tbuckley/cabot-search huggingface dataset:
Regulation of Estrogen-Dependent Transcription by the LIM Cofactors CLIM and RLIM in Breast Cancer
Authors: Steven A. Johnsen, Cenap Güngör, Tanja Prenzel, Sabine Riethdorf, Lutz Riethdorf, Naoko Taniguchi-Ishigaki, Thomas Rau, Baris Tursun, J. David Furlow, Guido Sauter, Martin Scheffner, Klaus Pantel, Frank Gannon, Ingolf Bach
Journal: Cancer Research (2008)

Abstract Mammary oncogenesis is profoundly influenced by signaling pathways controlled by estrogen receptor α (ERα). Although it is known that ERα exerts its oncogenic effect by stimulating the proliferation of many human breast cancers through the activation of target genes, our knowledge of the underlying transcriptional mechanisms remains limited. Our published work has shown that the in vivo activity of LIM homeodomain transcription factors (LIM-HD) is critically regulated by cofactors of LIM-HD proteins (CLIM) and the ubiquitin ligase RING finger LIM domain-interacting protein (RLIM). Here, we identify CLIM and RLIM as novel ERα cofactors that colocalize and interact with ERα in primary human breast tumors. We show that both cofactors associate with estrogen-responsive promoters and regulate the expression of endogenous ERα target genes in breast cancer cells. Surprisingly, our results indicate opposing functions of LIM cofactors for ERα and LIM-HDs: whereas CLIM enhances transcriptional activity of LIM-HDs, it inhibits transcriptional activation mediated by ERα on most target genes in vivo. In turn, the ubiquitin ligase RLIM inhibits transcriptional activity of LIM-HDs but enhances transcriptional activation of endogenous ERα target genes. Results from a human breast cancer tissue microarray of 1,335 patients revealed a highly significant correlation of elevated CLIM levels to ER/progesterone receptor positivity and poor differentiation of tumors. Combined, these results indicate that LIM cofactors CLIM and RLIM regulate the biological activity of ERα during the development of human breast cancer. [Cancer Res 2009;69(1):128–36]
Clinical Experience With Crizotinib in Patients With Advanced <i>ALK</i>-Rearranged Non–Small-Cell Lung Cancer and Brain Metastases
Authors: Daniel B. Costa, Alice T. Shaw, Sai-Hong I. Ou, Benjamin J. Solomon, Gregory J. Riely, Myung-Ju Ahn, Caicun Zhou, S. Martin Shreeve, Paulina Selaru, Anna Polli, Patrick Schnell, Keith D. Wilner, Robin Wiltshire, D. Ross Camidge, Lucio Crinò
Journal: Journal of Clinical Oncology (2015)

Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
Authors: Yusuke Shono, Andrea Z. Tuckett, Samedy Ouk, Hsiou-Chi Liou, Grégoire Altan-Bonnet, Jennifer J. Tsai, Jennifer E. Oyler, Odette M. Smith, Mallory L. West, Natalie V. Singer, Ekaterina Doubrovina, Dmitry Pankov, Chandresh V. Undhad, George F. Murphy, Cecilia Lezcano, Chen Liu, Richard J. O'Reilly, Marcel R.M. van den Brink, Johannes L. Zakrzewski
Journal: Cancer Discovery (2014)

Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.
Congenital abnormalities of the conduction system in two patients with tachyarrhythmias.
Authors: S Bharati, R Bauernfiend, M Scheinman, B Massie, M Cheitlin, P Denes, D Wu, M Lev, K M Rosen
Journal: Circulation (1979)

Serial sections of the conduction system (CS) were performed in two patients with recurrent tachyarrhythmias. Case 1, a 34-year-old female who had dual atrioventricular (AV) nodal pathways with recurrent paroxysmal supraventricular tachycardia, committed suicide. Autopsy revealed an abnormally formed atrial septum with insertion of eustachian valve on the AV part of the pars membranacea. The intercuspid portion of the pars membranacea was muscular. The AV node was located adjacent to the membranous part of the ventricular septum rather than the central fibrous body. In addition, there was an accessory anterior AV node on the parietal wall of the right atrium. Case 2, a 13-year-old boy with history of recurrent ventricular tachycardia, died suddenly. CS revealed a right-sided, markedly septated bundle. The first part of right bundle branch was divided into three parts, which later joined together. Both cases showed fatty infiltration of the atrial septum, more than normal for the age of the patients. The relationship of the recurrent tachyarrhythmias to the congenital abnormalities in the CS in the two cases and the fatty infiltration is reviewed.
Meta consent: a flexible and autonomous way of obtaining informed consent for secondary research
Authors: T. Ploug, S. Holm
Journal: BMJ (2015)

A rapidly increasing capability for storing, linking, and analysing health data has led to new opportunities for research. However, it also raises new ethical and regulatory concerns. Central among these is the question of the conditions under which secondary research can use data that were collected as part of routine healthcare practice or for a specific research project. Does secondary use require renewed informed consent from the original participants?

