tbuckley/cabot-search huggingface dataset:
Abstract 2940: A role for PAX8 in promoting tumor cell type-specific proliferation through positively regulating E2F1 transcription and stabilizing RB protein
Authors: Mike R. Eccles, Caiyun G. Li, Jennifer E. Nyman, Antony W. Braithwaite
Journal: Cancer Research (2011)

Abstract The PAX proteins are tissue-specific developmental regulators required for fetal development. In most cases, PAX expression is silenced post-natally, although it is maintained in some adult tissues. Several PAX proteins interact with RB, a key protein involved in cell cycle regulation. The phosphorylation of RB leads to the mobilization of the master regulator of cell cycle progression, E2F1. It is presently unknown how the growth and differentiation of a tissue is coordinated in a tissue-specific manner with the regulation of the cell cycle in order to facilitate terminal differentiation, or how this process might be disrupted in cancer. PAX gene dysregulation is observed in many cancer types with PAX8 being frequently expressed in renal cell carcinoma (RCC), bladder, ovarian and thyroid cancer cell lines. We investigated the effect on the RB-E2F1 pathway of knocking-down PAX8 using siRNAs in cell lines corresponding to these four cancer types. Knockdown of PAX8 led to a striking reduction in E2F1 mRNA and protein in cancer cell lines, as well as a reduction in levels of E2F1 target genes, including cyclin A2 (CCNA2) and CDC6, induction of a G1/S cell cycle arrest, the onset of cellular senescence, and a proteosome-dependent destabilization of RB protein, with RB1 mRNA levels remaining unaffected. Using ChIP and luciferase reporter assays we showed that PAX8 binds to and transcriptionally regulates the E2F1 promoter. These data suggest that the expression of PAX8 is associated with transcriptional activation of E2F1 and stabilization of RB protein in cancer cell lines. During development in normal tissues we presume that expression of PAX8 coordinates cell proliferation with tissue-specific growth. In cancer, however, the expression of PAX8 continues unabated, and PAX8 silencing leads cancer cells to undergo cell cycle arrest, and subsequently to become senescent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2011-2940
Abstract 775: The antiproliferative effects of <i>Mucuna macrocarpa</i> stem extract on HL-60 leukemia cells
Authors: Chin-Wen Chi, Kuan-Hung Lu, Yuh-Fang Chang, Pen-Hui Yi, Ting-Ting Chen, Yu-Ling Ho, Yuan-Shiun Chang
Journal: Cancer Research (2010)

Abstract Mucuna macrocarpa Wallich (Leguminosae) is believed to hold blood circulation activating effects, and has been used as a folk remedy in Southeast Asia for the treatment of various hematologic and circulatory related ailments. The objective of this study was to investigate whether crude methanolic extract of M. macrocarpa (CMEMM) possessed antileukemic effects on HL-60 human leukemia cells. CMEMM was prepared from dried stems of this plant, and phytochemical analyses of CMEMM revealed major components included lipids (tetracosanoic acid), sterols (mixture of β-sitosterol and stigmasterol), carbohydrates (sucrose and D-pinitol), triterpenoids (friedelin) and isoflavones (medicarpin, calycosin, afrormosin and genistein). The apoptosis-inducing effects of CMEMM were investigated using HL-60 cells in vitro and in vivo. With treatment of 25 to 75 µg/ml CMEMM, the in vitro antiproliferative effect on HL-60 cells increased in a dose- and time-dependent manner during the 72 h treatment period. The concentration of CMEMM that exhibited a 50% growth inhibition (IC50) for 72 h exposure was 36.4 μg/ml. Apoptosis triggered by CMEMM in HL-60 cells was confirmed by the following observations: (1) characteristic apoptotic nuclear fragmentation, (2) dose-dependent accumulation of sub-G1 phase in cell cycle analyses, (3) increased percentages of annexin V-positive apoptotic cells, and (4) dose-dependent elevation of active caspase-3. Additionally, the in vivo effect of CMEMM (500 mg/kg/day i.p.) on suppression of HL-60 tumor growth was observed in mouse xenografts. Moreover, CMEMM exerted anti-inflammatory activities by suppressing production of proinflammatory cytokines, TNF-α and IL-6, in lipopolysaccharide-activated RAW264.7 macrophages. These results together suggest that CMEMM exerted a novel antileukemic effects via an apoptotic pathway on HL-60 cells. Further characterization of the active components in CMEMM and their action in antitumor response will be important for future clinical application. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 775.
DIAGNÓSTICO RÁPIDO DE CÁNCER COLORECTAL: ¿JUSTIFICA LA SOBRECARGA DE LAS SALAS DE ENDOSCOPIA?
Authors: M Alburquerque Miranda, A Fernández Alvarez, I Sánchez Pérez, A Smarrelli, C Ledezma Frontado, L Vidal Plana, F González-Huix Llado
Journal: Endoscopy (2013)

