tbuckley/cabot-search huggingface dataset:
Transfection of Antisense <i>p53</i> Tumor Suppressor Gene Oligodeoxynucleotides Into Rat Carotid Artery Results in Abnormal Growth of Vascular Smooth Muscle Cells
Authors: Hidetsugu Matsushita, Ryuichi Morishita, Motokuni Aoki, Naruya Tomita, Yoshiaki Taniyama, Hironori Nakagami, Takashi Shimozato, Jitsuo Higaki, Yasufumi Kaneda, Toshio Ogihara
Journal: Circulation (2000)

Background —Although loss of activity of an antioncogene, the p53 tumor suppressor gene product, has been postulated in the pathogenesis of human restenosis, little is known about the role of p53 in the regulation of vascular smooth muscle cell (VSMC) growth. In this study, to clarify the role of p53 in the pathogenesis of restenosis, we examined transfection of antisense p53 oligodeoxynucleotides (ODN) into VSMC in vitro and rat carotid artery in vivo. Methods and Results —The specificity of antisense p53 ODN was confirmed by a significant decrease in p53 protein. Transfection of antisense p53 ODN into VSMC resulted in a significant increase in DNA synthesis and cell number as compared with sense and scrambled ODN ( P &lt;0.01). Importantly, transfection of antisense p53 ODN into rat intact carotid artery resulted in a significant increase in the ratio of neointima to medial area at 2 and 4 weeks after transfection, accompanied by a significant decrease in p53 protein ( P &lt;0.01). Moreover, cotransfection of wild-type p53 plasmid completely abolished neointimal formation induced by antisense p53 ODN. The sustained effect of a single antisense ODN administration was confirmed by the kinetics of ODN in the vessel wall with the use of FITC-labeled ODN. Conclusions —Overall, the present study demonstrated that loss of p53 by antisense p53 ODN resulted in an abnormal VSMC growth in vitro and in vivo. These results demonstrated the potential contribution of p53 to the pathogenesis of restenosis.
Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severity
Authors: Eleonora Gambineri, Lucia Perroni, Laura Passerini, Lucia Bianchi, Claudio Doglioni, Franco Meschi, Riccardo Bonfanti, Yves Sznajer, Alberto Tommasini, Anita Lawitschka, Anne Junker, Desiree Dunstheimer, Peter H. Heidemann, Giantonio Cazzola, Marco Cipolli, Wilhelm Friedrich, Dragana Janic, Nadira Azzi, Erick Richmond, Silvia Vignola, Arrigo Barabino, Giuseppe Chiumello, Chiara Azzari, Maria-Grazia Roncarolo, Rosa Bacchetta
Journal: Journal of Allergy and Clinical Immunology (2008)
New methods for identification of crystalline material in joints
Authors: D. V. Doyle, P. R. Crocker
Journal: Annals of the Rheumatic Diseases (1983)

Annals ofthe Rheumatic Diseasesdifficult to focus on), but identification by shape alone is not sufficient.Other crystals include recently injected corticosteroids, also cholesterol which is seen as flat plates.We have seen red/brown crystals from a haemarthrosis aspirate.These were identified as bilirubin.Occasionally crystals are seen which cannot be identified, and some of these may be the alternative crystal forms of calcium pyrophosphate,3 or of calcium phosphate.
COX-2 Blockade Suppresses Gliomagenesis by Inhibiting Myeloid-Derived Suppressor Cells
Authors: Mitsugu Fujita, Gary Kohanbash, Wendy Fellows-Mayle, Ronald L. Hamilton, Yoshihiro Komohara, Stacy A. Decker, John R. Ohlfest, Hideho Okada
Journal: Cancer Research (2011)

Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E₂ (PGE₂). Because PGE₂ induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE₂ production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b(+)Ly6G(hi)Ly6C(lo) granulocytic MDSCs in both the bone marrow and the TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration.
Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts
Authors: Adam D Pfefferle, Jason I Herschkowitz, Jerry Usary, Joshua Harrell, Benjamin T Spike, Jessica R Adams, Maria I Torres-Arzayus, Myles Brown, Sean E Egan, Geoffrey M Wahl, Jeffrey M Rosen, Charles M Perou
Journal: Genome biology (2013)

