tbuckley/cabot-search huggingface dataset:
A9.6 Identification of New Potential Therapeutic Targets for the Treatment of Rheumatoid Arthritis: ENTPD1 (CD39) and 5NTE1 (CD73)
Authors: Jonathan D Finn, Lisa van Baarsen, Jan van Ittersum, Ciska Braam, Maria C Lebre, Paul P Tak, Margriet J Vervoordeldonk
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Adenosine and ATP are known to have important immunomodulatory properties. Extracellular ATP has multiple roles in inflammation and can act as a damage-associated molecular pattern (DAMP) that can activate the immune system. Conversely, adenosine is primarily anti-inflammatory and can inhibit the production of pro-inflammatory molecules by immune cells. The modulation of ATP and adenosine levels are an essential part of the induction and resolution of an inflammatory response. ENTPD1 (CD39) is a membrane-bound ectonucleoside triphosphate diphosphohydrolase enzyme that converts ATP and ADP to AMP 5NTE1 (CD73) is a 5′ ecto-nucleotidase that dephosphorylates AMP to form adenosine. We investigated the role of genes in the adenosine pathway in patients with rheumatoid arthritis (RA) and determined whether expression of CD39 and CD73 would have an effect in an in vitro inflammation model. <h3>Materials and Methods</h3> Gene expression analysis using 43k cDNA microarrays (Stanford Functional Genomics Facility) was performed on total RNA extracted from RA synovial tissues obtained by arthroscopy. Adenosine pathway gene expression was compared between high-inflammation versus low-inflammation tissue type synovial biopsies. ATPase levels were measured in synovial fluid (SF) from RA (n = 10) or osteoarthritis (OA) (n = 6) patients. Adeno-associated viral (AAV) vectors expressing CD39 or CD73 were generated and used to transduce HEK 293 cells or RA fibroblast-like synoviocytes (FLS) and these transduced cells were co-cultured with LPS-activated human monocytes (THP-1) in the presence of ATP. Pro-inflammatory cytokine/chemokine (IL-6, CCL2) production was measured by ELISA. <h3>Results</h3> Genes involved in the ATP:adenosine pathway, including CD73, were differentially expressed in high-inflammation synovial tissues, consistent with the hypothesis that there is skewing of the ATP:adenosine balance during inflammation. The half-life of ATP was significantly increased in SF from RA patients compared with OA (t<sub>1/2</sub> = 8.0 versus 4.5 min., p = &lt;0.05), indicating that there was a significant decrease in ATPase activity in RA SF HEK 293 cells and RA FLS cell lines transduced with CD39-and/or CD73-expressing AAV5 vectors demonstrated high CD39 and CD73 activity. THP-1 cells stimulated with LPS showed lower levels (&gt;80% reduction p = &lt;0.05) of IL-6 and CCL2 secretion when co-cultured with CD39 and CD73 expressing HEK293 cells or FLS cells in the presence of ATP. <h3>Conclusions</h3> Together, these data suggest that synovial inflammation in RA is characterised by skewing of the ATP:adenosine balance. This could be reversed by overexpression of CD39 or CD73. Thus, these data show that the ATP:adenosine pathway may be a novel therapeutic target for the treatment of RA.
IN PATIENTS WITH SEVERE ADVANCED HEART FAILURE, NON RESPONSE TO DECREASE LV FILLING PRESSURE IS NOT ASSOCIATED WITH WORSE SURVIVAL AND OUTCOMES: INSIGHTS FROM THE ESCAPE (EVALUATION STUDY OF CONGESTIVE HEART FAILURE AND PULMONARY ARTERY CATHETERIZATION EFFECTIVENESS) TRIAL
Authors: Francisco Y. Macedo, Wenyaw Chan, Anita Deswal, Kumudha Ramasubbu, Andrew Civitello, Biykem Bozkurt
Journal: Journal of the American College of Cardiology (2015)
Distribution of Research Awards from the National Institutes of Health among Medical Schools
Authors: Ernest Moy, Paul F. Griner, David R. Challoner, David R. Perry
Journal: New England Journal of Medicine (2000)

Previous studies have demonstrated that a small number of the 125 medical schools in the United States receive a disproportionately large share of the research awards granted by the National Institutes of Health (NIH). We assessed whether the distribution of NIH research awards to medical schools changed between 1986 and 1997.
Correlation of Malignancy and Sensitivity to Prior Treatment in Metastatic Breast Cancer Treated with Eribulin
Authors: T. Iwasa, J. Tsurutani, H. Matsuoka, K. Okamoto, T. Shimizu, T. Kurata, K. Nakagawa, T. Azumi, Y. Hashimoto, Y. Komoike
Journal: Annals of Oncology (2013)
A Geometric Method of Measuring the Left Ventricular Ejection Fraction on Gated Tc-99m Sestamibi Myocardial Imaging
Authors: STEFAN D. MIRON, ROBERT FINKELHOR, JOHN H. PENUEL, ROBERT BAHLER, ERROL M. BELLON
Journal: Clinical Nuclear Medicine (1996)

