tbuckley/cabot-search huggingface dataset:
Molecular Pathways: microRNAs, Cancer Cells, and Microenvironment
Authors: Ioana Berindan-Neagoe, George A. Calin
Journal: Clinical Cancer Research (2014)

Abstract One of the most unexpected discoveries in molecular oncology over the last decade is the interplay between abnormalities in protein-coding genes and short noncoding microRNAs (miRNA) that are causally involved in cancer initiation, progression, and dissemination. This phenomenon was initially defined in malignant cells; however, in recent years, more data have accumulated describing the active participation of miRNAs produced by microenvironment cells. As hormones, miRNAs can be released by a donor cell in various forms of vesicles or as “free” molecules secreted by active mechanisms. These miRNAs spread as signaling molecules that are uptaken either as exosomes or as “free” RNAs, by cells located in other parts of the organism. Here, we discuss the communication between cancer cells and the microenvironment through miRNAs. We further expand this in a more translational context and present miRNAs as predictors of treatment response, as crucial agents in targeted therapeutics, and as significant molecules to target. Clin Cancer Res; 20(24); 6247–53. ©2014 AACR.
Angiogenesis modulates adipogenesis and obesity
Authors: Yihai Cao
Journal: Journal of Clinical Investigation (2007)

Substantial evidence shows that neoplastic and nonneoplastic tissue growth is dependent on angiogenesis. Neovascularization and adipogenesis are temporally and spatially coupled processes during prenatal life and they continue to reciprocally interact via paracrine signaling systems throughout adult life. Activated adipocytes produce multiple angiogenic factors including leptin, angiopoietins, HGF, GM-CSF, VEGF, FGF-2, and TGF-β, which either alone or collectively stimulate neovascularization during fat mass expansion. Thus antiangiogenic agents provide a novel therapeutic option for prevention and treatment of human obesity and its related disorders.
Differential Response to Trichloroethylene-Induced Hepatosteatosis in Wild-Type and PPARα-Humanized Mice
Authors: Doni Hikmat Ramdhan, Michihiro Kamijima, Dong Wang, Yuki Ito, Hisao Naito, Yukie Yanagiba, Yumi Hayashi, Naoki Tanaka, Toshifumi Aoyama, Frank J. Gonzalez, Tamie Nakajima
Journal: Environmental Health Perspectives (2010)

BackgroundTrichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor α (PPAR) α, which is involved in lipid homeostasis and anti-inflammation.ObjectiveWe examined the role of mouse and human PPARα in TRI-induced hepatic steatosis and toxicity.MethodsMale wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements.ResultsPlasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Pparα-null and hPPARα mice. No differences were observed in TRI-mediated induction of hepatic PPARα target genes except for a few genes that differed between mPPARα and hPPARα mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPARγ in Pparα-null and hPPARα mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFκB) p52 mRNA and protein in all mice regardless of PPARα genotype.ConclusionsNFκB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARα may be involved in TRI-induced hepatosteatosis. However, human PPARα may afford only weak protection against TRI-mediated effects compared with mouse PPARα.
Portion Sizes and Beyond — Government's Legal Authority to Regulate Food-Industry Practices
Authors: Jennifer L. Pomeranz, Kelly D. Brownell
Journal: New England Journal of Medicine (2012)

der too close.With strong empirical research, it should be possible to identify which marketing strategies place people at risk or undermine their health, as well as to quantify the magnitude of risk.This kind of knowledge should be applied in informing regulations that could govern the design and placement of foods in retail outlets to protect consumers.We need to test new approaches to risk reduction that do not place additional cognitive demands on the population, such as limiting the types of foods that can be displayed in prominent end-of-aisle locations and restricting foods associated with chronic diseases to locations that require a deliberate search to find.Harnessing marketing research to control obesity could help millions of people who desperately want to reduce their risks of chronic diseases.
Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma
Authors: Nathalène Truffaux, Cathy Philippe, Janna Paulsson, Felipe Andreiuolo, Léa Guerrini-Rousseau, Gaétan Cornilleau, Ludivine Le Dret, Catherine Richon, Ludovic Lacroix, Stéphanie Puget, Birgit Geoerger, Gilles Vassal, Arne Östman, Jacques Grill
Journal: Neuro-Oncology (2014)

Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG). We explored in vitro on new DIPG models the efficacy of dasatinib, a multi-tyrosine kinase inhibitor targeting this receptor. Gene expression profiles were generated from 41 DIPGs biopsied at diagnosis and compared with the signature associated with sensitivity/resistance to dasatinib. A panel of 12 new DIPG cell lines were established from biopsy at diagnosis, serially passaged, and characterized by gene expression analyses. Effects of dasatinib (1–10 μM) on proliferation, invasion, and cytotoxicity were determined on 4 of these cell lines using live-cell imaging and flow cytometry assays. Downstream signaling and receptor tyrosine kinases (RTKs) were assessed by western blot and phospho-RTK array. The effect of the combination with the c-Met inhibitor cabozantinib was studied on cellular growth and invasion analyzed by the Chou–Talaly method. DIPG primary tumors and cell lines exhibited the gene expression signature of sensitivity to dasatinib. Dasatinib reduced proliferation (half-maximal inhibitory concentration = 10–100 nM) and invasion (30%–60% reduction) at 100 nM in 4/4 cultures and induced apoptosis in 1 of 4 DIPG cell lines. Activity of downstream effectors of dasatinib targets including activin receptor 1 was strongly reduced. Since multiple RTKs were activated simultaneously in DIPG cell lines, including c-Met, which can be also amplified in DIPG, the benefit of the combination of dasatinib with cabozantinib was explored for its synergistic effects on proliferation and migration/invasion in these cell lines. Dasatinib exhibits antitumor effects in vitro that could be increased by the combination with another RTK inhibitor targeting c-Met.
Neuromuscular Diseases: A Practical Approach to Diagnosis and Management
Authors: Irwin M. Siegel
Journal: JAMA (1982)

It is remarkable how much information this concise volume manages to convey in less than 300 pages of text. The subject matter is organized into 20 chapters, divided into six sections. The first section, "General Principles," includes investigative methods and a review of normal and abnormal electromyograms and muscle, and nerve biopsy, and closes with a discussion of compensatory mechanisms in neuromuscular diseases. The next part catalogues a simple working classification of neurogenic disorders by anatomic site of pathology. Myopathies are listed according to whether they are congenital or acquired. There is a separate grouping for those muscle diseases (eg, polymyositis) about which more is known. Section 3 deals with neurogenic disorders and contains an excellent chapter on nerve compression, entrapment syndromes, and other mononeuropathies. Section 4 considers the muscular dystrophies and acquired myopathies, section 5 disorders of the neuromuscular junction, and section 6 miscellaneous clinical problems, including muscle cramps,
Jaundice Following the Administration of 50 mg. of Chlorpromazine
Authors: Ralph M. Sussman, Philip Sumner
Journal: New England Journal of Medicine (1955)

CURRENT interest in chlorpromazine — 10 (ydimethylaminopropyl) -2-chlorophenothiazine —hydrochloride is reflected in the widespread use of this drug in many of the specialties of medicine. First introduced by French workers,1 , 2 it has been used for the suppression of nausea and vomiting of varied origin.3 4 5 More recently, it has been recommended for the treatment of mental disturbances6 , 7 and intractable hiccup.8 The known side effects are drowsiness, postural hypotension,9 which may lead to renal insufficiency, tachycardia, dryness of the mouth, nasal congestion, pyrosis and constipation. Miosis and sometimes mydriasis, mild increase in temperature, agranulocytosis,10 11 12 eosinophilia13 and allergic reactions, which are for the . . .
The genome sequence of African rice (Oryza glaberrima) and evidence for independent domestication
Authors: Muhua Wang, Yeisoo Yu, Georg Haberer, Pradeep Reddy Marri, Chuanzhu Fan, Jose Luis Goicoechea, Andrea Zuccolo, Xiang Song, Dave Kudrna, Jetty S S Ammiraju, Rosa Maria Cossu, Carlos Maldonado, Jinfeng Chen, Seunghee Lee, Nick Sisneros, Kristi de Baynast, Wolfgang Golser, Marina Wissotski, Woojin Kim, Paul Sanchez, Marie-Noelle Ndjiondjop, Kayode Sanni, Manyuan Long, Judith Carney, Olivier Panaud, Thomas Wicker, Carlos A Machado, Mingsheng Chen, Klaus F X Mayer, Steve Rounsley, Rod A Wing
Journal: Nature Genetics (2014)