New developments in data handling and analysis throw up new problems, such as whether it is possible to make patient data unidentifiable, and to what degree.1 2 If the use of identifiable data requires informed consent, we must carefully reconsider whether informed consent is robust enough to withstand the more complex ethical challenges that technology brings with it; for example, in relation to the level of privacy protection that can be offered now and in the future.3 In this paper we propose a model for resolving these tensions—“meta consent.”

Historically, informed consent in clinical healthcare gave doctors permission to perform acts that would otherwise have been classed as physical assaults. Later, the requirements were extended to protect the individual against risk of harm, to protect personal autonomy (defined as the right to form and pursue one’s own goals and values), and to protect the individual’s privacy and right to control personal information.

At least two factors have the potential to override the requirement for informed consent. Firstly, society may have an interest in gaining access to personal health data to, for example, make research possible. Secondly, it may be impossible to obtain consent. The current focus on “big data” sets these two factors in sharp relief. On the one hand, building and linking vast databases of individual health data has considerable potential for promoting health and benefiting society, as …
Pretargeted Radioimmunotherapy for B-Cell Lymphomas
Authors: Damian J. Green, John M. Pagel, Anastasia Pantelias, Nathan Hedin, Yukang Lin, D. Scott Wilbur, Ajay Gopal, Donald K. Hamlin, Oliver W. Press
Journal: Clinical Cancer Research (2007)

Abstract Relapsed or treatment refractory B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. High-dose chemoradiotherapy and stem cell transplantation can cure some patients with relapsed or refractory lymphoma, but the majority of such patients die of progressive disease. We have investigated the potential utility of pretargeted radioimmunotherapy using monoclonal antibody-streptavidin, immunoconjugates, and fusion proteins in combination with N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid biotin for treatment of lymphomas using mouse and primate models. We have targeted a variety of cell surface antigens, including CD20, CD22, CD45, and HLA-DR, using conventional and pretargeted radioimmunotherapy. These studies showed the marked superiority of pretargeted radioimmunotherapy for each of the antigenic targets in terms of superior biodistributions, more complete tumor regressions, and longer survival. We are optimistic that this novel approach will provide a meaningful prolongation of survival for patients with relapsed or refractory lymphomas.
KRP-203, a Novel Synthetic Immunosuppressant, Prolongs Graft Survival and Attenuates Chronic Rejection in Rat Skin and Heart Allografts
Authors: Hisashi Shimizu, Masafumi Takahashi, Takashi Kaneko, Takashi Murakami, Yoji Hakamata, Shinji Kudou, Tetsuya Kishi, Kazunori Fukuchi, Satoru Iwanami, Kazuhiko Kuriyama, Tokutaro Yasue, Shin Enosawa, Koshi Matsumoto, Izumi Takeyoshi, Yasuo Morishita, Eiji Kobayashi
Journal: Circulation (2005)

A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation.KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720.These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.
Claudin-1 polymorphism modifies the effect of mold exposure on the development of atopic dermatitis and production of IgE
Authors: Ho-Sung Yu, Mi-Jin Kang, Ji-Won Kwon, So-Yeon Lee, Eun Lee, Song-I. Yang, Young-Ho Jung, Kyungmo Hong, Young-Joon Kim, Seung-Hwa Lee, Ha-Jung Kim, Hyung Young Kim, Ju-Hee Seo, Byoung-Ju Kim, Hyo-Bin Kim, Soo-Jong Hong
Journal: Journal of Allergy and Clinical Immunology (2014)
Sample-level enrichment analysis unravels shared stress phenotypes among multiple cancer types
Authors: Gunes Gundem, Nuria Lopez-Bigas
Journal: Genome Medicine (2012)

Adaptation to stress signals in the tumor microenvironment is a crucial step towards carcinogenic phenotype. The adaptive alterations attained by cells to withstand different types of insults are collectively referred to as the stress phenotypes of cancers. In this manuscript we explore the interrelation of different stress phenotypes in multiple cancer types and ask if these phenotypes could be used to explain prognostic differences among tumor samples.We propose a new approach based on enrichment analysis at the level of samples (sample-level enrichment analysis - SLEA) in expression profiling datasets. Without using a priori phenotypic information about samples, SLEA calculates an enrichment score per sample per gene set using z-test. This score is used to determine the relative importance of the corresponding pathway or module in different patient groups.Our analysis shows that tumors significantly upregulating genes related to chromosome instability strongly correlate with worse prognosis in breast cancer. Moreover, in multiple tumor types, these tumors upregulate a senescence-bypass transcriptional program and exhibit similar stress phenotypes.Using SLEA we are able to find relationships between stress phenotype pathways across multiple cancer types. Moreover we show that SLEA enables the identification of gene sets in correlation with clinical characteristics such as survival, as well as the identification of biological pathways/processes that underlie the pathology of different cancer subgroups.
Transforming Growth Factor-β Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells
Authors: Mingfang Ao, Karin Williams, Neil A. Bhowmick, Simon W. Hayward
Journal: Cancer Research (2006)