Geometric measurements of the left ventricular diameters as used in biplane angiocardiography and echocardiography were applied to gated SPECT Tc-99m sestamibi myocardial scintigrams in order to calculate the left ventricular ejection fraction. These measurements take no longer than 5 minutes and require no additional computer software. In a review of 79 examinations, the left ventricular ejection fraction calculated using these measurements correlated well with the echocardiographically estimated ejection fraction (r = 0.78, P < 0.0001). The technique is highly reproducible with an intraobserver correlation of r = 0.94 and interobserver correlation of r = 0.93.
Abstract 4743: Genome-wide gene-centric discovery of disease variants in neuroblastoma
Authors: Le B. Nguyen, Sharon Diskin, Hakon Hakonarson, John M. Maris, Hongzhe Li
Journal: Cancer Research (2010)

Abstract Genome-wide associations studies (GWAS) have been increasingly utilized to identify novel genetic variants for complex human diseases. As we are interested in disease causal variants that have a high likelihood of impacting protein encoding genes, we developed a gene-centric genome-wide association approach. This method computes the aggregated effect of all SNPs mapped on a gene normalized by the number of SNPs on this gene. Therefore, this method is able to identify genes whose SNPs have marginal effect size by conventional statistical methods because the Bonferroni correction criteria are relaxed since the number of genes in the human genome is far less than the number of SNPs on the array. We applied this gene-centric method to both high-risk and low-risk neuroblastoma, a cancer of early childhood with less than 40% cure rate in high-risk patients and more than 95% survival rate in low-risk patients. We utilized a discovery set of 1627 cases and 2575 control subjects, and an independent replication set with 398 cases and 1507 control subjects. First, we provided proof of concept by replicating each prior association study result reported by our lab, including the hypothetical gene FLJ44180 at chromosome band 6p22, BARD1 at 2q35 and LMO1 at 11p15 (P=9.92×10−11, &amp;lt;1.00×10−30, and 1.80 ×10−7, respectively). Additionally, we also discovered two new association signals that robustly replicated in low-risk cases only: DUSP12 at 1q23 (P=3.03 ×10−6) and DDX4 at 5q11 (P=2.39×10−6). These data suggest that a gene-centric statistical approach to GWAS data can identify causal variants in relatively rare phenotypic subsets. 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 4743.
Benign Recurrent Intrahepatic Cholestasis
Authors: Robert H. Schapiro, Kurt J. Isselbacher
Journal: New England Journal of Medicine (1963)

INTRAHEPATIC cholestasis as a manifestation of liver disease is not an unusual finding. Such obstruction to bile flow may occur quite frequently in acute and chronic hepatitis and primary biliary cirrhosis and occasionally follows the use of therapeutic agents such as chlorpromazine.1 It may also occur in alcoholic patients having a fatty liver,2 as well as in erythroblastosis fetalis,3 intrahepatic biliary atresia4 and the so-called idiopathic jaundice of pregnancy.5 However, in all these conditions, except for the idiopathic jaundice of pregnancy, it is most unusual to have repeated or recurrent episodes of cholestasis, without the presence of some extrahepatic obstruction. . . .
P3-17-11: Dovitinib (TKI258), a Dual Inhibitor of FGFR and VEGFR, Induces Tumor Growth Suppression in Xenograft Models of Primary Human Breast Cancer.
Authors: MM Shi, R Linnartz, R Versace, Porta D Graus, A Kay, M Dugan
Journal: Cancer Research (2011)

