tbuckley/cabot-search huggingface dataset:
Interleukin-10/Interleukin-5 Responses at Birth Predict Risk for Respiratory Infections in Children with Atopic Family History
Authors: Guicheng Zhang, Julie Rowe, Merci Kusel, Anthony Bosco, Kathy McKenna, Nicholas de Klerk, Peter D. Sly, Patrick G. Holt
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Respiratory infections in early life are associated with risk for wheezing bronchiolitis, especially in children at high risk of atopy. The underlying mechanisms are unknown, but are suspected to involve imbalance(s) in host defense responses against pathogens stemming from functional immaturity of the immune system in this age group.To assess the contribution of eosinophil-trophic IL-5, and the potent antiinflammatory cytokine IL-10, to risk for infection in early life.We prospectively monitored a cohort of 198 high-risk children to age 5 years, recording every acute respiratory infection episode and classifying them by severity. We measured cord blood T-cell capacity to produce IL-10 and IL-5, and related these functions to subsequent infection history. IL-10 and IL-5 were associated, respectively, with resistance versus susceptibility to infections. The greatest contrasting effects of these two cytokines were seen when they were considered in combination by generating IL-10/IL-5 response ratios for each subject. The low IL-10/high IL-5 T-cell response phenotype was strongly associated with susceptibility to all grades of acute respiratory infection, relative to the more resistant high IL-10/low IL-5 phenotype.Excessive production of IL-5 by T cells at birth is associated with heightened risk for subsequent severe respiratory infections, and this risk is attenuated by concomitant IL-10 production. The underlying mechanisms may involve IL-10-mediated feedback inhibition of IL-5-dependent eosinophil-induced inflammation, which is a common feature of host antiviral responses in early life.
Antibodies to intermediate filaments in polymyalgia rheumatica/giant cell arteritis: do they reflect the underlying disease activity rather than the acute phase response?
Authors: I Monteagudo, V Corrigall, G S Panayi, G Pountain, B L Hazleman
Journal: Annals of the Rheumatic Diseases (1994)

Antibodies to intermediate filaments in polymyalgia rheumatica/giant cell arteritis: do they reflect the underlying disease activity rather than the acute phase response?
Response to Letter Regarding Article, “Coronary Artery Calcium: Should We Rely on This Surrogate Marker?”
Authors: Rita F. Redberg
Journal: Circulation (2006)

Should We Rely on This Surrogate Marker?"Drs Schmermund and Erbel take issue with my assertion 1 that coronary artery calcium (CAC) scores, as of now, are not reliable predictors of cardiac events.However, they offer no data to refute this statement.First, they correctly note that CAC is related to coronary atherosclerosis.This relation, however, does not mean CAC is a predictor of cardiac events.Indeed, as coronary atherosclerosis is so prevalent, "only a small proportion of persons with atherosclerosis and detectable coronary calcium will eventually develop clinical coronary events." 2 Therefore, although levels of coronary calcium and atherosclerosis are associated with increased cardiac events on a population level, the relationship in any individual person is weak.Indeed, calcification may stabilize atherosclerotic lesions and make them less likely to rupture and cause an acute cardiac event.Secondly, Schmermund and Erbel argue that CAC scores add prognostic information "over and above" cardiovascular risk factors.I respectfully disagree.The great majority of cardiac events that CAC predicts 3-5 are soft events-revascularizations and unstable angina.Use of such soft events as end points may be misleading.As stated in the 2000 American College of Cardiology/American Heart Association Expert Consensus document, the test result itself often determines who undergoes these procedures, and it is improper to include them as events predicted by the test. 6In addition, the high rate of revascularization after CAC testing is of concern, because no data show any benefit of revascularization in asymptomatic patients. 7hirdly, the studies cited include no data regarding the best proof of incremental predictive value, an increase in area under the receiver operator characteristic curve for risk prediction from CAC testing that is incremental to Framingham Risk Scoring (FRS).Finally, they seem to suggest that calcification does not correlate with cardiac events in people taking statins, but that calcification does correlate in others.Although this hypothesis is interesting, it remains untested.We are fairly skilled at cardiac risk prediction.FRS remains the reference standard, and no test, CAC included, has been shown to significantly increase the accuracy of FRS.More importantly, additional tests such as evaluation of CAC levels have not been shown to lead to better patient outcomes.Risk factors in FRS, including high blood pressure and cholesterol levels, indisputably may be lowered to reduce cardiovascular risk.CAC cannot be treated, even if lowering CAC were shown to reduce cardiovascular risk.On one point, we are in agreement: We clearly need more epidemiological and clinical trial data on the use of CAC.
325. In Vitro Gene Knockdown of Rat Pyruvate Dehydrogenase E1 α mRNA by Self- Complementary Adeno-Associated Virus-Mediated Small Interfering RNA Delivery
Authors: Zongchao Han, Marina Gorbatyuk, Alfred Lewin, Arun Srivastava, Peter Stacpoole
Journal: Molecular Therapy (2006)