Introducción: Un objetivo del circuito de diagnóstico rápido (CDR) del cáncer colorectal (CCR) es realizar una colonoscopia en menos de15 días desde la derivación del paciente. Objetivo: Evaluar la recomendación de colonoscopia del CDR y comparar los resultados del manejo del CCR. Métodos: Estudio prospectivo, marzo 2012 – marzo 2013. Pacientes atendidos en el CDR-CCR. Analizamos la concordancia entre criterios de derivación y los confirmados en atención especializada (AE). Calculamos (en días) las fases del CDR, la frecuencia de CCR y comparamos los resultados de su manejo en el CDR vs. no-CDR. Análisis: programa SPSS 15.0. Resultados: Incluimos 240 pacientes, edad: 66,74 ± 14,32 años, Mujeres: 110 (45,83%). El 79,58% procedían de atención primaria, siendo rectorragia: 47,5%, el criterio de derivación más frecuente. Hubo buena concordancia en antecedentes familiares de CCR, fecatest (+), anemia ferropénica y rectorragia (kappa> 0,8). Alteración del ritmo intestinal y masa rectal tuvieron pobre concordancia (kappa< 0,6). Se confirmó el CDR en AE (CDR-C) en 159 pacientes (66,25%). En 55,1% se logró el objetivo de colonoscopia < 15 días, valor que se elevó al 70% en los CDR-C (p < 0,001). La frecuencia de CCR en el CDR fue de 18,33% (44 casos), que se elevó a 25,16% (p < 0,001) en los CDR-C. Esta frecuencia representó el 53,66% del global de CCR en nuestro hospital. En el CDR, el CCR se diagnosticó en menos tiempo que en los no-CDR (p = 0,023). No hubo diferencia en el TNM ni en el tipo, ni demora de tratamiento. En los no-CDR, la cirugía urgente fue más frecuente (13,16 vs. 2,27%), aunque con p < 0,055. Conclusiones: En el CDR, la recomendación de colonoscopia se alcanzó en 55,1% de pacientes; la frecuencia del CCR representó el mayor porcentaje del global de CCR, se diagnosticó en menos tiempo y la cirugía urgente fue menos frecuente. Uniformizar adecuadamente los criterios reduciría derivaciones innecesarias.
Abstract 3615: Erlotinib in combination with different chemotherapeutics is active in a SCID mouse/ human melanoma model
Authors: Nikolaus Schicher, Hubert Pehamberger, Christoph Hoeller
Journal: Cancer Research (2010)

Abstract Erlotinib is a novel EGF-receptor targeting drug which has been tested in various cancers for its activity, has shown impressive results in non small cell lung cancer, but has so far failed as a single agent in other cancer types. We and others have recently shown that the combination of erlotinib with e.g. the monoclonal VEGF antibody bevacizumab or chemotherapy is more powerful in inducing apoptosis and reducing proliferation or angiogenesis. Due to the fact that erlotinib induces accumulation of tumor cells in the G1-phase of the cell cycle this leads to the assumption that erlotinib prior to or concomitant with chemotherapy might negatively interact with it. The aim of our study was to test different dosing schedules of erlotinib in combination with dacarbazine, paclitaxel or cisplatin in a SCID mouse/ human melanoma xenotransplantation model with 518 A2 and M24 met cell lines. We hypothesize that pausing erlotinib before chemotherapy leads to greater apoptosis. Six to eight week old female SCID mice were injected with 518 A2 or M24 met melanoma cells and treated either with erlotinib, dacarbazine, paclitaxel or cisplatin as single agents or a combination of erlotinib with either chemotherapy. Groups were divided in control, erlotinib, chemotherapy, erlotinib concurrently with chemotherapy or with a break of 5 days prior to chemotherapy. While the cytotoxic drugs did show single agent activity in the model system used, the combination with erlotinib exhibited a higher reduction in tumor volume. These effects were substantiated by immunohistochemical analysis where we observed a reduction of angiogenesis and proliferation as well as an increase in apoptosis in the combined treatment arms as assessed with ki-67, CD31 and cleaeved caspase 3 staining, respectively. Interestingly, withholding erlotinib before treatment did not alter the activity of dacarbazine, thereby excluding an inhibitory effect of EGF-receptor inhibition under these conditions. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3615.
Abstract LB-388: Macrophage migration inhibitory factor (MIF) plays a role in proliferation, differentiation, and survival of Ewing tumor cells through the activation of several kinases
Authors: Hyung-Gyoo Kang, Xian Fang Liu, Poul HB Sorensen, Timothy J. Triche
Journal: Cancer Research (2010)