Abstract Background Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing. Results Transcriptomic profiles of 27 murine models of mammary carcinoma and normal mammary tissue were determined using gene expression microarrays. Hierarchical clustering analysis identified 17 distinct murine subtypes. Cross-species analyses using three independent human breast cancer datasets identified eight murine classes that resemble specific human breast cancer subtypes. Multiple models were associated with human basal-like tumors including TgC3(1)- Tag , TgWAP- Myc and Trp53 -/- . Interestingly, the TgWAPCre- Etv6 model mimicked the HER2-enriched subtype, a group of human tumors without a murine counterpart in previous comparative studies. Gene signature analysis identified hundreds of commonly expressed pathway signatures between linked mouse and human subtypes, highlighting potentially common genetic drivers of tumorigenesis. Conclusions This study of murine models of breast carcinoma encompasses the largest comprehensive genomic dataset to date to identify human-to-mouse disease subtype counterparts. Our approach illustrates the value of comparisons between species to identify murine models that faithfully mimic the human condition and indicates that multiple genetically engineered mouse models are needed to represent the diversity of human breast cancers. The reported trans -species associations should guide model selection during preclinical study design to ensure appropriate representatives of human disease subtypes are used.
Postmastectomy Radiation and Survival in Older Women With Breast Cancer
Authors: Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Deron H. Galusha, Cary P. Gross
Journal: Journal of Clinical Oncology (2006)

Purpose Clinical trials indicate that postmastectomy radiation therapy (PMRT) improves survival for women age younger than 70 years with high-risk breast cancer. However, for women age 70 years or older, the benefits of PMRT are unknown. As recent evidence suggests that certain adjuvant treatments appropriate for younger women may only be marginally beneficial for older women, we sought to determine whether PMRT improves survival for older women with breast cancer. Methods Using the Surveillance, Epidemiology and End Results Medicare data spanning 1992 to 1999, we identified 11,594 women age 70 years or older treated with mastectomy for invasive breast cancer. A proportional hazards model adjusted for clinical-pathologic covariates tested whether PMRT was associated with improved overall survival for low-risk (T1/2 N0), intermediate-risk (T1/2 N1), and high-risk (T3/4 and/or N2/3) patients. Results A total of 502 (7%) of 7,416 low-risk, 242 (11%) of 2,145 intermediate-risk, and 785 (38%) of 2,053 high-risk patients received PMRT. Median follow-up was 6.2 years. For low- and intermediate-risk patients, PMRT was not associated with survival. For high-risk patients, PMRT was associated with a significant improvement in survival (hazard ratio, 0.85; 95% CI, 0.75 to 0.97; P = .02). Five-year adjusted survival was 50% for patients not treated with PMRT or chemotherapy, 56% for patients treated with PMRT only, 57% for patients treated with chemotherapy only, and 59% for patients treated with both PMRT and chemotherapy. Conclusion PMRT is associated with improved survival for older women with high-risk breast cancer. Randomized clinical trials are urgently needed to confirm this finding and define optimal treatment strategies for this patient group.
Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake
Authors: William A Flavahan, Qiulian Wu, Masahiro Hitomi, Nasiha Rahim, Youngmi Kim, Andrew E Sloan, Robert J Weil, Ichiro Nakano, Jann N Sarkaria, Brett W Stringer, Bryan W Day, Meizhang Li, Justin D Lathia, Jeremy N Rich, Anita B Hjelmeland
Journal: Nature Neuroscience (2013)
Computerized Adaptive Diagnosis and Testing of Mental Health Disorders
Authors: Robert D. Gibbons, David J. Weiss, Ellen Frank, David Kupfer
Journal: Annual Review of Clinical Psychology (2015)

In this review we explore recent developments in computerized adaptive diagnostic screening and computerized adaptive testing for the presence and severity of mental health disorders such as depression, anxiety, and mania. The statistical methodology is unique in that it is based on multidimensional item response theory (severity) and random forests (diagnosis) instead of traditional mental health measurement based on classical test theory (a simple total score) or unidimensional item response theory. We show that the information contained in large item banks consisting of hundreds of symptom items can be efficiently calibrated using multidimensional item response theory, and the information contained in these large item banks can be precisely extracted using adaptive administration of a small set of items for each individual. In terms of diagnosis, computerized adaptive diagnostic screening can accurately track an hour-long face-to-face clinician diagnostic interview for major depressive disorder (as an example) in less than a minute using an average of four questions with unprecedented high sensitivity and specificity. Directions for future research and applications are discussed.
Barriers to new drug development in respiratory disease
Authors: Peter J. Barnes, Sergio Bonini, Werner Seeger, Maria G. Belvisi, Brian Ward, Anthony Holmes
Journal: European Respiratory Journal (2015)