Abstract Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-β can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-β generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-β expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-β on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1CAFTD1, BPH1CAFTD3, and BPH1CAFTD5. The data show that TGF-β has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-β. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-β. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-β by blocking Smad3 and p21 nuclear translocation. On TGF-β stimulation of the tumorigenic sublines, the activated Akt allows the cell to escape cell cycle arrest. The phosphatidylinositol 3-kinase/Akt pathway is also involved in TGF-β-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-β signaling show increased invasion with EMT, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-β can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo. (Cancer Res 2006; 66(16): 8007-16)
Evidence of myogenic vascular control in the rat cerebral cortex.
Authors: H G Bohlen, S L Harper
Journal: Circulation Research (1984)

The potential presence of myogenic regulation in the cerebral microvasculature of the rat was investigated using a method which alters intravascular pressure without appreciably changing cerebral perfusion pressure (arterial minus venous pressure). The entire rat was placed in a sealed box, with the cranial cavity open to the atmosphere and prepared for in vivo microscopy. By increasing the ambient pressure in the box, both systemic arterial and venous pressure could be changed by nearly equal amounts (+/- 20 mm Hg). Heart and respiratory rates were not influenced by changing ambient pressure by +/- 20 mm Hg. At elevated ambient pressures, cortical arterioles constricted in linear proportion to the ambient pressure, whereas subatmospheric ambient pressures caused vasodilation whose magnitude was about equal at ambient pressures of -6 to -18 mm Hg. The calculated vessel wall tension typically remained within about +/- 10-15% of control during changes of transmural pressure of +/- 20-40%. In all cases, arteriolar responses to changes in ambient and intravascular pressure reached a new steady state within 10-15 seconds and were sustained for up to 30 minutes. These data are interpreted to indicate the presence of a myogenic vascular response in the brain vasculature of the rat.
Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation
Authors: I KEHAT, R HEINRICH, O BENIZHAK, H MIYAZAKI, J GUTKIND, A ARONHEIM
Journal: Cardiovascular Research (2006)

Atrial fibrillation is the most prevalent clinically significant cardiac arrhythmia. Atrial dilatation, a predictor of atrial fibrillation, is thought to result from increased ventricular pressure. However, the underlying molecular mechanisms responsible for atrial dilatation are largely unknown. Here we sought to examine whether the expression of a basic leucine zipper inhibitor protein, JDP2, in the heart is sufficient for the generation of atrial dilatation.A tetracycline-regulated transgene was used to express JDP2 specifically in the mouse heart. Mice hearts were dissected and subjected to Northern and Western analysis, or analyzed by ECG recording and echocardiography. Regulation of gene expression was studied using electromobility shift assays and luciferase gene reporter analysis.Expression of JDP2 resulted in massive bi-atrial dilatation, defects in conduction, and a lethal phenotype. These effects were developmentally independent, acquired during adulthood, and were reversible upon abolishing of JDP2 expression. Connexin 40 and myosin light chain 2a expression were identified as potential target genes.Expression of basic leucine zipper transcription inhibitors is sufficient to results in atrial dilatation. This dilatation is acquired postnatally and is reversible. Thus, basic leucine zipper transcription inhibitors may be a relevant therapeutic target for preventing atrial dilatation and atrial fibrillation.
Comprehensive Textbook of Thoracic Oncology Joseph Aisner, Rodrigo Arriagada, Mark R. Green, et al., eds. Baltimore: Williams &amp; Wilkins, 1996. 1 1 18 pp. $149. ISBN 0-683-00062-4
Authors: J. D. Hainsworth
Journal: JNCI Journal of the National Cancer Institute (1997)
[Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure
Authors: A Baartscheer
Journal: Cardiovascular Research (2003)

Objective: Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX (ΔGexch). Methods: The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of ΔGexch were calculated. Results: With increasing stimulation frequency, 0.2–3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged ΔGexch decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of ΔGexch decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. Conclusions: [Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode ΔGexch secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode ΔGexch may account for increased contribution of NCX to e–c coupling in HF.
Low Turnover Osteodystrophy and Vascular Calcification Are Amenable to Skeletal Anabolism in an Animal Model of Chronic Kidney Disease and the Metabolic Syndrome
Authors: Matthew R. Davies, Richard. J. Lund, Suresh Mathew, Keith A. Hruska
Journal: Journal of the American Society of Nephrology (2005)

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.