
Health Care Use During 20 Years Following Bariatric Surgery
Authors: Martin Neovius, Kristina Narbro, Catherine Keating, Markku Peltonen, Kajsa Sjöholm, Göran Ågren, Lars Sjöström, Lena Carlsson
Journal: JAMA (2012)

THE LAST 3 DECADES, the prevalence of obesity greatly increased.The most significant increases have occurred among patients with a body mass index [BMI] of 35 or higher (BMI is calculated as weight in kilograms divided by height in meters squared). 1,2uch individuals, who are eligible for bariatric surgery, represent 15% of the adult population, 3 incur a disproportionate share of health care costs relative to moderately obese individuals (BMI, 30-34.9), 4 and have greater risk of premature death. 5ariatric surgery reduces weight and improves diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea. 6][9][10][11][12] Although there are many benefits from bariatric surgery, it is not known whether these translate to reduced long-term health care use.The Swedish study is a long-term prospective, matched cohort study that tracks the effects of bariatric surgery and
Abstract 901: Mitotic kinase inhibitors synergize with PI3K and Akt inhibitors in a novel model of anaplastic thyroid carcinomas
Authors: Marika A. Russo, Antonio Di Cristofano
Journal: Cancer Research (2012)

Abstract Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. We have generated a mouse model in which the simultaneous selective activation of the PI3K pathway and inactivation of p53 in the thyroid epithelial cells leads to the development of ATCs. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control, such as Aurora kinase A (AURKA), its co-activator TPX2, and Polo like kinase-1 (PLK1). These proteins are crucial driving forces for normal mitotic spindle formation, centrosome maturation and separation, and their overexpression has been demonstrated in a wide range of tumors. MLN8237 (AURKA inhibitor), TAK960 and GSK461364 (PLK1 inhibitors) are a promising new generation of anti-mitotic agents. We show that these molecules inhibit cell proliferation and induce cell death in mouse ATC-derived cell lines and in the human ATC cell lines CAL62 and C643. A dose-dependent decrease in the degree of chromosome alignment and spindle bipolarity during mitosis is observed after the treatments, together with a change in mitotic index indicated by the decrease of the mitotic marker pHisH3. FACS analysis reveals a G2/M phase arrest followed by apoptosis. Furthermore, small molecule inhibitors of PI3K or AKT potently synergize with these anti-mitotic compounds. Taken together these data suggest that AURKA and PLK1 inhibitors are promising therapeutic agents against undifferentiated thyroid carcinoma cells, and that concurrent inhibition of key driver pathways is a viable option to increase efficacy in this otherwise invariably lethal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 901. doi:1538-7445.AM2012-901
Phase II Trial of Intravenous Administration of Reolysin® (Reovirus Serotype-3-dearing Strain) in Patients with Metastatic Melanoma
Authors: Evanthia Galanis, Svetomir N Markovic, Vera J Suman, Gerard J Nuovo, Richard G Vile, Timothy J Kottke, Wendy K Nevala, Michael A Thompson, Jean E Lewis, Kandelaria M Rumilla, Victoria Roulstone, Kevin Harrington, Gerald P Linette, William J Maples, Matt Coffey, James Zwiebel, Kari Kendra
Journal: Molecular Therapy (2012)

Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 1010 TCID50 on days 1–5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75–90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13–96 days) and 165 days (range 15 days–15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing. Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 1010 TCID50 on days 1–5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75–90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13–96 days) and 165 days (range 15 days–15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing.
Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits
Authors: Ming-Kai Pan, Chun-Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, Chung-Chin Kuo
Journal: Journal of Clinical Investigation (2014)

Parkinson's disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.
Cytotoxicity of bile salts against biliary epithelium: A study in isolated bile ductule fragments and isolated perfused rat liver
Authors: A Benedetti, D Alvaro, C Bassotti, A Gigliozzi, G Ferretti, T La Rosa, A Di Sario, L Baiocchi, A M Jezequel
Journal: Hepatology (1997)

We evaluated cytotoxic effects of different unconjugated and glycine- and taurine-conjugated bile salts (BS) against bile duct epithelial cells in isolated bile ductule fragments and isolated perfused rat liver. Ultrastructural morphometric studies were performed in polarized rat bile ductule fragments exposed in vitro to increasing concentrations (10-100 μmol/L) of lithocholate (LCA), deoxycholate (DCA), chenodeoxycholate (CDCA), cholate (CA), ursodeoxycholate (UDCA), their taurine-conjugates, and glycoconjugates of cholic (GCA) or chenodeoxycholic acid (GCDCA) for 20, 30, or 75 minutes. To evaluate the cytotoxicity of unconjugated hydrophobic bile salts against biliary epithelium (BDE) in the whole liver, livers were isolated from rats with impaired taurine-conjugation capacity (β-alanine treatment) and perfused for 70 minutes with 2 μmol/min LCA (n = 6), CDCA (n = 6), CA (n = 6), or 0.5 μmol/min tauro-LCA (n = 4). In isolated bile ductule fragments, hydrophobic unconjugated bile salts (LCA, CDCA, DCA) induced a marked damage of intracellular organelles, mainly mitochondria. The damage started at a concentration of 10 μmol/L and became prominent at concentrations higher than 50 μmol/L. No damage of the apical and basolateral membrane was seen and tight junctions appeared intact. UDCA, taurine and glycoconjugated bile salts failed to induce any evident ultrastructural alteration. In taurine- depleted isolated livers, perfused with LCA, CDCA, or CA, bile duct epithelial cells showed no evidence of intracellular damage, despite the increased biliary excretion of unconjugated BS. Marked alterations of the apical cell membrane were seen only in livers perfused with LCA and in isolated segments of the biliary epithelium. In contrast with biliary epithelium, hepatocytes showed prominent subcellular damage with CA and CDCA, and profound alterations of the canalicular membrane with LCA and tauro-LCA. We have shown that, in vitro , BDE cells are not damaged by taurine- or glycine-conjugated BS, but they are very sensitive to cytotoxicity of hydrophobic unconjugated BS. Such sensitivity is not present in the whole liver, probably because of the specificity of BS transport processes, the microvascular architecture of the bile ductal system, and the presence in bile of a physiological surfactant, such as phospholipids.
The fate of clinical sports injury prevention abstracts presented at the 1st world conference on sports injury prevention in oslo 2005
Authors: K Knobloch, U Yoon
Journal: British Journal of Sports Medicine (2011)