Despite enormous unmet medical needs in respiratory medicine, very few new classes of safe and effective therapy have been introduced over the past 40 years. In spite of its enormous burden, respiratory medicine appears to have fewer new approved therapies than other common disease areas, such as cardiovascular, metabolic and neurological diseases, with fewer drug candidates and a higher failure rate. Furthermore, as in other areas of drug discovery, the time for drug development is getting longer and the risk of failure ever higher, leading to enormous and growing development costs. In order to identify some of the barriers to drug discovery in respiratory medicine, a European Respiratory Society Presidential Summit was held on July 2–3, 2014, in Rome, Italy. This meeting brought together respiratory scientists, clinicians, regulators, clinical pharmacologists and the pharmaceutical industry from across Europe to explore how these barriers might be overcome to facilitate the future development of new and effective therapies for respiratory diseases. This editorial highlights some of the opportunities for improving respiratory drug development that were discussed at the 2014 European Respiratory Society Presidential Summit. These include the development of more predictive preclinical disease models, the regulatory framework needed for better respiratory drug development, and how Germany is hoping to address the issues discussed above through a recently established national centre for lung research. The 2014 ERS Presidential Summit discusses how development of new respiratory drugs can be accelerated <http://ow.ly/IcOsZ>
Actualites de physiologie pathologique. La biologie de l'inflammation
Authors: A. St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1967)

This review of aspects of the pathology of inflammation consists of eleven papers by international experts and is of considerable interest to those con- cerned with the treatment and nature of the rheumatic processes.First is a review of the evidence for the participation of histamine in the primary inflam- matory response.It has been impossible to duplicate the many features of inflammation purely by local injection of histamine, but studies based on histamine-releasing agents, anti-histaminic com- pounds, and compounds which can deplete the skin of histamine, all show that histamine does take some part in the inflammatory reaction (Parrot, Ruff, and Saindelle).Boissier guides us through the thickets of the permutations and combinations of the many different anti-inflammatory drugs, inflammatory stimuli, and animals in which these are tested.The remarkable species variation is again brought out.Rocha e Silva explains the action of bradykinin antagonists and other kinin antagonists (some work by inhibiting precursors, others destroy the kinins after production).In his view, we are still a long way from having a specific anti-bradykinin; the compounds currently available all have anti-hista- minic or anti-serotonin activity to a greater or lesser extent.Perhaps the biggest gap in our anti- inflammatory armamentarium is the lack of a powerful pure antiserotonin compound.E. Kelemen and his wife describe elegant experiments based on the analysis of radio-iodine-labelled albumin in inflam-
Mesenchymal Stem Cells as a Biological Drug for Heart Disease
Authors: Cristina Sanina, Joshua M. Hare
Journal: Circulation Research (2015)

Cell-based treatment represents a new generation in the evolution of biological therapeutics. A prototypic cell-based therapy, the mesenchymal stem cell, has successfully entered phase III pivotal trials for heart failure, signifying adequate enabling safety and efficacy data from phase I and II trials. Successful phase III trials can lead to approval of a new biological therapy for regenerative medicine.
Barium Reduces Resting Blood Flow and Inhibits Potassium-Induced Vasodilation in the Human Forearm
Authors: Matthew Dawes, Christine Sieniawska, Trevor Delves, Rahul Dwivedi, Philip J. Chowienczyk, James M. Ritter
Journal: Circulation (2002)

