tbuckley/cabot-search huggingface dataset:
Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo
Authors: Russell G. Jones, Michael Parsons, Madeleine Bonnard, Vera S.F. Chan, Wen-Chen Yeh, James R. Woodgett, Pamela S. Ohashi
Journal: The Journal of Experimental Medicine (2000)

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4+CD8+ double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I–restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen–specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-XL. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-κB activation via accelerated degradation of the NF-κB inhibitory protein IκBα. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-κB) in vivo in T lymphocytes.
Re: Playing the Old Piano: Another Tune for Endocrine Therapy
Authors: D. Koeberle, L. Perey, B. Thuerlimann
Journal: JNCI Journal of the National Cancer Institute (2004)

Osipo et al. (1) report the paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. In their article, they proposed a two-phase evolution of acquired resistance to tamoxifen. A novel mechanism, called phase II resistance by the authors, was observed after long-term treatment with tamoxifen. The growth of these MCF-7TAMLT breast tumors became dependent on tamoxifen. In the experimental systems, physiologic levels of estradiol were able to induce tumor regression; in this specific hormonal environment, second-line treatment with fulvestrant promoted growth of those tumors. In an accompanying editorial, which we have read with interest, Hayes (2) suggested that Osipo’s data might argue against the use of fulvestrant in patients with tumor progression after aromatase inhibitor therapy was discontinued because of the reappearance of sufficient estrogen levels that could stimulate tumor growth. Extrapolation of these laboratory results into the clinical setting appears to contradict the results of an ongoing multicenter phase II trial conducted by the Swiss Group for Clinical Cancer Research (SAKK). Patients with advanced breast cancer who progressed on prior endocrine therapy, first with tamoxifen and later with nonsteroidal aromatase inhibitors, were treated with fulvestrant
Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks
Authors: Kouichi Tabu, Taichi Kimura, Ken Sasai, Lei Wang, Norihisa Bizen, Hiroshi Nishihara, Tetsuya Taga, Shinya Tanaka
Journal: Molecular Cancer (2010)

Abstract Background An increasing number of studies support the presence of stem-like cells in human malignancies. These cells are primarily responsible for tumor initiation and thus considered as a potential target to eradicate tumors. CD133 has been identified as an important cell surface marker to enrich the stem-like population in various human tumors. To reveal the molecular machinery underlying the stem-like features in tumor cells, we analyzed a promoter of CD133 gene using human colon carcinoma Caco-2 and synovial sarcoma Fuji cells, which endogenously express CD133 gene. Results A reporter analysis revealed that P5 promoter, located far upstream in a human CD133 gene locus, exhibits the highest activity among the five putative promoters (P1 to P5). Deletion and mutation analysis identified two ETS binding sites in the P5 region as being essential for its promoter activity. Electrophoretic mobility shift assays demonstrated the specific binding between nuclear factors and the ETS binding sequence. Overexpression of dominant-negative forms of Ets2 and Elk1 resulted in the significant decrease of P5 activity. Furthermore, treatment of Fuji cells with a specific MEK/ERK inhibitor, U0126, also markedly decreased CD133 expression, but there was no significant effect in Caco-2 cells, suggesting cell type-specific regulation of CD133 expression. Instead, the side population, another hallmark of TSLCs, was dramatically diminished in Caco-2 cells by U0126. Finally, Ras-mediated oncogenic transformation in normal human astrocytes conferred the stem-like capability to form neurosphere-like colonies with the increase of CD133 mRNA expression. Conclusions In conclusion, the Ras/ERK pathway at least in part contributes to the maintenance and the acquisition of stem-like hallmarks, although the extent of its contribution is varied in a cell type-specific manner. These findings could help our comprehensive understanding of tumor stemness, and also improve the development of eradicative therapies against human malignancies.
Expression of the Carcinoembryonic Antigen Gene Is Inhibited by SOX9 in Human Colon Carcinoma Cells
Authors: Philippe Jay, Philippe Berta, Philippe Blache
Journal: Cancer Research (2005)

