tbuckley/cabot-search huggingface dataset:
Abstract 1652: Age Adjusted Modification of the Duke Treadmill Score Nomogram
Authors: Amir H Sadrzadeh Rafie, Gannon W Sungar, Jonathan Myers, Victor F Froelicher
Journal: Circulation (2007)

Background : The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification of patients referred for routine exercise testing, but it does not consider age. Our objectives were to determine if age could improve the prognostic power of the DTS and if so, to modify the DTS nomogram to include age. Methods and Results : Analyses were performed on 1959 patients referred for exercise testing at the Palo Alto Veterans Affairs Medical Center from 1997 to 2004. After removal of female and heart failure patients, 1759 male veterans (age range: 23 to 86 years) remained. The DTS was calculated as follows: [(exercise time) − (5 × maximum ST-segment deviation) − (4 × treadmill angina index)]. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were plotted. Cox survival analysis was performed entering age and the DTS. Age and the DTS had similar magnitude but opposite signs yielding the following score: [Age − DTS]. The new score yielded an area under the ROC curve of 0.80 compared to 0.76 for the DTS. Using this equation, a nomogram was constructed by adding age to the original DTS nomogram. The point at which Age-DTS line intersects the drawing line from the DTS to the corresponding value for age indicates average annual cardiovascular mortality adjusted for age. Conclusions : We propose an age adjusted DTS nomogram that improves the prognostic estimates of average annual cardiovascular mortality over the DTS alone. This nomogram requires external validation and extension to women.
Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response
Authors: Songqing Tang, Taoyong Chen, Mingjin Yang, Lei Wang, Zhou Yu, Bin Xie, Cheng Qian, Sheng Xu, Nan Li, Xuetao Cao, Jianli Wang
Journal: Cellular and Molecular Immunology (2015)
Dopamine receptors, neuroleptics, and schizophrenia
Authors: S H Snyder
Journal: American Journal of Psychiatry (1981)

The antipsychotic effects of neuroleptic drugs are mediated by dopamine DA-2 receptors, and dopamine DA-1 receptors, linked to cyclic AMP formation, are not involved. Dopamine receptor binding is enhanced in brain specimens of deceased schizophrenic patients, an increase which may relate to chronic neuroleptic treatment. The binding of 3H-butyrophenones to dopamine receptors can be used for a radioreceptor assay that detects blood levels of all clinically used neuroleptics and their pharmacologically active metabolites and may facilitate routine monitoring of blood levels.
Highlights of the 2006 Scientific Sessions of the European Society of Cardiology
Authors: Jeroen J. Bax, Bernard De Bruyne, Anselm K. Gitt, Steen Kristensen, Cecilia Linde, Don Poldermans, Fausto J. Pinto, Piotr Ponikowski, Bernard D. Prendergast, Enrico Abagiti-Rosei, Sidney C. Smith, Karin R. Sipido, Ernst E. van der Wall, Michal Tendera, Michel Komajda
Journal: Journal of the American College of Cardiology (2006)
Abortion and the Psychiatrist
Authors: P. Darby
Journal: BMJ (1963)

May I, through your columns, suggest that confused patients should not be allowed to leave a mental hospital except to the care of a competent relative or friend ?The present " open doors " policy in mental hospitals is being carried too far, and results in some of these unfortunate patients being exposed to unnecessary danger, as well as causing additional work for the police, mental welfare officers, and police surgeons.-I am, etc., Oxford.
Comparative microarray analysis of gene expression in PC3 prostate carcinoma cells following treatment with NSAIDs ibuprofen and COX-2 specific NS398
Authors: Moly John Aryankalayil, Sanjeewani T. Palayoor, C. Norman Coleman
Journal: Cancer Research (2006)