Mutations in the E1 α subunit (PDHA1) of the gene pyruvate dehydrogenase complex (PDC) are one of the most common causes of congenital lactic acidosis. An animal model of the E1 α deficiency would provide insight into the pathologic role of PDC mutations in genetic mitochondrial diseases. Small interfering RNAs (siRNAs) designed to cleave the messenger RNA (mRNA) of the E1 α subunit, were constructed and tested in vitro to assess the feasibility of producing a gene knockdown in rats. HEK 293 cells were co- transfected with a rat PDHA1 expression vector and eight naked siRNAs that specifically targeted rat E1 α mRNA.
Estrogen Therapy for Postmenopausal Females
Authors: Robert B. Greenblatt
Journal: New England Journal of Medicine (1965)

ULTIMATELY, as senescence of the ovary sets in — abruptly in some and slowly in others —there is a corresponding decline in estrogen production. The estrogen deficit substantially alters the anabolic-catabolic ratio, and adversely influences metabolic balances. Although the menopause is a physiologic process and represents a period of adjustment to a new milieu intérieur, it is a hormonal-deficiency state.Many physicians still hold the opinion that this period is physiologic, proscribing hormonal treatment but prescribing all manner of sedation.1 The basic principle of therapy should be not only to assuage symptoms but also to cushion the metabolic insult . . .
Hepatic Infarction Detected on Tc-99m Sulfur Colloid Imaging
Authors: TIMOTHY S. BURKE, JAMES L. TATUM
Journal: Clinical Nuclear Medicine (1990)

Hepatic infarctions are rarely encountered, and scintigraphic findings are reported even less frequently in this entity. A patient who developed a left hepatic lobe infarct after surgical resection of a celiac axis aneurysm is described and a brief review of hepatic infarction is presented.
Role of epicardial mesothelial cells in the modification of phenotype and function of adult rat ventricular myocytes in primary coculture.
Authors: H Eid, D M Larson, J P Springhorn, M A Attawia, R C Nayak, T W Smith, R A Kelly
Journal: Circulation Research (1992)

Adult rat ventricular myocytes undergo a well-documented sequence of phenotypic changes during adaptation to primary culture. However, we observed that coculture of myocytes with a specific subset of nonmyocyte cardiac cells could slow and even reverse the process of adaptation. These nonmyocyte cells were isolated and identified by immunohistochemical and ultrastructural criteria as being of epicardial mesothelial origin. When added to long-term primary cultures of adult ventricular myocytes, epicardial mesothelial cells appeared to induce myofibrillar arrays that were more organized than those seen in noncocultured myocytes; these changes that occurred were concurrent with the appearance of large amplitude contractions and multicellular synchronous beating that was facilitated by gap junctions between myocytes and epicardial mesothelial cells. The changes in morphology and function were accompanied by a marked increase in beta-myosin heavy chain isoform transcription in cocultured myocytes, a return to the ratio of cardiac to skeletal alpha-actin expected in adult rat myocardium, and a much reduced expression of smooth muscle alpha-actin. These changes in myocyte phenotype and function appeared to require epicardial cell-myocyte contact, or close apposition, because media conditioned by epicardial mesothelial cells alone or in coculture had no effect. Thus, these rapid and reversible changes in myocyte ultrastructure, function, and gene expression may provide a useful in vitro model with which to study the mechanism responsible for regulating the plasticity of ventricular myocyte phenotype and the role of specific cell-cell interactions.
Insomnia in Prion Diseases: Sporadic and Familial
Authors: Pierluigi Gambetti, Piero Parchi
Journal: New England Journal of Medicine (1999)

