tbuckley/cabot-search huggingface dataset:
Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation
Authors: H. Peterziel, J. Muller, A. Danner, S. Barbus, H.-K. Liu, B. Radlwimmer, T. Pietsch, P. Lichter, G. Schutz, J. Hess, P. Angel
Journal: Neuro-Oncology (2012)

Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB.
Inducible DNA breaks in Ig S regions are dependent on AID and UNG
Authors: Carol E. Schrader, Erin K. Linehan, Sofia N. Mochegova, Robert T. Woodland, Janet Stavnezer
Journal: The Journal of Experimental Medicine (2005)

Class switch recombination (CSR) occurs by an intrachromosomal deletion whereby the IgM constant region gene (Cμ) is replaced by a downstream constant region gene. This unique recombination event involves formation of double-strand breaks (DSBs) in immunoglobulin switch (S) regions, and requires activation-induced cytidine deaminase (AID), which converts cytosines to uracils. Repair of the uracils is proposed to lead to DNA breaks required for recombination. Uracil DNA glycosylase (UNG) is required for most CSR activity although its role is disputed. Here we use ligation-mediated PCR to detect DSBs in S regions in splenic B cells undergoing CSR. We find that the kinetics of DSB induction corresponds with AID expression, and that DSBs are AID- and UNG-dependent and occur preferentially at G:C basepairs in WRC/GYW AID hotspots. Our results indicate that AID attacks cytosines on both DNA strands, and staggered breaks are processed to blunt DSBs at the initiating ss break sites. We propose a model to explain the types of end-processing events observed.
Rectus abdominis muscle strains in tennis players
Authors: Javier Maquirriain, Juan P Ghisi, Antonio M Kokalj
Journal: British Journal of Sports Medicine (2007)

Rectus abdominis muscle strains are common and debilitating injuries among competitive tennis players. Eccentric overload, followed by forced contraction of the non-dominant rectus abdominis during the cocking phase of the service motion is the accepted injury mechanism. A tennis-specific rehabilitation program emphasising eccentrics and plyometric strengthening of the abdominal wall muscles, contributes to the complete functional recovery in tennis players, and could help reduce recurrences.
Tracking down the sources of experimental contamination in microbiome studies
Authors: Sophie Weiss, Amnon Amir, Embriette R Hyde, Jessica L Metcalf, Se Jin Song, Rob Knight
Journal: Genome biology (2014)

A recent report warns that DNA extraction kits and other laboratory reagents are considerable sources of contamination in microbiome experiments. The issue of contamination is particularly problematic for samples of low biomass.
Novel Phase I Dose De-escalation Design Trial to Determine the Biological Modulatory Dose of the Antiangiogenic Agent SU5416
Authors: Afshin Dowlati, Kelly Robertson, Tomas Radivoyevitch, John Waas, Nicholas P. Ziats, Paul Hartman, Fadi W. Abdul-Karim, Jay K. Wasman, Jack Jesberger, Jonathan Lewin, Keith McCrae, Percy Ivy, Scot C. Remick
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where “dose de-escalation” was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose. Experimental Design: Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. Results: Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of &amp;gt;35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. Conclusion: SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.
Reliability and Validity of Depressive Personality Disorder
Authors: Katharine A. Phillips, John G. Gunderson, Joseph Triebwasser, Catherine R. Kimble, Gianni Faedda, In Kyoon Lyoo, Jo Renn
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: Depressive personality disorder was introduced into DSM-IV's appendix amid controversy. While that disorder appears to be a reliable and valid one, the authors offer new data about its relationship to major depression, dysthymic disorder, and other personality disorders. METHOD: The authors assessed 54 subjects with early-onset, long-standing mild depressive features for depressive personality disorder, axis I and axis II disorders, family history, and treatment history; they conducted follow-up interviews 1 year after the baseline assessment. Subjects with (N=30) and without (N=24) depressive personality disorder were characterized and compared in terms of those variables. RESULTS: Although depressive personality disorder and dysthymia co-occurred in some subjects, 63% of subjects with depressive personality disorder did not have dysthymia, and 60% did not have current major depression. Although subjects with depressive personality disorder were more likely than the mood disorder comparison group to have another personality disorder, 40% had no such disorder. Contrary to study hypotheses, mood disorder was not more common in first-degree relatives of subjects with depressive personality disorder than in relatives of the comparison group. Subjects with and without depressive personality disorder had similar rates of past treatment with medication and psychotherapy; however, the duration of psychotherapy was significantly longer for subjects with than for those without depressive personality. The depressive personality diagnosis was relatively stable over the 1-year follow-up period. CONCLUSIONS: Depressive personality disorder appears to be a relatively stable condition with incomplete overlap with axis I mood disorders and personality disorders. Further studies are needed to better characterize its treatment response and relationship to axis I mood disorders. (Am J Psychiatry 1998; 155:1044–1048)
Tempol Protects against Oxidative Damage and Delays Epithelial Tumor Onset in Fanconi Anemia Mice
Authors: Qing-Shuo Zhang, Laura Eaton, Eric R. Snyder, Scott Houghtaling, James B. Mitchell, Milton Finegold, Carter Van Waes, Markus Grompe
Journal: Cancer Research (2008)