144    Background and purpose:  Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and COX-2 activity at micromolar concentrations, although antitumor and radiosensitizing effects of NSAID are seen at much higher concentrations. We hypothesized that the gene expression profiles for treatment with non-specific NSAIDs (ibuprofen) and COX-2 specific (NS-398) agents would differ as would different concentrations of each agent explaining, in part, the effects observed in radiation sensitization.  Methods : We treated PC3 cells with low and high concentration NS-398, (10μM and100μM), and ibuprofen, (0.1mM&1.5mM) for 24h and analyzed the differences in gene expression by microarray analysis. Total RNA from treated and untreated cells was analyzed for differential gene expression using CodeLink Human Whole Genome microarrays (∼55,000 unique transcripts) from GE Healthcare (Piscataway, NJ). Data from the arrays was processed and analyzed using CodeLink 4.1 (GE Healthcare) and GeneSpring 6.1 (Agilent Technologies) software.  Results:  After normalization and data filtering, 545 genes (>2-fold) were identified as commonly expressed genes in the cells treated with higher concentrations of NS398 and ibuprofen, relative to untreated cells. Of these, 333 were well-annotated genes and 212 were genes with ESTs and other poorly annotated transcripts. In general, fewer genes were altered in cells treated with low concentrations of NSAIDs as compared to the cells treated with high concentrations. In cells treated with 10μM NS398 only 9 genes were up-regulated and 4 down-regulated, whereas, 133 genes were up-regulated and 179 down-regulated following treatment with 100μM NS398. Similarly, treatment with 0.1mM concentration ibuprofen showed 14 up- and 13 down-regulated genes whereas 1.5mM ibuprofen treatment resulted in138 up-regulated and 184 down-regulated genes. Gene ontology analysis of all 545 common genes indicated that at high concentration both NSAIDs primarily down regulated the expression of genes regulating DNA binding, replication and repair; cell cycle regulation; and mitotic and meiotic chromosome. Genes regulating cell growth, maintenance, communication, and proliferation; apoptosis and developmental processes had similar numbers of up- and down-regulated genes. Analysis of differentially altered genes by the two NSAIDs is in progress.  Conclusion:  These microarray data have revealed several molecular targets of NSAIDs and will help in understanding the antitumor and radiosensitizing effects of NSAIDs.
High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma
Authors: Marie-Hélène Delfau-Larue, Wolfram Klapper, Françoise Berger, Fabrice Jardin, Josette Briere, Gilles Salles, Olivier Casasnovas, Pierre Feugier, Corinne Haioun, Vincent Ribrag, Catherine Thieblemont, Michael Unterhalt, Martin Dreyling, Elizabeth Macintyre, Christiane Pott, Olivier Hermine, Eva Hoster
Journal: Blood (2015)
Planned Parenthood at Risk
Authors: George P. Topulos, Michael F. Greene, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2015)

Planned Parenthood is under attack — again. This time, a campaign of misinformation about the retrieval of fetal tissue used in research and therapy is the excuse. When women have made the decision to terminate a pregnancy, Planned Parenthood allows them the opportunity to have the fetal tissue that would otherwise be discarded be used by qualified researchers to help answer important medical questions. The organization does so carefully, following all applicable laws and ethical guidelines. In a Perspective article now published in the Journal, Charo presents compelling arguments defending these uses of fetal tissue.1 Planned Parenthood, its physicians, and . . .
Abstract 17179: Tissue Factor Pathway Inhibitor Regulates Vascular Patterning in the Developing Zebrafish
Authors: Scott J Hoffman, Eric W Holroyd, Christopher K Pierret, Victoria M Bedell, Stephen C Ekker, Robert D Simari
Journal: Circulation (2011)

Background: The tissue factor pathway regulates vascular structure in the adult through regulation of thrombin generation and signaling. Deletion of tissue factor pathway inhibitor (TFPI) in the mouse results in early intrauterine lethality, precluding study of vascular development. In addition, the carboxyl terminus of TFPI may have a TF-independent effect on vascular structure. We sought to determine the role of TFPI and its carboxyl terminus in vascular development of zebrafish. Methods and results: TFPI mRNA localization studies demonstrated expression in the developing kidney, gut, and vasculature of the zebrafish. We further assessed the role of TFPI in zebrafish angiogenesis, by injecting translational and splice-inhibiting morpholino (MO) oligonucleotides directed against zebrafish TFPI mRNA into embryos from the double transgenic zebrafish Tg(Fli1GFP); Tg(GATA1dsRed) expressing GFP in vascular endothelium and dsRed in erythroid cells. Knockdown of TFPI protein expression was subsequently confirmed by immunoblotting. In a dose-dependent manner, multiple non-overlapping MOs targeting the translation initiation site of TFPI independently and synergistically led to the formation of abnormally targeted intersegmental arteries which crossed somite boundaries by 48 hours post fertilization (hpf). Additionally, a plethoric caudal vein plexus with increased honeycombing was present by 24 hpf. This latter aspect of the phenotype was most striking after a MO targeted against a splice site involving the Kunitz 3 and carboxyl terminus domains of zebrafish TFPI was injected alone. Conclusions: TFPI is expressed during zebrafish development. Morpholino knockdown of TFPI expression alters both arterial and venous patterning in the developing zebrafish, indicating a fundamental role for TFPI in targeting of newly-formed blood vessels. Moreover, different domains of the TFPI protein may preferentially act on distinct vascular networks.
Abstract 18767: Association of Protein-Coding Genetic Variants with Coronary Arterial Calcification in 21,000 Individuals of European and African Ancestries
Authors: Pradeep Natarajan, Lawrence F Bielak, Joshua C Bis, Donald Bowden, Mary F Feitosa, Vilmundur Guðnason, Shih-Jen Hwang, Sekar Kathiresan, Maryam Kavousi, Leo-Pekka Lyytikäinen, Hayato Tada, Jessica Van Setten, Lisa R Yanek, Jie Yao, Laura M Yerges-Armstrong, Christopher J O’Donnell
Journal: Circulation (2014)