In 1920 and 1921, Creutzfeldt and Jakob described a rapidly progressive form of dementia that was apparently sporadic; the description of the familial form appeared shortly thereafter.1 Between 1928 and 1936, Gerstmann, Sträussler, and Scheinker described a slowly progressive familial disease characterized by cerebellar signs. The discovery in 1957 of a third such disease, kuru, a subacute condition affecting a New Guinean tribe that practiced cannibalism, suggested that Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and kuru were related. Since all three diseases were shown to be transmissible to animals, they were grouped under the name “transmissible spongiform encephalopathies” and later came to . . .
MECHANISM OF THYMUS-INDEPENDENT IMMUNOCYTE TRIGGERING
Authors: Antonio Coutinho, Eva Gronowicz, Wesley W. Bullock, Göran Möller
Journal: The Journal of Experimental Medicine (1974)

The present experiments were performed in order to analyze the mechanism by which thymus-independent antigens (nonspecific B-cell mitogens) can induce specific immune responses to antigenic determinants present on the same molecule. The hapten NNP was coupled to the B-cell mitogen, lipopolysaccharide (LPS). The conjugate retained full mitogenic activity and bound specifically to NNP-reactive cells. NNP-LPS activated polyclonal as well as specific anti-NNP antibody synthesis, but the optimal concentrations for induction of specific anti-NNP cells were several orders of magnitude lower than the concentrations required for polyclonal activation. These low concentrations failed to activate nonspecific cells, but they induced specific thymus-independent responses of high-avidity NNP-specific cells with the typical kinetics of antigenic responses in vitro. Furthermore, hapten-specific cells were paralyzed by NNP-LPS concentrations that were optimal for induction of polyclonal activation. Specific activation and paralysis could be abolished by free hapten indicating that selective binding of NNP-LPS to hapten-specific cells was responsible for the specificity of the response. However, the triggering signal lacked specificity, since high-avidity specific anti-NNP cells could still be activated by stimulating concentrations of NNP-LPS in the presence of free hapten, even though the Ig receptor combining sites were presumably occupied by NNP. The findings show that B cells with specific Ig receptors for the antigenic determinants on mitogen molecules preferentially bind these molecules and become activated at concentrations still unsufficient to trigger other B cells that lack specific receptors. It is suggested that activation for primary IgM responses in B cells is the result of "one nonspecific signal." This nonspecific signal is provided by the mitogenic properties of some antigens (highly thymus independent or, alternatively, by nonspecific T-cell factors (for highly T cell-dependent antigens), or both, and the surface structures responsible for triggering are not the Ig receptors. The specific Ig receptors only act as passive focusing devices for nonspecific stimuli, entitling the cell to be selectively activated, even though both the signal and the receptors for the triggering are nonspecific.
Abstract 4336: Oncolytic reovirus as a novel therapy for neuroblastoma
Authors: Amelia Kellar, Nicole Redding, Karen Blote, Qiao Shi, Jason Spurrell, Paul Beaudry, Don Morris
Journal: Cancer Research (2011)

Abstract Background: Neuroblastoma (NB), a tumour of neurocrest progenitor cells of the sympathetic nervous system, is the most common extracranial pediatric tumour and accounts for approximately 15 percent of childhood cancer mortality. Even with surgery, radiation therapy, aggressive cytotoxic chemotherapy including autologous stem cell transplantation and more recently immunotherapy, high risk neuroblastoma has only a 30 percent predicted survival rate. Reovirus, a double-stranded RNA virus, has been shown to be effective against a myriad of cancers through its ability to preferentially lyse cancer cells with aberrant Ras pathway signaling. In this study, we investigate the potential of reovirus (serotype 3, strain Dearing) as a novel treatment for neuroblastoma and neuroblastoma tumour initiating cells (nbTIC). Experimental Design/Results: Reovirus induces dramatic cytotoxic effects at a multiplicity of infection (MOI) of 40 within 48h as assessed by WST-1 viability assays for the IMR-32, IMR-5, SK-N-AS, SK-N-SH, LAN-1, LAN-5, and SHEP human neuroblastoma cell lines in vitro. Interestingly the human neuroblastoma tumor-initiating cell lines, NB-12, NB88 and NB122 (kind gift from Dr David Kaplan) were also found to be very sensitive to reovirus-induced cytotoxicity, suggesting a role for reovirus treatment of refractory neuroblastoma. In order to further study reovirus, immunotherapy and neuroblastoma, a syngeneic, immunocompetent murine model (Neuro2a, A/J neuroblastoma model) was utilized to test reovirus-induced cytotoxicity and RV-directed immunotherapy of Neuro2A in vitro and in vivo. Preliminary data suggest that the Neuro2a cells are exquisitely sensitive to reovirus in vitro. Updated results will be presented. Conclusion: These preclinical results suggest that reovirus holds promise as a novel therapeutic for neuroblastoma and that it warrants further investigation in early phase clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4336. doi:10.1158/1538-7445.AM2011-4336
Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease
Authors: Hervé Acloque, Meghan S. Adams, Katherine Fishwick, Marianne Bronner-Fraser, M. Angela Nieto
Journal: Journal of Clinical Investigation (2009)