Abstract Cytokines and chemokines are involved in various mechanisms of cell signaling networks, which control cell growth, proliferation, differentiation, and survival. In normal cells, expression of cytokines and their downstream cell signaling pathways are tightly and accurately regulated. However, it has been shown that cytokine signaling pathways are deregulated in many tumors. Thus, identification and understanding of deregulated cytokines and their related pathways may provide unique and promising opportunities for better-targeted therapies of cancer. In the previous experiments we showed that Macrophage migration Inhibitory Factor (MIF) is highly expressed in Ewing tumor cells and it is involved in the proliferation and survival of Ewing tumors. Our present data implies that MIF might functionally contribute to Ewing tumor cell growth, differentiation and survival through the activation of several kinases such as AMPK (AMP activated protein kinase), Paxillin and PYK2 (Protein Tyrosine Kinase2). In conclusion, coupled with earlier and present studies about MIF-dependent effects on Ewing tumors our data suggested that MIF might be involved in various pathways of Ewing tumor biology and might be a promising target of Ewing tumor cells therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-388.
Aromatic hydrocarbon receptor polymorphism: development of new methods to correlate genotype with phenotype.
Authors: A Maier, J Micka, K Miller, T Denko, C Y Chang, D W Nebert, None Alvaro Puga
Journal: Environmental Health Perspectives (1998)

Differential CYP1A1 inducibility, reflecting variations in aromatic hydrocarbon receptor (AHR) affinity among inbred mouse strains, is an important determinant of environmental toxicity. We took advantage of the Ahr polymorphism in C57BL/6 and DBA/2 mice to develop an oligonucleotide-hybridization screening approach for the rapid identification of DNA sequence differences between Ahr alleles. Oligonucleotides containing single-base changes at polymorphic sites were immobilized on a solid support and hybridized with C57BL/6 or DBA/2 AHR cDNA radiolabeled probes. The observed hybridization patterns demonstrate that this approach can be used to detect nucleotide differences in the Ahr coding region with very high accuracy. In parallel experiments, we used a yeast two-hybrid system to assess phenotypic differences in AHR function. AHR activation, as measured by beta-galactosidase reporter activity in Saccharomyces cerevisiae strain SFY526, was determined following treatment with varying doses of the AHR ligand beta-naphthoflavone (BNF). We found that the C57BL/6 AHR has about a 15-fold higher affinity for BNF than the DBA/2 AHR, in much better agreement with results reported for whole-animal studies than the values observed by in vitro ligand-binding assays. Using C57BL/6 and DBA/2 AHR chimeric proteins, we also confirmed the previously reported observation that an A375V change is principally responsible for the high- to low-affinity AHR phenotype. There has been no straightforward method to reliably and reproducibly phenotype large numbers of humans for CYP1A1 inducibility or AHR affinity. Screening human AHR cDNAs by oligonucleotide-hybridization and yeast two-hybrid methodologies will be invaluable for the rapid and unequivocal determination of changes in DNA sequence and receptor-ligand affinities associated with human AHR polymorphisms.
OP0135 Clinical and therapeutic features of 270 patients with macrophage activation syndrome enrolled in a multinational survey:
Authors: S. Davì, B. Lattanzi, E. Demirkaya, S. Rosina, A. Novelli, N. Ruperto, A. Martini, R.Q. Cron, A. Ravelli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> A multinational collaborative effort aimed to develop a new set of criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) has been recently started. The first step of the project, based on a Delphi survey, has been completed (Davì S et al. J Rheumatol 2011;38:764-8). The second step, whose goal is to collect the data of a sizable sample of children with MAS and with potentially "confusable" conditions, is currently under way. <h3>Objectives</h3> To describe the demographic, clinical, laboratory, histopathologic, therapeutic and prognostic features of children with MAS collected so far in the data-collection phase of the project. <h3>Methods</h3> Investigators who participated in the Delphi survey were asked to enter the information of their patients with MAS collected retrospectively in a web-based database, developed at the coordinating center (the Istituto G. Gaslini of Genoa, Italy). <h3>Results</h3> At the 31st of December, 2011, 270 patients with sJIA-associated MAS have been entered in the study website by 76 investigators from 27 countries. 155 (57,4%) patients were females and 115 (42,6%) were males. The age at onset of sJIA ranged from 0.2 to 19,5 years (median 5 years) and the disease duration from onset of sJIA and onset of MAS ranged from 0 to 15,1 years (median 4,1 years). MAS occurred at onset of sJIA in 50 (18,5%) patients. The frequency of the clinical, laboratory and histopathologic features of MAS is reported in the Table. The most frequently reported trigger of MAS was active disease (33%), followed by infection (26,3%) and medication toxicity (7%). 54 (20%) patients were admitted in the ICU. Therapeutic interventions included iv steroids (83,3%), oral steroids (66,3%), cyclosporine (63,7%), other immunosuppressants (8,9%), iv Ig (33,%), etoposide (8,5%), anakinra (7%), and plasma exchange (3,7%). The mortality rate was 8%. <h3>Conclusions</h3> Hyperferritinemia, falling platelet count and increased liver enzymes were the most frequently observed laboratory abnormalities. Notably, the frequency of falling leukocyte count was unexpectedly low. Also unexpectedly, liver and spleen enlargement were recorded more frequently than persistent continuous fever. Hemophagocytosis was noticed in around one third of patients who underwent bone marrow aspirate. As expected, corticosteroids and cyclosporine were the most commonly administered medications. <h3>Disclosure of Interest</h3> None Declared
Secretory Component Deficiency
Authors: W. Strober, R. Krakauer, H.L. Klaeveman, H.Y. Reynolds, D.L. Nelson
Journal: New England Journal of Medicine (1976)