The cultivation of rice in Africa dates back more than 3,000 years. Interestingly, African rice is not of the same origin as Asian rice (Oryza sativa L.) but rather is an entirely different species (i.e., Oryza glaberrima Steud.). Here we present a high-quality assembly and annotation of the O. glaberrima genome and detailed analyses of its evolutionary history of domestication and selection. Population genomics analyses of 20 O. glaberrima and 94 Oryza barthii accessions support the hypothesis that O. glaberrima was domesticated in a single region along the Niger river as opposed to noncentric domestication events across Africa. We detected evidence for artificial selection at a genome-wide scale, as well as with a set of O. glaberrima genes orthologous to O. sativa genes that are known to be associated with domestication, thus indicating convergent yet independent selection of a common set of genes during two geographically and culturally distinct domestication processes.
Retinoid agonist Am80-enhanced neutrophil bactericidal activity arising from granulopoiesis in vitro and in a neutropenic mouse model
Authors: Wanjing Ding, Hiroyuki Shimada, Lin Li, Rahul Mittal, Xiaokun Zhang, Koichi Shudo, Qiaojun He, Nemani V. Prasadarao, Lingtao Wu
Journal: Blood (2012)
Book Review Human Anatomy: Text and colour atlas Second edition. By J.A. Gosling, P.F. Harris, J.R. Humpherson, I. Whitmore, and P.L.T. Willan. Approximately 400 pp., illustrated. London, Gower, 1991. $49.50. (Distributed in the U.S. by J.B. Lippincott, Philadelphia.)
Authors: Barbara C. Fullerton
Journal: New England Journal of Medicine (1991)
Leukotriene D<sub>4</sub>Activates Alveolar Epithelial Na,K-ATPase and Increases Alveolar Fluid Clearance
Authors: Daniel E. Sloniewsky, Karen M. Ridge, Yochai Adir, Francine P. Fries, Arturo Briva, Jacob I. Sznajder, Peter H. S. Sporn
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Cysteinyl leukotrienes are increased during acute lung injury in animals and humans. In this study, we determined the effect of leukotriene D4 (LTD4) on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. LTD4 (1 x 10(-7) M) increased Na,K-ATPase activity at 1 and 5 minutes by 14% (p < 0.05) and 31% (p < 0.001), respectively, in A549 alveolar epithelial cells. This was accompanied by recruitment of Na,K-ATPase alpha1 subunits from intracellular compartment(s) to the basolateral plasma membrane. LTD4-induced alpha1 Na,K-ATPase membrane translocation was blocked by the dual cysteinyl LT1 (cysLT1)/ cysteinyl LT3 (cysLT3) receptor antagonist BAY-u9773, but not by the cysLT1 antagonist MK571, implicating the cysLT3 receptor. Expression of mRNA for cysLT2, but not cysLT1, was confirmed in A549 cells and rat alveolar type 2 cells by reverse transcriptase-polymerase chain reaction. Finally, compared with control, LTD4 (1 x 10(-11) M) increased alveolar fluid clearance by 41% (p < 0.001) in isolated, perfused rat lungs; this was also blocked by BAY-u9773 but not MK571. By activating alveolar epithelial Na,K-ATPase and increasing alveolar fluid reabsorption, cysteinyl leukotrienes may, in part, have a beneficial role in the acute respiratory distress syndrome.
A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells
Authors: Kathryn W. Juchem, Britt E. Anderson, Cuiling Zhang, Jennifer M. McNiff, Anthony J. Demetris, Donna L. Farber, Andrew J. Caton, Warren D. Shlomchik, Mark J. Shlomchik
Journal: Blood (2011)
Abstract A9: Preclinical modeling of responses and resistance of residual metastatic disease to adjuvant chemotherapy
Authors: Chi-Ping Day, John Carter, Carrie Bonomi, Melinda Hollingshead, Glenn Merlino
Journal: Clinical Cancer Research (2010)