Abstract Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and marked cancer susceptibility. FA patients have an elevated risk of developing hematologic malignancies and solid tumors. Using Fancd2−/− knockout mice as a model of FA, we examined the potential of tempol, a nitroxide antioxidant and a superoxide dismutase mimetic, as a tumor-delaying agent for solid tumors. Dietary tempol increased the mean tumor-free survival time of Fancd2−/− Trp53+/− mice by 27% (P &amp;lt; 0.01), from 308 to 390 days, without changing the overall tumor spectrum. More strikingly, tempol delayed the onset of epithelial tumors and increased the mean epithelial tumor-free survival time by 38% (P &amp;lt; 0.0001), from 312 to 432 days, in Fancd2−/− Trp53+/− mice. These results show that tempol can significantly delay tumor formation in Fancd2−/− Trp53+/− mice. Furthermore, tempol treatment did not adversely affect the repopulating ability of FA hematopoietic stem cells. The reduction in oxidative DNA damage in tempol-treated FA fibroblasts and mice suggests that its tumor-delaying function may be attributed to its antioxidant activity. [Cancer Res 2008;68(5):1601–8]
Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201
Authors: Allen R. Chauvenet, Paul L. Martin, Meenakshi Devidas, Stephen B. Linda, Beverly A. Bell, Joanne Kurtzberg, Jeanette Pullen, Mark J. Pettenati, Andrew J. Carroll, Jonathan J. Shuster, Bruce Camitta
Journal: Blood (2007)
New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge
Authors: Julie Schanz, Heinz Tüchler, Francesc Solé, Mar Mallo, Elisa Luño, José Cervera, Isabel Granada, Barbara Hildebrandt, Marilyn L. Slovak, Kazuma Ohyashiki, Christian Steidl, Christa Fonatsch, Michael Pfeilstöcker, Thomas Nösslinger, Peter Valent, Aristoteles Giagounidis, Carlo Aul, Michael Lübbert, Reinhard Stauder, Otto Krieger, Guillermo Garcia-Manero, Stefan Faderl, Sherry Pierce, Michelle M. Le Beau, John M. Bennett, Peter Greenberg, Ulrich Germing, Detlef Haase
Journal: Journal of Clinical Oncology (2012)

Purpose The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. Patients and Methods Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. Results In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P &lt; .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. Conclusion In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.
Evaluation of asymptomatic subjects with low forced expiratory ratios (FEV1/VC).
Authors: S Kivity, A Solomon, Y Schwarz, I Trajber, M Topilsky
Journal: Thorax (1994)