Background — Increasing extracellular K + concentration within and just above the physiological range hyperpolarizes and relaxes vascular smooth muscle in vitro. These actions involve inwardly rectifying potassium channels (K IR ) and Na + /K + ATPase, which are inhibited, respectively, by Ba 2+ and ouabain. The role (if any) of K IR in controlling human resistance vessel tone is unknown, and we investigated this in the forearm. Methods and Results — Blood flow was measured by plethysmography in healthy men. Drugs and electrolytes were infused through the brachial artery. BaCl 2 (4 μmol/min, also used in subsequent experiments) increased Ba 2+ plasma concentration in the infused forearm to 50±0.8 μmol/L (mean±SEM) and reduced blood flow by 24±4% (n=8, P &lt;0.001) without causing systemic effects. Ouabain (2.7 nmol/min), alone and with BaCl 2 , reduced flow by 10±2% and 28±3%, respectively (n=10). Incremental infusions of KCl (0.05, 0.1, and 0.2 mmol/min) increased flow from baseline by 1.0±0.2, 2.0±0.4, and 4.2±0.5 mL/min per deciliter forearm, respectively. Responses to KCl (0.2 mmol/min) were inhibited by BaCl 2 , alone and plus ouabain, by 60±9% and 88±6%, respectively (both P ≤0.01). In control experiments, norepinephrine (240 pmol/min) reduced blood flow by 24±2% but had no significant effect on K + -induced vasodilation. BaCl 2 , alone or with ouabain, did not significantly influence responses to verapamil or nitroprusside. Conclusions — Ba 2+ increases forearm vascular resistance. K + -induced vasodilation is selectively inhibited by Ba 2+ and almost abolished by Ba 2+ plus ouabain, suggesting a role for K IR and Na + /K + ATPase in controlling basal tone and in K + -induced vasorelaxation in human forearm resistance vessels.
Cost-Effectiveness of Treatment of Diabetic Macular Edema
Authors: Suzann Pershing, Eva A. Enns, Brian Matesic, Douglas K. Owens, Jeremy D. Goldhaber-Fiebert
Journal: Annals of Internal Medicine (2014)

Macular edema is the most common cause of vision loss among patients with diabetes.To determine the cost-effectiveness of different treatments of diabetic macular edema (DME).Markov model.Published literature and expert opinion.Patients with clinically significant DME.Lifetime.Societal.Laser treatment, intraocular injections of triamcinolone or a vascular endothelial growth factor (VEGF) inhibitor, or a combination of both.Discounted costs, gains in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).All treatments except laser monotherapy substantially reduced costs, and all treatments except triamcinolone monotherapy increased QALYs. Laser treatment plus a VEGF inhibitor achieved the greatest benefit, gaining 0.56 QALYs at a cost of $6975 for an ICER of $12 410 per QALY compared with laser treatment plus triamcinolone. Monotherapy with a VEGF inhibitor achieved similar outcomes to combination therapy with laser treatment plus a VEGF inhibitor. Laser monotherapy and triamcinolone monotherapy were less effective and more costly than combination therapy.VEGF inhibitor monotherapy was sometimes preferred over laser treatment plus a VEGF inhibitor, depending on the reduction in quality of life with loss of visual acuity. When the VEGF inhibitor bevacizumab was as effective as ranibizumab, it was preferable because of its lower cost.Long-term outcome data for treated and untreated diseases are limited.The most effective treatment of DME is VEGF inhibitor injections with or without laser treatment. This therapy compares favorably with cost-effective interventions for other conditions.Agency for Healthcare Research and Quality.
A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes
Authors: Michael H. Cho, Peter J. Castaldi, Craig P. Hersh, Brian D. Hobbs, R. Graham Barr, Ruth Tal-Singer, Per Bakke, Amund Gulsvik, Raúl San José Estépar, Edwin J. R. Van Beek, Harvey O. Coxson, David A. Lynch, George R. Washko, Nan M. Laird, James D. Crapo, Terri H. Beaty, Edwin K. Silverman
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.To identify genetic determinants of quantitative imaging phenotypes.We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD.The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes.Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci.
<i>PIK3CA</i> Mutations in Intraductal Papillary Mucinous Neoplasm/Carcinoma of the Pancreas
Authors: Frank Schönleben, Wanglong Qiu, Nancy T. Ciau, Daniel J. Ho, Xiaojun Li, John D. Allendorf, Helen E. Remotti, Gloria H. Su
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic-α (PIK3CA) gene in various human solid tumors. More than 75% of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The mutational status of PIK3CA in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) has not been evaluated previously. Experimental Design: To evaluate a possible role for PIK3CA in the tumorigenesis of IPMN and IPMC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing. Results: We identified four missense mutations in the nine screened exons of PIK3CA from 36 IPMN/IPMC specimens (11%). One of the four mutations, H1047R, has been previously reported as a hot-spot mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic. Conclusion: This is the first report of PIK3CA mutation in pancreatic cancer. Our data provide evidence that the oncogenic properties of PIK3CA contribute to the tumorigenesis of IPMN/IPMC.