Abstract Introduction: The objective of this study was to evaluate the efficacy of dovitinib (TKI258), a small-molecule dual inhibitor of fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) in mouse models of human breast cancer. Molecular epidemiological studies have implicated that FGFR1 and FGFR2 gene amplification plays a critical role in breast cancer tumorigenesis. FGFR1 gene amplification correlates with gene expression and is associated with poor prognosis in patients with estrogen receptor-positive (ER+) tumors. Dual FGFR/VEGFR inhibitory activities of dovitinib make it an attractive molecule for targeting breast cancer. Experimental Design: Dovitinib was evaluated in 3 primary human breast carcinoma xenograft models with different histological and molecular profiles: a triple-negative breast cancer model (HBCx-15), a HER2+ model (HBCx-5), and an ER+ model (HBCx-3). Dovitinib was administered orally at 20- and 40-mg/kg dose levels (n = 8–10/group), once daily for 21 consecutive days. Results: At a dose of 40 mg/kg, dovitinib demonstrated strong antitumor efficacy as a single agent, particularly in the ER+ HBCx-3 and the HER2+ BCx-5 tumor models (ΔT/T0 = −26.42% and ΔT/ΔC = 5.09%, respectively), whereas the response was less significant in the triple negative breast cancer HBCx-15 model (ΔT/ΔC = 31.7%). Conclusion: Dovitinib showed significant antitumor effect in human breast cancer xenograft mouse models. This study provides a strong rationale for clinical investigation of dovitinib in patients with advanced breast cancer, particularly in patients with ER+ and HER2+ disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-11.
SAT0450 Are females with rheumatoid arthritis caught in a vicious circle of pain, fatigue and sleep disturbance?:
Authors: C. Austad, T.K. Kvien, T. Uhlig
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Sleep quality is an important aspect of health and well-being and the Outcome Measures in Rheumatology Clinical Trials group has identified sleep quality as a key concern for rheumatoid arthritis (RA) patients1. Patient reported sleep-disturbance is included in the RAID (RA Impact of Disease) score, but not in many other core patient reported outcomes (PROs) and is seldom reported in clinical trials. <h3>Objectives</h3> To assess self-reported sleep disturbance in a large sample of patients from a population based RA registry and identify factors associated with self-reported sleep disturbance. <h3>Methods</h3> In a population based RA registry in Oslo, Norway, 868 patients aged 20-79 years (mean (SD) age 59.9 (12.3) years, disease duration 13.0 (10.8) years, 77.1% females) responded in 2009 to a mailed questionnaire (response rate 60.6%). 844 patients answered the numeric rating scale (NRS) on sleep disturbance due to RA (part of the RAID questionnaire) within the last week, and use of benzodiazepine like sleeping drugs (zopiclone/zolpidem = z-hypnotics) and other medications used in the treatment of RA. Other PROs included 100mm visual analogue scales (VAS) for pain, fatigue and global disease activity (patglob), HAQ (0-3, 3 worst), SF-36 with physical (PCS) and mental (MCS) component scores (0-100, 0=worst), RA Disease Activity Index (RADAI, 0-10, 10 worst) and RAID score (0-10, 10=extreme/very poor). Use of z-hypnotics was significantly associated with MCS, PCS, HAQ, RADAI, RAID, NRS sleep disturbance, VAS pain/fatigue/patglob (all p&lt;0.001), and with disease duration (p=0.03). Linear regression analyses were used to identify factors independently associated with sleep disturbance (0-10 NRS, 10=extreme sleep disturbance) and adjusted for age, gender and disease duration. <h3>Results</h3> Females used z-hypnotics more frequently than males (10.2% vs. 3.5%, p=0.01), but no significant gender differences were seen for age, VAS pain, VAS patglob, MCS, RADAI, or use of sDMARDs, biologics or prednisolone. Adjusted linear regression analyses with sleep disturbance assessed by NRS identified significant associations with gender (B=0.40, 95% CI 0.06, 0.74), HAQ (B=0.40, 95% CI 0.13, 0.67), RADAI (B=0.42, 95% CI 0.27, 0.57) and 10unit increase in VAS pain (B=0.15, 95% CI 0.04, 0.27), VAS fatigue (B=0.18, 95% CI 0.11, 0.25) and MCS (B= -0.51, 95% CI -0.65, -0.38). <h3>Conclusions</h3> Sleep disturbance is to a higher degree reported by females and is independently associated with increased pain, fatigue and worse mental and physical function. Improving sleep quality may reduce RA impact of disease and should be addressed in daily clinical practice when treating patients with RA. <h3>References</h3> Kirwan JR, Newman S, Tugwell PS, Wells GA. Patient Perspective on Outcomes in Rheumatology A Position Paper for OMERACT 9. J Rheumatol 2009;36(9):2067-70. <h3>Disclosure of Interest</h3> None Declared
HEPATICOGASTROSTOMÍA ENDOSCOPICA (HGE) TEMPORAL CON PRÓTESIS METÁLICAS CUBIERTAS (PMC) PARA DRENAJE Y ACCESO TERAPÉUTICO EN PATOLOGÍA BILIAR BENIGNA NO SUSCEPTIBLE DE CPRE
Authors: R Ruiz-Zorrilla, S Del Val, A Vargas, I Peñas Herrero, N Alcaide Suárez, G Flores, J Barrio Andrés, P Díez-Redondo, C De la Serna Higuera, M Pérez-Miranda
Journal: Endoscopy (2012)