The human carcinoembryonic antigen (CEA) is overexpressed in many types of human cancers and is commonly used as a clinical marker. In colon cancer, this overexpression protects cells against apoptosis and contributes to carcinogenesis. Therefore, CEA-expressing cells as well as CEA expression itself constitute potential therapeutic targets. In this report, we show that the transcription factor SOX9 down-regulates CEA gene expression and, as a probable consequence, induces apoptosis in the human colon carcinoma cell line HT29Cl.16E.
Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway
Authors: Takahiro Horie, Koh Ono, Hitoo Nishi, Kazuya Nagao, Minako Kinoshita, Shin Watanabe, Yasuhide Kuwabara, Yasuhiro Nakashima, Rieko Takanabe-Mori, Eiichiro Nishi, Koji Hasegawa, Toru Kita, Takeshi Kimura
Journal: Cardiovascular Research (2010)

A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox).The aim of the present study was to investigate the role(s) of miRNAs in acute Dox-induced cardiotoxicity. Methods and resultsNeuregulin-1-ErbB signalling is essential for maintaining adult cardiac function.We found a significant reduction in ErbB4 expression in the hearts of mice after Dox treatment.Because the proteasome pathway was only partially involved in the reduction of ErbB4 expression, we examined the involvement of microRNAs (miRs) in the reduction of ErbB4 expression.miR-146a was shown to be up-regulated by Dox in neonatal rat cardiac myocytes.Using a luciferase reporter assay and overexpression of miR-146a, we confirmed that miR-146a targets the ErbB4 3 ′ UTR.After Dox treatment, overexpression of miR-146a, as well as that of siRNA against ErbB4, induced cell death in cardiomyocytes.Re-expression of ErbB4 in miR-146a-overexpressing cardiomyocytes ameliorated Dox-induced cell death.To examine the loss of miR-146a function, we constructed 'decoy' genes that had tandem complementary sequences for miR-146a in the 3 ′ UTR of a luciferase gene.When miR-146a 'decoy' genes were introduced into cardiomyocytes, ErbB4 expression was up-regulated and Dox-induced cell death was reduced. ConclusionThese findings suggested that the up-regulation of miR-146a after Dox treatment is involved in acute Dox-induced cardiotoxicity by targeting ErbB4.Inhibition of both ErbB2 and ErbB4 signalling may be one of the reasons why those patients who receive concurrent therapy with Dox and trastuzumab suffer from CHF.
Predictors of long-term PAP-adherence in obstructive sleep apnea syndrome
Authors: Otto D. Schoch, Florent Baty, Jolanda Niedermann, Jochen J. Ruediger, Martin H. Brutsche
Journal: European Respiratory Journal (2012)

Introduction:   Few studies have assessed long-term adherence to positive airway pressure therapy (PAP) in OSAS. The aim of this retrospective study was to determine adherence and its potential predictors.    Methods:   All patients (pts) treated at the St.Gallen sleep centre from 11/2001 to 4/2011 were included for analysis of baseline data and follow-up information. The primary dependent variable of interest was continued use of PAP. Kaplan-Meier estimates and Cox-proportional hazards regression were used to model the risk of loss of adherence. A multivariate regression analysis was performed for age, gender, Epworth sleepiness score (ESS), BMI, apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) at baseline.    Results:   During the study period, of 2160 pts started on PAP, 42(2%) died on PAP, 91(4%) no longer needed PAP (weight reduction, alternative treatments) and 311(14%) were lost to follow-up. In 1716 pts, adherence at 1y was 74(95% CI: 71-76)%, at 5y 56(53-59)%, and at 8y 52(49-56)%. Results of univariate and multivariate analyses are summarized in the figure.    Conclusion:   Adherence is independently associated with clinical (ESS) and polysomnographic (ODI, AHI) measures of OSAS severity, but not with BMI, age, gender. Most pts who stopped PAP were lost to follow-up. With a relatively low long-term adherence, intensified efforts and alternative or novel follow-up options (e.g. telemetry) to support such patients should be tested.
Photosensitizing drugs may lower the narrow-band ultraviolet B (TL-01) minimal erythema dose
Authors: H. Cameron, R.S. Dawe
Journal: British Journal of Dermatology (2000)