Background The World Congress of Sports Injury Prevention initiates in Oslo in 2005 as a unique and comprehensive sports medicine prevention conference. Objective The number and quality of presented abstracts published in BJSM followed by a full paper in the subsequent years is unknown. Hypothesis Randomised controlled trials (RCT) are more likely to be published as full paper versus observational studies following the conference presentation. Design All 154 oral abstracts of the World Congress of Sports Injury Prevention 2005 Oslo and the potential subsequent full text were analysed. Main outcome measures Frequency of publication, time to publication, impact factor, score of CONSORT criteria for RCTs and STROBE for observational studies, as well as minor and major inconsistencies. Results Overall, 76 of the 154 (49%) presented abstracts were published in a peer-reviewed journal with an impact factor of 1.946±0.812. There was no significant difference between the impact factor for RCTs (2.122±1.015) versus observational studies (1.913±0.765, p=0.469). The full paper of RCTs abstracts was published after 17±13 months and after 12±14 months in observational studies (p=0.323) There was a trend towards more observational abstracts being published as a full paper rather than RCTs (71% vs 47%, p=0.078). All of the published abstracts had at least one minor inconsistency while 65% had at least major inconsistencies. Results changed in 90% versus 68% (p=0.158), data were added in 60% versus 30% (p=0.065), and deleted in 40% versus 30%, (p=0.534). An opposite result was published in 0% versus 5% (p=0.481). Conclusion There was no significant difference in the likelihood between RCTs and observational studies being published as full papers after the World Congress of Sports Injury Prevention 2005, neither for impact factor and time to publication. Only about half of the presented abstracts get published in a peer-reviewed journal within 4 years after the conference presentation.
Salmonella Pericarditis: Report of a Case and Review of the Literature
Authors: HUGH S. LEVIN
Journal: Annals of Internal Medicine (1961)

ExcerptPrior to the antibiotic era, bacterial infection was one of the common causes of pericarditis. The incidence of bacterial pericarditis has decreased considerably with the use of antimicrobial agents. The organisms most frequently implicated are the pneumococcus, staphylococcus, hemolytic streptococcus, and tubercle bacillus (1-5). Pericardial involvement in salmonellosis is uncommon (4-5). It is the purpose of this paper to report and discuss the case of a child with salmonella septicemia and pericarditis and to summarize the previously reported cases.CASE REPORTA five-year-old white boy was seen for the first time at Children's Hospital on January 8, 1960. During the...
Lithium and motor vehicle crashes
Authors: Samy Suissa, Mahyar Etminan, Brenda Hemmelgarn
Journal: BMJ (2004)

Research on preventing road traffic injuries in developing countries is neededEditor-The dedication of the World Health Organization's World Health Day 2004 to road safety is recognition of the global threat of road traffic injuries.Increasing population size, vehicle ownership, road infrastructure, and transnational transportation have created a substantial public health burden.However, little epidemiological research has been conducted into preventing road traffic injuries in developing countries.Currently global research and development funding per disability adjusted life year for HIV, asthma, and blindness are $26.2,$10.8, and $5.4, respectively, while only $0.40 for road traffic injuries. 1 Epidemiological studies of successful interventions preventing road traffic injuries have been conducted in developed countries. 2But to assume the same effectiveness in developing countries is inappropriate because of behavioural, vehicular, and environmental differences.A pooled analysis of street lighting intervention data from developed countries shows a protective effect, 3 particularly in pedestrian injury (relative risk 0.56), the most common road traffic injuries in developing countries.Annually, 1.2 million deaths are attributed to road traffic crashes, 85% occurring in developing countries. 4If an intervention such as street lighting could reduce deaths by as much as 30%, there is a potential to save thousands of lives.Various international aid agencies are investing in road infrastructure development.These initiatives could be coupled with the need to develop concrete epidemiological data.Innovative strategies, such as step wedge study design, 5 could lead to the evolution of an evidence based public health approach to this problem.
<i>Ice (2)</i>
Authors: Thomas B. Cole
Journal: JAMA (2013)

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