Introducción: El acceso por USE a la vía biliar permite el drenaje paliativo en la obstrucción neoplásica tras CPRE fallida. La experiencia preliminar con la HGE como alternativa a la vía percutánea para drenaje biliar en pacientes con derivaciones biliodigestivas y estenosis anastomótica o coledocolitiasis, y en pacientes con transección biliar completa, es ambigua. Objetivo: Evaluar la viabilidad de la HGE mediante PMC transmurales como método de drenaje y puerta de entrada para terapéutica biliar guiada por radiología o colangioscopia transhepática en pacientes con anatomía compleja. Análisis de tendencias evolutivas. Material y método: Revisión 18 pacientes (9 varones; 66.5 [47–91] años) en los que se practicó HGE mediante PMC como ruta de intervención y drenaje biliar intercurrente. Se comparan un periodo inicial (jun 2006- jul 2011) y posterior (8/2011–7/2012) en cuanto a indicación, técnica, complicaciones, intervenciones y éxito terapéutico final. Resultados: Se planteó HGE temporal en 9 pacientes de cada periodo (Tabla), tras excluir 3 del inicial (2 sin diana para punción; 1 sin datos evolutivos) y 1 del posterior (pendiente de intervención a través de la PMC). La proporción litiasis (hepatolitiásis)/estenosis (transección) fue similar en ambos periodos. Solo un caso de cada grupo tuvo una HGE temporal para drenaje sin intervencionismo asociado. La PMC se pudo retirar en todos los 15 casos restantes, pero la carga terapéutica (número de sesiones), la incidencia de complicaciones, y el tiempo de permanencia de la HGE fueron mayores en el periodo inicial. La tasa de éxito terapéutico final (extracción de las litiasis y/o canalización de las estenosis/transección) fue mayor en el periodo posterior. Conclusiones: Estos datos muestran un uso cada vez más frecuente y eficaz de la HGE temporal en pacientes biliares no susceptibles de solución endoscópica convencional. Pueden evitarse así hepatectomías o derivaciones biliares, aunque este nuevo abordaje endoscópico sigue resultando gravoso.
P17.34 * CONCURRENT CHEMORADIOTHERAPY IN GLIOBLASTOMA MULTIFORME: RETROSPECTIVE STUDY
Authors: R. R. Ghali, M. A. Ellithy, A. S. Saad, R. Z. Elia, D. N. K. Boulos
Journal: Neuro-Oncology (2014)

BACKGROUND: Concurrent radiotherapy with Temozolomide (TMZ) is the standard of care in management of Glioblastoma Multiforme (GBM) since it led to survival benefit over radiotherapy alone. On the basis of this evidence, we initiated this study. The aim of this work was to investigate the efficacy and tolerability of radiotherapy plus TMZ in the treatment for newly diagnosed patients with GBM. METHODOLOGY: This is a retrospective descriptive study including newly diagnosed patients with GBM in clinical oncology department at Ain Shams University Hospitals during the period from January 2010 till December 2012. Eligible patients were treated with radiotherapy to a total dose of 60Gy/ 30 fractions/ 6 weeks concurrently with TMZ 75mg/m2 daily during the course of radiation followed by TMZ as adjuvant treatment for up to 6 cycles. RESULTS: During the period from January 2010 till December 2012, 57 GBM patients were enrolled in this retrospective study. The majority of the study group were males and constituted 77.2% (n = 44) while females constituted 22.8% (n = 13). The mean age was 52.2 years +/-10.2 SD and ranged from 28 to 74 years. Regarding performance status (PS) by SWOG classification 4 patients were classified as being PS 0, 49 patients were PS 1 and 4 patients were PS 2. Ten patients (17.5%) showed partial response (PR),24 patients (42.1%) showed stationary disease (SD), while 23 patients (40.4%) showed progressive disease (PD). The median progression free survival time was 8 months (95% CI 6.97-9.02months) and the median overall survival time was 16 months (95% CI 15.08-16.91 months). Regarding grade 3/4 treatment related toxicity during the entire study period (entire study period was defined as from study entry to 7 days after disease progression); there was no grade 3 or 4 hematological related toxicity. Grade 3/4 nausea and vomiting was observed in 5% (n = 3), fatigue in 10.5% (n = 6) and infection in 7% (n = 4) of study group CONCLUSION: Concurrent radiotherapy plus TMZ in the treatment of newly diagnosed GBM is effective and safe. Further larger prospective comparative studies are warranted to document this finding.
Abstract 1109: Identification of a novel MDM2 splice transcript that lacks nuclear transport signals but harbors the p53 binding motif in human glioma cells
Authors: Gamil Antoun, Francis Ali-Osman
Journal: Cancer Research (2010)