Heightened bronchial hyperreactivity is frequently associated with airflow limitation, atopy, or cigarette smoking. The purpose of this study was to evaluate healthy subjects with significantly low values of forced expiratory volume in one second/vital capacity % (FEV1/VC%) by measuring their airway response to exercise and methacholine challenge, compared with a control group with normal spirometric values.Eighty four healthy subjects with significantly low flow rates (group A, FEV1/VC% < 2 SD% predicted) were evaluated and compared with 37 subjects with normal flow rates (group B). Static lung volumes, spirometric tests, exercise, and methacholine challenges were performed.Lung volumes were normal for both groups. Mean FEV1/VC% was 69% for group A and 82% for the control group. Salbutamol improved baseline FEV1 in eight subjects in group A (mean 15%), while methacholine induced a drop in FEV1 in 12 subjects. The dose-response curve to methacholine reached a plateau in all the responders. None of the subjects in the control group improved their baseline FEV1/VC% to salbutamol, but three showed bronchial hyperreactivity similar to those in group A.Bronchial hyperreactivity does not occur more often in asymptomatic subjects with mildly low FEV1/VC% so these subjects do not require special investigations for airway disease.
TPL2 mediates autoimmune inflammation through activation of the TAK1 axis of IL-17 signaling
Authors: Yichuan Xiao, Jin Jin, Mikyoung Chang, Mako Nakaya, Hongbo Hu, Qiang Zou, Xiaofei Zhou, George C. Brittain, Xuhong Cheng, Shao-Cong Sun
Journal: The Journal of Experimental Medicine (2014)

Development of autoimmune diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), involves the inflammatory action of Th1 and Th17 cells, but the underlying signaling mechanism is incompletely understood. We show that the kinase TPL2 is a crucial mediator of EAE and is required for the pathological action of Th17 cells. TPL2 serves as a master kinase mediating the activation of multiple downstream pathways stimulated by the Th17 signature cytokine IL-17. TPL2 acts by linking the IL-17 receptor signal to the activation of TAK1, which involves a dynamic mechanism of TPL2–TAK1 interaction and TPL2-mediated phosphorylation and catalytic activation of TAK1. These results suggest that TPL2 mediates TAK1 axis of IL-17 signaling, thereby promoting autoimmune neuroinflammation.
The Clinton Health Care Plan
Authors: Bill Clinton
Journal: New England Journal of Medicine (1992)

The American health care system has the potential to provide every citizen with the best care in the world. Yet the system as currently financed and organized is plagued by two problems: health care costs are increasing at unsustainable rates, and Americans cannot be sure that they will have health care coverage when they need it. We cannot afford four more years of political gridlock on health care. We must reform the health care system so that all American families have access to affordable high-quality health care. My plan offers a framework for this reform, and, as president, I will . . .
Polarized Signaling Endosomes Coordinate BDNF-Induced Chemotaxis of Cerebellar Precursors
Authors: Pengcheng Zhou, Marimelia Porcionatto, Mariecel Pilapil, Yicheng Chen, Yoojin Choi, Kimberley F. Tolias, Jay B. Bikoff, Elizabeth J. Hong, Michael E. Greenberg, Rosalind A. Segal
Journal: Neuron (2007)
Bridging the gap between systems biology and medicine
Authors: Gilles Clermont, Charles Auffray, Yves Moreau, David M Rocke, Daniel Dalevi, Devdatt Dubhashi, Dana R Marshall, Peter Raasch, Frank Dehne, Paolo Provero, Jesper Tegner, Bruce J Aronow, Michael A Langston, Mikael Benson
Journal: Genome Medicine (2009)

Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains.
PACE4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression
Authors: Daniel E. Bassi, Ricardo Lopez De Cicco, Jonathan Cenna, Samuel Litwin, Edna Cukierman, Andres J.P. Klein-Szanto
Journal: Cancer Research (2005)