Abstract The questionable predictive power of available preclinical models is explained in part by their failure to adequately replicate the clinical setting. Prevailing human xenograft models do not consider advanced disease, require the use of immunocompromised mice that reconstitute aberrant tumor-host interactions, and employ delayed tumor growth as an endpoint, which has limited clinical relevance. To overcome these deficiencies, we have developed a rapid preclinical model of spontaneous metastasis that more accurately recapitulates clinical procedures for advanced non-small cell lung cancer patients. Lewis Lung Carcinoma tumor tissue that was never adapted to cell culture was stably labeled using lentivirus-encoding bioimaging markers, inoculated into syngeneic C57BL/6 mice, and resected upon reaching a predetermined size. Mice were then treated in a setting akin to post-surgical, first-line adjuvant chemotherapy using cisplatin, paclitaxel and/or antiangiogenic agents. As in the clinic, these drugs were most effective against progression in combination. However, the response of metastases to agents could not be predicted from, and often opposed, their effects on subcutaneous tumors. Time to macrometastatic onset, instead of growth, correlated with mouse survival. Moreover, the most effective adjuvant chemotherapy did not inhibit growth, but rather extended the equivalent of clinical dormancy. These results indicate that metastatic disease is driven by micrometastatic to macrometastatic transition, and resistance to therapies is caused by the failure to maintain clinical dormancy. Identification of the mechanisms involved in these processes will provide new targets of anti-cancer therapies and biomarkers for monitoring therapeutic efficacy. We demonstrate the inadequacies of current preclinical models, and introduce a paradigm for a more clinically relevant model that may more accurately predict therapeutic response in late-stage cancer patients. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A9
Cholestatic Jaundice in Adults
Authors: Murry G. Fischer
Journal: JAMA (1981)

IN TWO prior publications in this series, algorithms were presented that primarily dealt with the diagnosis of jaundice in the newborn<sup>1</sup>and with medical causes of jaundice in older children and adults.<sup>2</sup>In the latter publication, the author concluded that "the most difficult problem in the diagnosis of jaundice is the differentiation of intrahepatic from extrahepatic cholestasis." Our algorithms pursue this problem by branching logic using current diagnostic modalities that have become available during the past few years (Fig 1). When conjugated hyperbilirubinemia exists with increasing total bilirubin levels of more than 3 mg/dL, visualization of the biliary tree by conventional oral or intravenous cholecystography (IVC) is unlikely and should not be attempted. The initial step is to determine if there has been recent biliary tract surgery. When a T-tube is still in situ, T-tube cholangiography is the simplest way to opacify the biliary tree and clarify
Abstract 1860: Metabolomics for the identification of prognostic biomarkers of pancreatic cancer.
Authors: Keith Unger, Prabhjit Kaur, Amrita K. Cheema
Journal: Cancer Research (2013)