Abstract MDM2 a nuclear phosphoprotein binds with E3 ubiquitin ligase activity, binds and targets p53 for proteosomal degradation, hence is a negative regulator of p53. Consequently, over-expression of MDM2 results in the loss of p53 tumor suppressor function even in the absence of inactivating mutations in the p53 gene. To date, more than 40 different alternative spliced MDM2 transcript variants have been reported in both normal and tumor cells, with most of these lacking, in part or in full, the p53 binding domain of MDM2. In this study, we examined the levels of MDM2 gene expression in a panel of glioblastoma (GBM) cell lines and in vivo primary tumor xenografts by quantitative PCR /RT-PCR and examined the full length MDM2 cDNAs for the presence of MDM2 splice transcript variants using the nested PCR technique and a combination of direct sequencing and TA vector sequencing. The results showed a significant heterogeneity in MDM2 expression and in MDM2 splice variants among the tumors. Importantly, we identified a novel splice MDM2 transcript that was consistently associated with low MDM2 transcript levels in the tumors. Sequence analysis of this MDM2 spliced transcript showed it to harbor an internal deletion of three exons, namely 7, 8, and 9, containing the nuclear localization signal (NLS), the nuclear export signal (NES) and a portion of the acidic domain (AD). The p53 binding domain was fully conserved. The deletion caused a shift in the MDM2 open reading frame that created a stop codon (TGA) at codon 316. The spliced MDM2 transcript encoded a truncated MDM2 protein that harbors the functional p53 binding motif capable of interacting with the p53 protein but without the ability to localize to the nucleolus. Overall, our results with the 15 tumors showed no strong correlation between the presence of this novel splice MDM2 transcript and the expression levels of p53in the tumors. Studies are ongoing to determine the functional consequences of this novel MDM2 spliced variant on p53 downstream function in glioma cells. Supported by grants RO1CA112519, RO1CA127872, RO1CA91438, P30CA114236 and P5OCA108786 from the National Institutes of Health (USA). 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 1109.
Abstract 4501: Energetic risk and prostate cancer-specific and all-cause mortality in two large cohorts of men with localized prostate cancer
Authors: Jing Ma, Edward Giovannucci, Paul L. Nguyen, Weiliang Qiu, Jorge Chavarro, Bernard Rosner, Nancy R. Cook, Elizabeth A. Platz, J. Michael Gaziano, Michael Pollak, Meir J. Stampfer
Journal: Cancer Research (2012)

Abstract Objective: To examine whether high energetic risk predisposes men with localized prostate cancer (PC) to higher risk of PC-specific mortality or all-cause mortality. Methods: Among men with localized PC, prediagnostic body mass index (BMI) and plasma C-peptide (a marker of insulin production) were available for 691 men (301 overall deaths, 78 PC deaths) in the Physicians’ Health Study (discovery set) and 1111 men (262 overall deaths, 56 PC deaths) in the Health Professionals Follow-up Study (validation set). High energetic risk was defined as BMI 25-29.9 kg/m2 and C-peptide in the highest quartile or BMIα30 kg/m2. We used the Cox-regression model to estimate risk, adjusting for age, smoking, diabetes, and D'Amico risk defined by stage, Gleason grade and prostate-specific antigen (PSA). Results: Results were similar in both cohorts; the combined hazard ratio (HR)s (95% confidence interval, CI) associated with high energetic risk (25% of study population) were 2.2 (1.5-3.3) for PC-specific mortality and 1.4 (1.1-1.7) for all-cause mortality. The risk of PC-specific mortality according to low- intermediate-, or high-D'Amico risk were 1.0 (reference), 2.6, 6.4 for low energetic risk, and 5.0, 6.1, 9.4 for high energetic risk. The corresponding HRs for all-cause mortality were 1.0 (reference), 1.3, 2.1, 2.1, 2.1, and 2.3. Compared to D'Amico risk alone, incorporating energetic risk significantly improved the predictability of PC-specific mortality (C-statistic from 0.72 to 0.78, P&amp;lt;0.001). Conclusion: Adding energetic risk to D'Amico risk groups significantly improved prediction of PC-specific and all-cause mortality, and identifies 20% D'Amico “low-risk” patients who may be poor candidates for active surveillance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4501. doi:1538-7445.AM2012-4501