Introduction: Coronary arterial calcification (CAC) is a marker of subclinical atherosclerosis in asymptomatic individuals, and is a heritable risk factor that correlates with the risk of coronary artery disease (CAD) development. Genotyping protein-coding regions of the genome with an array is a scalable approach to potentially discover causal low-frequency and rare protein-coding mutations with large phenotypic effects. Methods: Using the Illumina HumanExome BeadChip, we genotyped 247,870 variants (of which 231,539 are in exons) in each of 17,953 participants of European ancestry and 3,078 participants of African ancestry without clinical CAD from the Diabetes Heart Study, Framingham Heart Study, Family Heart Study, Cardiovascular Health Study, Rotterdam Study, Age Gene/Environment Susceptibility Study, Multi-Ethnic Study of Atherosclerosis, Dutch &amp; Belgian Lung Cancer Screening Trial, Young Finns Study, Gene Study of Atherosclerosis Risk in Families, High Risk Plaque Bioimage Study, Old Order Amish Study, and Jackson Heart Study. We tested whether protein-coding variants, individually or aggregated within a gene, were associated with CAC, both as a continuous and binary variable. Results: We first robustly replicated prior CAC genomic non-coding association signals at 9p21 (p=9.85 x 10-29) and PHACTR1 (p=4.10 x 10-23) identified in GWAS based on HapMap imputation. A rare nonsynonymous variant in APOB (rs5742904) was associated with increased CAC (p=1.01 x 10-10) although this signal was driven by the Old Order Amish where it is a known founder mutation. The nonsynonymous APOE rs7412 variant (maf=0.078), the APOE epsilon2 allele, was associated with reduced CAC (p=2.61 x 10-9). Additionally, there was evidence of association for the nonsynonymous SSTR3 rs4988466 variant (maf=0.046) (p=7.77 x 10-8). SSTR3 is involved in cell proliferation, among other functions. Gene-based burden approaches did not yield statistically significant associations. Conclusions: We discovered nonsynonymous coding variants in APOB, APOE, and SSTR3 associated with CAC in a meta-analysis approach of 21,000 individuals using an exon-enriched genotyping array.
Functional characterization of novel p53 mutants
Authors: Elisabet O. Berge, Stian Knappskog, Johan R. Lillehaug, Per E. Lønning
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3353 

Background: The tumour supressor gene TP53 is frequently mutated in human cancers. Previously we have shown mutations in the L2/L3 domains of the p53 protein to be associated with resistance to doxorubicin. During this work several novel mutations located within or in close proximity to the L2/L3 domains of the p53 protein were discovered. In this study we present a functional characterisation of these mutants. Some other mutants found in a similar prospective study focusing on mechanisms of resistance to epirubicin in metastatic breast cancer are also included. Materials and methods: cDNA carrying the various p53 mutants were cloned into the expression vectors pcDNA3.1V5 and pcDNA4/HisMax. The mutant proteins were expressed in a panel of p53 negative cell lines. Subcellular localisation of the p53 mutants was monitored by immunofluorescence. Analysis of the capability to oligomerise and efficiency of DNA binding were performed by immunoprecipitation and electromobility shift assay (EMSA), respectively. Results: Wildtype p53 and all the studied mutants were predominantly localised in the nucleus, but the percentage of nuclear localisation ranged from 60 to 90% between the mutants. IP assays revealed that all mutants remained capable of binding wildtype p53, and hence are probably capable of forming the tetrameric structure characteristic of active p53 in vivo . Discussion: None of the characterised p53 mutants showed any major loss of function in the performed in vitro assays. However there were differences between some of the mutants and wildtype p53, and we speculate that these differences may be significant for the capability of a tumour to resist chemotherapy in vivo .
Evidence for a G-quadruplex in the promoter region of the hypoxia inducible factor-1 alpha (HIF-1α)
Authors: Richard L. De Armond, Michael Deniro, Laurence Hurley, Scot W. Ebbinghaus
Journal: Cancer Research (2004)