Journal Article Photosensitizing drugs may lower the narrow‐band ultraviolet B (TL‐01) minimal erythema dose Get access H. Cameron, H. Cameron Department of Dermatology, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K. E‐mail: hcameron@dundee.ac.uk Search for other works by this author on: Oxford Academic Google Scholar R.S. Dawe R.S. Dawe Department of Dermatology, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K. E‐mail: hcameron@dundee.ac.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 2, 1 February 2000, Pages 389–390, https://doi.org/10.1046/j.1365-2133.2000.03325.x Published: 01 February 2000
Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyperinnervation in Hearts With Chronic Left Ventricular Myocardial Infarction
Authors: Yasushi Miyauchi, Shengmei Zhou, Yuji Okuyama, Mizuho Miyauchi, Hideki Hayashi, Akira Hamabe, Michael C. Fishbein, William J. Mandel, Lan S. Chen, Peng-Sheng Chen, Hrayr S. Karagueuzian
Journal: Circulation (2003)

Background— The substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability. Methods and Results— We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly ( P &lt;0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD ( P &lt;0.01) and MAP amplitude ( P &lt;0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5- to 8-fold higher and were more heterogeneous in MI compared with control dogs. Conclusions— Chronic ventricular MI with no atrial involvement causes heterogeneous alteration of atrial electrical restitution and atrial sympathetic hyperinnervation that might provide important substrates for the observed increased AF vulnerability.
An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer
Authors: Andrew E Teschendorff, Ahmad Miremadi, Sarah E Pinder, Ian O Ellis, Carlos Caldas
Journal: Genome biology (2007)

Estrogen receptor (ER)-negative breast cancer specimens are predominantly of high grade, have frequent p53 mutations, and are broadly divided into HER2-positive and basal subtypes. Although ER-negative disease has overall worse prognosis than does ER-positive breast cancer, not all ER-negative breast cancer patients have poor clinical outcome. Reliable identification of ER-negative tumors that have a good prognosis is not yet possible.We apply a recently proposed feature selection method in an integrative analysis of three major microarray expression datasets to identify molecular subclasses and prognostic markers in ER-negative breast cancer. We find a subclass of basal tumors, characterized by over-expression of immune response genes, which has a better prognosis than the rest of ER-negative breast cancers. Moreover, we show that, in contrast to ER-positive tumours, the majority of prognostic markers in ER-negative breast cancer are over-expressed in the good prognosis group and are associated with activation of complement and immune response pathways. Specifically, we identify an immune response related seven-gene module and show that downregulation of this module confers greater risk for distant metastasis (hazard ratio 2.02, 95% confidence interval 1.2-3.4; P = 0.009), independent of lymph node status and lymphocytic infiltration. Furthermore, we validate the immune response module using two additional independent datasets.We show that ER-negative basal breast cancer is a heterogeneous disease with at least four main subtypes. Furthermore, we show that the heterogeneity in clinical outcome of ER-negative breast cancer is related to the variability in expression levels of complement and immune response pathway genes, independent of lymphocytic infiltration.
Role of ATP-Binding Cassette and Solute Carrier Transporters in Erlotinib CNS Penetration and Intracellular Accumulation
Authors: Mohamed A. Elmeliegy, Angel M. Carcaboso, Michael Tagen, Feng Bai, Clinton F. Stewart
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420. Experimental Design: After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b−/−, Abcg2−/−, Mdr1a/b−/−Abcg2−/−, and Abcc4−/−), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration–time data, and brain penetration (PBrain) was estimated by the ratio of ECF-to-unbound plasma area under concentration–time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers. Results: P Brain in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 PBrain in Abcg2−/− and Mdr1a/b−/−Abcg2−/− mice were significantly higher than in wild-type mice. Mdr1a/b−/− mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells. Conclusion: Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms. Clin Cancer Res; 17(1); 89–99. ©2010 AACR.
Breast implants: evidence based patient choice and litigation
Authors: J A M. Gray
Journal: BMJ (1999)