The events that convert adherent epithelial cells into individual migratory cells that can invade the extracellular matrix are known collectively as epithelial-mesenchymal transition (EMT). Throughout evolution, the capacity of cells to switch between these two cellular states has been fundamental in the generation of complex body patterns. Here, we review the EMT events that build the embryo and further discuss two prototypical processes governed by EMT in amniotes: gastrulation and neural crest formation. Cells undergo EMT to migrate and colonize distant territories. Not surprisingly, this is also the mechanism used by cancer cells to disperse throughout the body.
On the Mortality of Children at the Military Asylum, Southampton
Authors: J. Hennen
Journal: BMJ (1842)

mediate contact; one seems suspended above the other; both are smooth, tolerably oval, and to each a chord is attached.*Tle history of the case is tbis: whilst a very young child a nursemaid had, in play, crushed the testicle with a pair of tongs, and on re- covery from the injury it was found that the testicle was divided, and has ever remained so since; gra- dually increasing in bulk with the growth of the person, who is an athletic man, the father of a fine family of children.As you have added some observations to the case of Dr. Macann I have sent the above statement, thinking it may prove a solution to some others recorded as examples of supernumerary testicles.
550 HEPATITIS B VIRUS MUTANTS WITH TENOFOVIR DRUG RESISTANCE HAVE IMPAIRED REPLICATION EFFICIENCIES, WHICH CAN BE RESTORED BY ADDITIONAL PRECORE OR BASIC CORE PROMOTER MUTATIONS
Authors: S. Amini-Bavil-Olyaee, J. Sheldon, C. Trautwein, F. Tacke
Journal: Journal of Hepatology (2008)
Intrathecal triiodothyronine administration causes greater heart rate stimulation in hypothyroid rats than intravenously delivered hormone. Evidence for a central nervous system site of thyroid hormone action.
Authors: M Goldman, M B Dratman, F L Crutchfield, A S Jennings, J A Maruniak, R Gibbons
Journal: Journal of Clinical Investigation (1985)

To determine whether intracerebrally localized iodothyronines produce thyroid hormone-related functional effects, heart rate responses were compared in conscious hypothyroid rats given triiodothyronine (T3) by either the intrathecal or the intravenous route. A significant increase in heart rate occurred within 18 h after 1.5 nmol T3/100 g body wt was delivered intrathecally through a cannula previously placed in the lateral cerebral ventricle. Injection of the same T3 dose intravenously through an indwelling jugular catheter or injection of vehicle only by either route produced no significant increase in heart rate during the 48-h postinjection period of observation. These differences were observed even though integrated serum T3 concentrations were significantly lower after intrathecal than after intravenous T3 injection. The results indicate that thyroid hormone effects on heart rate are exerted within the brain as well as within the heart.
Genomic profiling of cell lines for personalized targeted therapy for hepatocellular carcinoma
Authors: Manjeet Deshmukh, Yujin Hoshida
Journal: Hepatology (2013)