Abstract Introduction: Although the survival outcomes of Pancreatic Ductal Adenocarcinoma (PDAC) continue to be poor, clinical and basic research in this field is disproportionately under-represented as compared to other cancer sites. Currently, there is no blood or fluid test for diagnosis or prognosis of PDAC. Sensitive and specific biomarkers are thus critical for improving clinical outcomes of PDAC. Our goal in this study was to identify molecular features that could be used for disease stratification. The underlying hypothesis was that targeted, quantitative evaluation of molecular fingerprints of PDAC in serum, calculated originally via matched tissue metabolomic profiles using an untargeted approach may have direct clinical applicability. Approach: We have used mass spectrometry based metabolomics, an emerging field that provides new information on biological perturbations based on changes in multiple endogenous metabolites. These metabolites represent the endpoint of cellular processes and are hence a direct readout of the phenotype or the physiological status. Detection of PDAC using a metabolomics approach is based on the establishment of specific key metabolite signatures in pancreatic tumor tissue derived from patients diagnosed with PDAC. A shortlisted panel of these putative markers was tested for their pre-clinical performance using serum samples from the same patients. This combinatorial approach allowed us to interrogate the PDAC tissue metabolome in a global and unbiased fashion and subsequently test the clinical applicability using a targeted approach in serum samples. Results: The untargeted metabolomics profiling resulted in the identification of a panel of key metabolites which could help discriminate PDAC tissue profiles from pancreatitis and colo-rectal tumor tissue. Validation of these metabolites in serum is ongoing. Conclusion: Our results demonstrate the power of metabolomics for developing clinical assays for diagnosis and prognosis of PDAC. Identification of cellular target molecules, associated with pancreas cancer oncogenesis, progression and metastasis is critical for designing new treatment options for advanced stage disease. Developing a specific and sensitive panel of bio-markers offers a pragmatic approach towards increasing overall survival rates; identify molecular targets for therapeutic development, improving treatment strategies and thus clinical outcomes Supported by American Cancer Society Citation Format: Keith Unger, Prabhjit Kaur, Amrita K. Cheema. Metabolomics for the identification of prognostic biomarkers of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2013-1860
Randomized trial of late elective angioplasty versus conservative management for patients with residual stenoses after thrombolytic treatment of myocardial infarction. Treatment of Post-Thrombolytic Stenoses (TOPS) Study Group.
Authors: S G Ellis, M R Mooney, B S George, E E da Silva, J D Talley, W H Flanagan, E J Topol
Journal: Circulation (1992)

BACKGROUND After thrombolytic therapy for patients with acute myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA) is frequently performed because of the presence of a "significant" infarct vessel stenosis demonstrated at predischarge coronary angiography. Several studies have shown PTCA performed early after thrombolysis to be unnecessary or even harmful. However, PTCA in these trials was generally performed 1-3 days after MI, when the milieu in the infarct artery may be unsuited for PTCA, and the incidence of major ischemic complications was high. To date, no trial has assessed whether delayed PTCA (4-14 days) should be performed in patients without evidence of ischemia on stress testing. METHODS AND RESULTS To test the hypothesis that delayed PTCA might provide clinical benefit compared with medical therapy alone, 87 patients treated within 6 hours of chest pain onset with thrombolytic therapy and with negative functional test were randomized between PTCA to be performed 4-14 days after MI versus no PTCA. Both groups received medical therapy. Patients with postinfarct angina or prior Q wave infarction in the infarct distribution were excluded. The primary study end point was increase in left ventricular ejection fraction with exercise measured by radionuclide studies 6 weeks after MI, a parameter known from other studies to correlate inversely with future ischemic events. Clinical outcome was also monitored for 12 months. There were no differences between the study groups for any prerandomization variable recorded. Mean age was 57 +/- 10 years, 84% of patients were male, 21% had prior MI, 36% had anterior MI, 7% had multivessel disease, and the infarct stenosis measured 70 +/- 17% before randomization. PTCA was successful in 38 of 42 patients (88%) but resulted in non-Q wave MI due to acute closure of the treated site in three of 42 (9.5%). There was no difference in 6-week resting ejection fraction or increase in ejection fraction with exercise between the two groups (47 +/- 12% and 6 +/- 8%, respectively, in the PTCA group; 49 +/- 10% and 5 +/- 9% in the no-PTCA group; p = NS for both.) There were no deaths in either group. Actuarial 12-month infarct-free survival was 97.8% in the no-PTCA group and 90.5% in the PTCA group (p = 0.07). CONCLUSIONS There was no functional or clinical benefit from routine late PTCA after MI treated with thrombolytic therapy in this relatively low-risk cohort of patients. These data strongly suggest that patients with an uncomplicated MI after thrombolytic therapy, even if they have a "significant" residual stenosis of the infarct vessel, should be treated medically if they are without evidence of ischemia on stress testing before hospital discharge.