The American plaintiff lawyer ranks high in the hierarchy of demons that haunt the quiet areas of a doctor's mind, but the plaintiff lawyer serves a useful and essential social function in a society in which the safety net for those who suffer severe health problems is gossamer thin. Tough, well organised, aggressive plaintiff lawyers, especially acting as a group, are a formidable force and they have achieved some spectacular successes—most recently in sponsoring and leading action against tobacco companies, whom they have brought to the bar of justice in the one country where they seemed most unassailable.1 Plaintiff lawyers can, of course, get things spectacularly wrong, as they did in the breast implant saga chillingly told by Marcia Angell in her book Science on Trial .2

The book reinforces all our worst fears about plaintiff …
Next-generation clinical sequencing in a children’s hospital
Authors: Stephen Kingsmore
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Comparison of the Canadian CT Head Rule and the New Orleans Criteria in Patients With Minor Head Injury
Authors: Ian G. Stiell
Journal: JAMA (2005)

ContextCurrent use of cranial computed tomography (CT) for minor head injury is increasing rapidly, highly variable, and inefficient. The Canadian CT Head Rule (CCHR) and New Orleans Criteria (NOC) are previously developed clinical decision rules to guide CT use for patients with minor head injury and with Glasgow Coma Scale (GCS) scores of 13 to 15 for the CCHR and a score of 15 for the NOC. However, uncertainty about the clinical performance of these rules exists.ObjectiveTo compare the clinical performance of these 2 decision rules for detecting the need for neurosurgical intervention and clinically important brain injury.Design, Setting, and PatientsIn a prospective cohort study (June 2000-December 2002) that included 9 emergency departments in large Canadian community and university hospitals, the CCHR was evaluated in a convenience sample of 2707 adults who presented to the emergency department with blunt head trauma resulting in witnessed loss of consciousness, disorientation, or definite amnesia and a GCS score of 13 to 15. The CCHR and NOC were compared in a subgroup of 1822 adults with minor head injury and GCS score of 15.Main Outcome MeasuresNeurosurgical intervention and clinically important brain injury evaluated by CT and a structured follow-up telephone interview.ResultsAmong 1822 patients with GCS score of 15, 8 (0.4%) required neurosurgical intervention and 97 (5.3%) had clinically important brain injury. The NOC and the CCHR both had 100% sensitivity but the CCHR was more specific (76.3% vs 12.1%, P&lt;.001) for predicting need for neurosurgical intervention. For clinically important brain injury, the CCHR and the NOC had similar sensitivity (100% vs 100%; 95% confidence interval [CI], 96%-100%) but the CCHR was more specific (50.6% vs 12.7%, P&lt;.001), and would result in lower CT rates (52.1% vs 88.0%, P&lt;.001). The κ values for physician interpretation of the rules, CCHR vs NOC, were 0.85 vs 0.47. Physicians misinterpreted the rules as not requiring imaging for 4.0% of patients according to CCHR and 5.5% according to NOC (P = .04). Among all 2707 patients with a GCS score of 13 to 15, the CCHR had sensitivities of 100% (95% CI, 91%-100%) for 41 patients requiring neurosurgical intervention and 100% (95% CI, 98%-100%) for 231 patients with clinically important brain injury.ConclusionFor patients with minor head injury and GCS score of 15, the CCHR and the NOC have equivalent high sensitivities for need for neurosurgical intervention and clinically important brain injury, but the CCHR has higher specificity for important clinical outcomes than does the NOC, and its use may result in reduced imaging rates.
Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster
Authors: Barbara J. Frankel, John E. Gerich, Ryoko Hagura, Rudy E. Fanska, George C. Gerritsen, Gerold M. Grodsky
Journal: Journal of Clinical Investigation (1974)

Hereditary insulin-deficient diabetes mellitus occurs in certain sublines of nonobese Chinese hamsters. Several characteristics of this syndrome are similar to those seen in insulin-deficient human diabetics. Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.