We studied a 15-year-old boy with chronic intestinal candidiasis who had normal serum IgA levels without IgA in his secretions. There was an elevated number of peripheral blood lymphocytes bearing surface IgA. In addition, the lymphocytes cultured in vitro with pokeweed mitogen produced IgA as well as other immunoglubulins. Despite this evidence of normal IgA synthetic capacity, the patient had greatly diminished levels of IgA in the saliva and jejunal fluid, and, as estimated by 14C-L-leucine incorporation, could not synthesize IgA locally at intestinal-mucosal sites. Finally, the patient had no detectable free secretory component in saliva or jejunal fluid in contrast to normal persons and to patients with IgA deficiency. The basis of this disorder is probably a defect in the homing of IgA precursor cells to secretory sites or in the selective proliferation/differentiation of IgA cells at such sites.
Control of Nasal-Staphylococcal-Carrier States
Authors: Haskell J. Weinstein
Journal: New England Journal of Medicine (1959)

THE increasing incidence of staphylococcal infections in hospitals has resulted in numerous studies of the various aspects contributing to the problem and the identification of some of the sources of such infections. The nasal-carrier state of hospital personnel, hospital patients and the general population has been extensively reported.1 2 3 4 5 6 7 The mechanisms by which such states contaminate the environment have been described by Hare and Thomas.8 They demonstrated that the danger is only partly created by direct emission of bacteria from the nose; the major pathway apparently is the indirect transmission of the organisms from the nose of the carrier to various . . .
A6.10 Anti citrullinated peptides/proteins antibodies induce secretion of CCL5/rantes by fibroblast like synoviocytes
Authors: R Capecchi, E Prediletto, F Pratesi, P Italiani, I Puxeddu, F Panza, P Migliorini
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder, characterised by a progressive joint damage, caused by a cellular infiltrate localised in the synovia. In RA, fibroblast like synoviocytes (FLS) acquire an aggressive phenotype and contribute to joint destruction also producing a variety of pro-inflammatory cytokines. In the pathogenesis of RA a pivotal role is played by fibroblast like synoviocytes (FLS), that produce cytokines that perpetuate inflammation. One of the serological markers of RA are anti citrullinated protein antibodies (ACPA), a family of autoantibodies recognising a wide variety of antigens all characterised by the deimination of arginine into citrulline. Among the different citrullinated targets, ACPA can bind viral citrullinated peptides (VCPs) and histone citrullinated peptides (HCPs). Despite their strict association with RA, so far little is known about the role of ACPA in the pathogenesis of the disease. <h3>Objective</h3> The aim of this work was to analyse the effects of anti VCPs and HCPs antibodies on <i>in vitro</i> cultured FLS. <h3>Methods</h3> FLS from RA and non RA patients were isolated from synovial fluid and used for experiments at 4–5th passage. Anti-VCPs and anti-HCPs antibodies were purified by affinity chromatography from RA patients sera and IgG from normal subjects were used as control antibodies. Anti-VCPs and –HCPs antibodies were incubated on subconfluent FLS; cells and supernatants were recovered at different time points. RANTES protein was quantified in the supernatants by sandwich ELISA and RANTES gene expression was evaluated by RT-PCR. To investigate intracellular signalling after ACPA