Abstract Collagen type IV degradation results in disruption and breakdown of the normal basement membrane architecture, a key process in the initiation of tumor microinvasion into the connective tissue. PACE4, a proprotein convertase, activates membrane type matrix metalloproteinases (MT-MMPs) that in turn process collagenase type IV. Because PACE4 is overexpressed in skin carcinomas and in vitro overexpression of PACE4 resulted in enhanced invasiveness, we investigated whether or not in vivo PACE4 expression leads to the acquisition of invasiveness and increased tumorigenesis. Two transgenic mouse lines were designed by targeting PACE4 to the epidermal basal keratinocytes. Transgenic keratinocytes showed increased processing of MT1-MMP and MT2-MMP resulting in collagenase IV activation and collagen type IV degradation. Higher collagenolytic activity partially disrupted normal basement membrane architecture favoring epithelial endophytic growth into the dermis and accelerating invasion and metastasis after chemical carcinogenesis. PACE4 overexpression resulted in enhanced susceptibility to carcinogenesis and tumor progression pointing to a new target for blocking tumor cell invasiveness.
Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis.
Authors: B Fishel, M Tishler, D Caspi, M Yaron
Journal: Annals of the Rheumatic Diseases (1989)

A 65 year old woman with rheumatoid arthritis developed marrow aplasia and jaundice owing to D-penicillamine treatment. Recovery of bone marrow was ineffective, and the patient finally died despite intensive therapeutic measures. The rare coexistence of myelotoxicity and hepatotoxicity is presented and discussed.
Angiotensin II Stimulates Platelet-Derived Growth Factor-B Chain Expression in Newborn Rat Vascular Smooth Muscle Cells and Neointimal Cells Through Ras, Extracellular Signal–Regulated Protein Kinase, and c-Jun N-Terminal Protein Kinase Mechanisms
Authors: Jun-o Deguchi, Masatoshi Makuuchi, Takashi Nakaoka, Tucker Collins, Yoh Takuwa
Journal: Circulation Research (1999)

Abstract —Platelet-derived growth factors (PDGFs) have been implicated in the pathogenesis of vascular proliferative disorders. Vascular smooth muscle cells (VSMCs) are one of the cell types that produce PDGF-B chain in proliferative lesions, although the mechanism of regulation of PDGF-B chain production in these cells is not well understood. In the present study, we demonstrate that angiotensin II (Ang II), which is also implicated in vascular stenosis after angioplasty and atherosclerosis, markedly stimulates PDGF-B chain mRNA expression in cultured newborn rat medial VSMCs and neointimal VSMCs via an AT 1 , but not in adult rat VSMCs. In newborn rat VSMCs, Ang II activates extracellular signal–regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 mitogen–activated protein kinase. The mitogen-activated protein/ERK (MEK) inhibitor PD98059, but not the p38 inhibitor SB203580, abrogates Ang II–induced PDGF-B mRNA expression. Transient transfection analysis using a PDGF-B promoter-luciferase gene reporter construct reveals that Ang II induces transcriptional activation of PDGF-B chain gene, which is abolished by the expression of a dominant negative form of either ERK or JNK, but not of p38. The expression of a dominant negative form of Ras abolishes the stimulatory effects of Ang II on ERK activity and PDGF-B mRNA expression. In adult rat VSMCs, Ang II activates ERK and JNK, but weakly induces Egr-1, a transcription factor implicated in PDGF-B chain gene expression, compared with newborn VSMCs. These data indicate that Ang II activates PDGF-B chain gene expression in VSMCs through mechanisms involving Ras-ERK and JNK.
Genetic endothelial systems biology of sickle stroke risk
Authors: Liming Chang Milbauer, Peng Wei, Judy Enenstein, Aixiang Jiang, Cheryl A. Hillery, J. Paul Scott, Stephen C. Nelson, Vidya Bodempudi, James N. Topper, Ruey-Bing Yang, Betsy Hirsch, Wei Pan, Robert P. Hebbel
Journal: Blood (2007)