Although a cancer cell line has limitations in modeling the physiological complexity in human cancer, it has shown to be useful as a convenient tool to interrogate the molecular mechanism of action of cancer therapeutics.1 Finn et al.2 tested an intriguing idea to use a human hepatocellular carcinoma (HCC) gene signature to probe genomic profiles of hepatoma cell lines to evaluate sensitivity to a molecular targeted agent, dasatinib, although more work is needed to determine its mechanism of action. The authors identified two groups of cell lines according to the presence of a gene signature of "progenitor/HB" subtype linked to a distinct median inhibitory concentration (IC50) profile as well as cell cycle arrest and apoptosis induced by dasatinib. Of note, the classification looks concordant with positivity of alpha-fetoprotein (AFP), which has been repeatedly reported as the major determinant of global transcriptome landscape in hepatoma cells.3, 4 We previously annotated the AFP-based subtypes of hepatoma cell lines with various molecular features and clinical phenotypes by using the gene signature assessment.5, 6 In the analysis, AFP-negative cells, corresponding "S1" subclass identified in our meta-analysis of human HCC cohorts, were characterized by activation of transforming growth factor beta (TGF-β) and Met pathways, suppression of the p53 pathway, overexpression of canonical Wnt pathway target genes, more disseminative phenotype, and in fact enrichment of the "progenitor/HB" signature. These may represent clues to the mechanism. In addition, these findings may collectively suggest that AFP is a predictive biomarker of dasatinib sensitivity. If this is confirmed and the drug shows a clinically meaningful effect in the subset of patients with non-AFP-producing HCC, this could have huge implications in the personalized HCC treatment because AFP is already available in clinics worldwide. Manjeet Deshmukh, Ph.D.Yujin Hoshida, M.D., Ph.D. Liver Cancer Program, Tisch Cancer Institute Division of Liver Diseases, Department of Medicine Icahn School of Medicine at Mount SinaiNew York, NY
Results of prescription event monitoring study of salmeterol
Authors: R D Mann
Journal: BMJ (1994)

EDITOR, - The prescription event monitoring study of salmeterol1 is now complete and has shown the number of deaths due to asthma in patients treated with the drug to be lower than that predicted. Last year Castle et al reported on 16 787 patients treated with salmeterol for 16 weeks.2 In these patients 54 deaths from all causes occurred (0.32%), including 12 from asthma (0.07%). The prescription event monitoring study has identified 1022 deaths (6.6%) in our cohort of 15 407 patients treated with salmeterol and observed for …
Exome sequencing and the genetic basis of complex traits
Authors: Adam Kiezun, Kiran Garimella, Ron Do, Nathan O Stitziel, Benjamin M Neale, Paul J McLaren, Namrata Gupta, Pamela Sklar, Patrick F Sullivan, Jennifer L Moran, Christina M Hultman, Paul Lichtenstein, Patrik Magnusson, Thomas Lehner, Yin Yao Shugart, Alkes L Price, Paul I W de Bakker, Shaun M Purcell, Shamil R Sunyaev
Journal: Nature Genetics (2012)
Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells
Authors: Michael André Kern, Dominic Schubert, Dina Sahi, Mirja Mareike Schöneweiβ, Ilona Moll, Anke Maria Haugg, Hans Peter Dienes, Kai Breuhahn, Peter Schirmacher
Journal: Hepatology (2002)

Recent studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies, including hepatocellular carcinoma (HCC), but so far it is unknown whether COX-2 contributes to the malignant growth and whether inhibition of COX-2 function modifies the malignant potential of liver tumors. COX-1 and COX-2 expression was determined in 4 liver tumor cell lines (Hep 3B, HuH-7, Hep G2, Sk-hep1) by Northern hybridization and Western immunoblot. The functional effects of the nonselective inhibitor sulindac sulfide and the COX-2 selective inhibitors SC-58635 and meloxicam were examined by 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide (MTT)-assays and BrdU uptake, morphology, and TUNEL analysis of apoptosis. Apoptosis regulating proteins were analyzed by Western immunoblot. COX-1 and COX-2 expression was demonstrable in all tested liver tumor cell lines. Sulindac sulfide (50 to 400 μmol/L), SC-58635 (6,25 to 400 μmol/L), and meloxicam (6.25 to 400 μmol/L) led to a significant time- and dose-dependent reduction of cell numbers of up to 80% ( P &lt; .05). At equimolar concentrations the effect was more pronounced when COX-2 was selectively blocked. COX-2 inhibition induced apoptosis and reduced tumor cell proliferation. Apoptosis after COX-2 inhibition with SC-58635 (50 μmol/L) was independent of BCL-2, BAX, and the phosphorylation status of AKT/PKB and BAD, but correlated with activation of caspase-9, caspase-3, and caspase-6. In conclusion, selective inhibition of COX-2 leads to a marked growth inhibition of human liver tumor cells, based on the induction of apoptosis and inhibition of proliferation and, thus, may offer therapeutic and preventive potential in human hepatocarcinogenesis.