stimulation, specific MAP kinase, already known to be activated during CCL5/RANTES production, were studied. <h3>Results</h3> Anti-VCPs and anti-HCPs from 5 RA patients induce RNA expression and secretion of RANTES from FLS as compared with normal IgG (p &lt; 0.001). No differences were observed between RA and non RA FLS. FLS stimulation with ACPA seems to induce phosphorylation of ERK, JNK and p38. <h3>Conclusions</h3> These results suggest a novel mechanism potentially involved in damage induced by ACPA, mediated by the production of RANTES in FLS. ACPA might play a role in activation and chemotaxis of T cells in synovial tissue with a perpetuation in inflammation and immune response. Studies are in progress to clarify the intracellular pathways implicated in the synthesis of RANTES induced by ACPA in FLS and to define the target of ACPA on FLS surface.
Abstract 2922: NDC-1308 inhibits growth of lung and pancreatic tumors in vivo by blocking chromosome replication of cancer cells
Authors: James G. Yarger, Steven Weitman, Steven Weitman, Bernd Meibohm, Stephen Gately, Steven Nye
Journal: Cancer Research (2010)

Abstract Identification of the cellular mechanisms that alter normal cell growth may be exploited for creating new drugs that treat cancers with unmet needs. For example, recent evidence by our group, and others, suggests that proliferation of lung and pancreatic cancer cells may be controlled by the estrogen receptors alpha (ER-alpha) and beta (ER-beta). If accurate, designing drugs that enhance the proposed inhibitory function of ER-beta versus the stimulatory function of ER-alpha, should lead to cessation of cell division and potentially to cell death. We previously demonstrated that an estradiol-like compound, NDC-1308, is cytotoxic to 14 different tumor cell lines in vitro with an EC50 of 10-20 uM. As predicted, receptor binding studies confirmed that NDC-1308 binds preferentially to ER-beta compared to ER-alpha. A more detailed in vitro analysis showed that NDC-1308 causes a substantial reduction in the transcription of 27 genes involved in chromosomal replication, likely disrupting the cell cycle of the cancer cells. To determine the efficacy of NDC-1308 to kill tumor cells in vivo, xenograft studies were carried out using SCID mice injected with A549 (lung) and BxPC3 (pancreas) tumor cell lines. Mice (N=15 per treatment group) were administered either 8, 16 or 24 mg/kg of NDC-1308 via tail vein injection. Depending on the schedule, the mice were dosed every other day or every third day and the tumor weights followed for two additional weeks after ending treatment. The results show that tumor size was substantially smaller (2 to 3-fold) in NDC-1308 treated animals versus untreated controls. We conclude that intravenous administration of NDC-1308 can cause a cessation of tumor growth in a mouse model of lung and pancreatic cancer. Consistent with the proposed mechanism of action and recent rat pharmacokinetic data (t1/2=120min), increasing the dose or decreasing the time between doses enhanced the effect of NDC-1308 on tumor growth in the xenograft model. Future studies will include large animal safety and toxicity studies leading to IND submission and Phase I clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2922.
CILOSTAZOL IMPROVES PROANGIOGENESIS FUNCTIONS IN HUMAN EARLY ENDOTHELIAL PROGENITOR CELLS AND HYBRID THERAPY PROVIDES A SYNERGISTIC EFFECT IN HINDLIMB ISCHAEMIA THROUGH STROMAL CELL-DERIVED FACTOR SYSTEM
Authors: Ting-Hsing Chao, Yi-Heng Li, Shih-Ya Tseng
Journal: Journal of the American College of Cardiology (2016)