3863   HIF-1 is a heterodimeric transcription factor consisting of HIF-1α and aryl hydrocarbon nuclear translocator (ARNT or HIF-1β) and is critical for the regulation of over forty genes required for cellular adaptation to hypoxia. Elevated levels of HIF-1α have been linked to worsened mortality in breast, kidney, cervical, esophageal, ovarian, and several other cancers. Although the physiological regulation of HIF-1α is through von Hippel Lindau (VHL) mediated ubiquitinylation and proteosomal degradation, elevated levels of HIF-1α may occur in tumors due to the loss of VHL or several other mechanisms that result in tumor angiogenesis. The goal of this project was to determine whether a polypurine/polypyrimidine tract in the HIF-1α promoter could form a guanine quadruplex and could be targeted by quadruplex interactive compounds to inhibit HIF-1α expression. Oligonucleotides representing the HIF-1α promoter and containing the polypurine sequence from -85 to -65 produced a potassium dependent electrophoretic mobility shift and a dimethyl sulfate footprint consistent with G-quadruplex formation. A DNA polymerase arrest assay was used to map a potassium dependent arrest site just prior to the G-quadruplex that was enhanced by several G-quadruplex interactive compounds including the cationic porphyrin, TmPyP4, but not by a control compound, TmPyP2, a structural isomer of TmPyP4. The specificity of the compounds for quadruplex DNA was demonstrated by the absence of interaction with a template that lacked secondary structure. We transfected the VHL −/− kidney cancer cell line RCC4 with a HIF-1α promoter-luciferase reporter construct and treated the transfectants with quadruplex interactive compounds. A 60% reduction in luciferase activity was observed in cells treated with TmPyP4 compared to TmPyP2 under both hypoxic and normoxic conditions. Real-time reverse transcription polymerase chain reaction and western blot showed a similar trend toward a decrease in HIF-1α mRNA and protein after treatment of RCC4 cells with TmPyP4 compared to TmPyP2. Taken together, these data provide the first evidence for the existence of a G-quadruplex in the HIF-1α promoter. The cationic porphyrins have been shown elsewhere to have anti-angiogenic acitivity in an  in vivo  model, and these data suggest that TmPyP4 and other quadruplex interactive compounds may exert an anti-angiogenic effect by suppressing HIF-1α expression.
Abstract P401: Plasma N-3 Polyunsaturated Fatty Acids are Associated with Worse Systolic Function and Heart Rate
Authors: Ilse Reinders, Adriana J van Ballegooijen, Marjolein Visser, Amany K Elshorbagy, Helga Refsum, Ronald M Henry, Katja van den Hurk, Jacqueline M Dekker, Giel Nijpels, Coen D Stehouwer, Ingeborg A Brouwer
Journal: Circulation (2013)
Characterization of nilotinib activity against a model of KIT-induced neoplasia using FDG-PET
Authors: Carleen Cullinane, Anthony Natoli, Yorlon Hui, Nelly Conus, Joseph Brueggen, Paul Manley, Grant McArthur
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2379 

Although imatinib has led to significant improvements in survival for patients with advanced gastrointestinal stromal tumor (GIST), the development of imatinib resistance remains a clinical challenge. Nilotinib (AMN107), a rationally designed inhibitor of the Bcr-Abl tyrosine kinase also inhibits the tyrosine kinase activity of KIT and exhibits activity against imatinib responsive and resistant GIST cells in vitro. The aim of this study was therefore was to investigate the effects of nilotinib on tumor metabolism in vivo using a preclinical model comprising FDC-P1 cell lines expressing KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to imatinib. Syngeneic DBA2/J mice bearing FDC-P1 V560G and D816V tumors on contralateral flanks were subjected to positron emission tomography (PET) using fluorodeoxyglucose (FDG). As observed previously, response to imatinib (100 mg/kg, p.o.) in this model is associated with a rapid reduction in tumor FDG uptake on PET (reduced to 75 % ± 9 % of baseline levels at 4 hr after administration). FDG PET imaging following nilotinib treatment revealed no change in FDG uptake in V560G tumors at 4 hr following a single 100 mg/kg dose p.o. while FDG uptake was reduced to 53 ± 0.08 % of baseline levels 4 hr following a second daily dose of 100 mg/kg. In contrast, no effect of nilotinib was observed on FDG PET uptake into D816V tumors or D816V tumor growth despite intra-tumoral drug levels reaching in excess of 10 μM at 4 hr after dosing. Biomarker analysis of tumors harvested on Day 2 of nilotinib treatment revealed inhibition of KIT phosphorylation in V560G but not D816V tumors. In vitro studies were performed to further understand the in vivo effects of nilotinib. Nilotinib inhibited the proliferation of the V560G and D816V cells with an IC50 of 3.1 ± 0.1 nM and 690 ± 70 nM, respectively (imatinib: 4 nM and 7 μM, respectively). In vitro apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line as measured by sub-G1 DNA content. In contrast, while 10 μM nilotinib induced >50 % apoptosis in the D816V cells after 16 hr, there was no demonstrable effect of 10 μM imatinib on cell survival at 24 hr. The in vitro and in vivo effects of nilotinib on V560G cells suggest that nilotinib and imatinib exert similar inhibitory effects against this model. In contrast, D816V cells were significantly more sensitive to effects of nilotinib than imatinib in vitro, but resistance to both drugs was observed in vivo despite the intra-tumoral level of nilotinib reaching an in vitro efficacious dose. The discordance between the in vitro and in vivo effects of nilotinib demonstrate the importance of in vivo based studies to elucidate mechanisms of drug efficacy.
Antibody targeting of endothelial Tie1 receptor as an anti-angiogenic sensitizer in tumor therapy
Authors: Pirjo Laakkonen, Daniel Dransfield, Pipsa Saharinen, Hajime Kubo, Gou Young Koh, Rakesh Jain, Clive Wood, Kari Alitalo
Journal: Cancer Research (2008)

2492  Tie1, an endothelial cell-specific receptor tyrosine kinase, is essential for the development of the vascular system. Targeted disruption of the Tie1 gene results in mouse embryonic lethality after mid-gestation due to severe edema, extensive hemorrhage and defective microvessel integrity. Tie1 expression is upregulated during wound healing, ovarian follicle maturation and tumor angiogenesis. Members of the angiopoietin ligand family that activate the related Tie2 receptor stimulate also Tie1 phosphorylation. We have here analyzed the effect of Tie1-targeted antibodies on human tumor growth in mouse xenograft models as a monotherapy and in combination with clinically approved anti-angiogenic agents. Our results show that antibody targeting Tie1 inhibits tumor growth. Immunohistochemical analysis indicated that anti-Tie1 treated tumors displayed a distinct vascular pattern with abnormal vessel sprouting, detachment of smooth muscle cells and increased hypoxia and necrosis. This vessel destabilization sensitizes tumor vasculature to other anti-angiogenic agents leading to improved efficacy. As the most effective inhibition of tumor progression may require inhibition of multiple angiogenic pathways, antibody-targeting of Tie1 may prove critical in such combinations.
Tumor suppressor gene penetrance determined by early life environmental exposure
Authors: Jennifer D. Cook, Barbara Davis, Sheng-Li Cai, Claudio Conti, J. Carl Barrett, Cheryl L. Walker
Journal: Cancer Research (2004)

4175   Inheritance of a tumor suppressor gene defect confers a high relative risk for cancer development; however, these susceptibility genes are rarely 100% penetrant. Gene-environment interactions are thought to contribute to individual differences in penetrance by facilitating or inhibiting acquisition of the subsequent somatic mutations required for tumorigenesis. For disorders such as cardiovascular disease and type 2 diabetes, a developmental programming hypothesis exists which proposes that as an alternative to contributing to somatic mutations, environmental exposures during fetal development alter normal adult physiological responses to increase risk for disease development later in life. We investigated whether developmental programming resulting from an environmental exposure could reprogram target cells to influence tumor suppressor gene penetrance in genetically susceptible individuals. Rats carrying a genetic defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene that spontaneously develop uterine leiomyoma were exposed to the xenoestrogen diethylstilbestrol (DES) on neonatal days 3-5, an important period of reproductive tract development. In carrier animals (Tsc-2Ek/+), developmental DES exposure increased tumor penetrance from 64% to 92% (p
Degradation-by-design: Surface modification with functional substrates that enhance the enzymatic degradation of carbon nanotubes
Authors: Adukamparai Rajukrishnan Sureshbabu, Rajendra Kurapati, Julie Russier, Cécilia Ménard-Moyon, Isacco Bartolini, Moreno Meneghetti, Kostas Kostarelos, Alberto Bianco
Journal: Biomaterials (2015)