tbuckley/cabot-search huggingface dataset:
Abstract 1272: Docosahexaenoic acid supplementation enhances the response of PC-3 prostate cancer cells to enzalutamide
Authors: Irvin V. Ma, Andrew R. Cooper, Ying Hu, Arianne G. Sorreta, Palvinder K. Bains, Prem Kumar, Ronald S. Pardini
Journal: Cancer Research (2018)

Abstract Prostate cancer is currently the second leading cause of death from cancer among men in the United States. Initial treatments generally focus on hormone therapy to inhibit the production of androgens, but most prostate cancers eventually become castration resistant and no longer respond to androgen-suppression therapy. The recent development of drugs that inhibit androgen binding to the androgen receptor (AR) have proven effective in treating castration-resistant prostate cancer (CRPC). Studies in our laboratory have shown that docosahexaenoic acid (DHA; C22:6 n-3), a long chain omega-3 polyunsaturated fatty acid (PUFA), inhibits tumorigenesis in both androgen-dependent (LNCaP) and androgen-independent (PC-3, DU145) prostate cancer cell lines in culture. Moreover, in vivo studies with n-3 PUFA supplementation have been shown to significantly reduce tumor growth of PC-3 and DU145 compared to corn oil diets rich in linoleic acid, (C18:2, n-6). With evidence suggesting that n-3 PUFA dietary supplementation can inhibit tumorigenesis in CRPC, the current study investigated the impact of DHA supplementation in combination with enzalutamide in PC-3 tumor cells. Enzalutamide is a Food and Drug Administration-approved treatment for patients with metastatic CRPC. Enzalutamide acts by interrupting the binding of androgens to the AR, which influences the AR signaling pathway–a target of interest in CRPC treatment. Cell viability was determined by measuring intracellular ATP in PC-3 cells treated with DHA and enzalutamide alone and in combination. Cell viability was reduced with the combination of DHA and enzalutamide compared to enzalutamide or DHA alone, suggesting that DHA enrichment can augment enzalutamide therapy with PC-3 cells in vitro. Studies have also shown that combinatorial treatments with enzalutamide and HIF-1α inhibitors result in synergistic inhibition of CRPC tumor proliferation, and our laboratory has shown that DHA inhibits HIF-1α by decreasing intracellular ATP in breast and lung cancer cells in vitro. These results serve as a prelude to a pilot clinical trial to evaluate the effects of nutritional supplementation with high levels of omega-3 fatty acids on enzalutamide inhibition of CRPC. Citation Format: Irvin V. Ma, Andrew R. Cooper, Ying Hu, Arianne G. Sorreta, Palvinder K. Bains, Prem Kumar, Ronald S. Pardini. Docosahexaenoic acid supplementation enhances the response of PC-3 prostate cancer cells to enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1272.
Abstract 1089: Role of high mobility group A2 (HMGA2) in prostate cancer
Authors: Ohuod A. Hawsawi, Liza Burton, Jodi Dougan, Ana Cecillia Millena, Peri Nagappan, Shafiq Khan, Valerie Odero-Marah
Journal: Cancer Research (2018)

Abstract Prostate cancer is the most highly diagnosed cancer in men and the second leading cause of death in the United States. Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. High mobility group A (HMGA2), a non-histone protein, has been shown to promote EMT in separate studies. Interestingly, wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in many cancers, but have not been investigated in prostate cancer. Jun-D is a transcriptional factor that might be regulated by HMGA2. Moreover, the function for each individual isoform is still not well understood. We hypothesize that each of the two isoforms of HMGA2 in will have different functions in prostate cancer. We stably overexpressed wild-type HMGA2 and truncated HMGA2 in LNCaP cells and measured the expression and the localization of EMT markers. We also measured reactive oxygen species (ROS) levels using DCFDA dye, since ROS has been associated with EMT. We performed migration and cell viability assays as well as Jun-D knockdown, a putative downstream effector of HMGA2. Our results showed that the overexpression of HMGA2 in LNCaP cells led to an increase in cell viability and migration for both wild-type and truncated HMGA2. We observed that wild-type, but not truncated HMGA2 promoted EMT. Additionally, Jun-D and ROS levels increased for truncated, but not significantly for wild-type HMGA2. Jun-D knockdown with siRNA decreased ROS and cell migration in cells with truncated HMGA2, but not in cells overexpressing wild-type HMGA2. Therefore, wild-type HMGA2 is the isoform that induces EMT, while the truncated form appears to have an alternate role in upregulating ROS via Jun-D. In conclusion, we show a link between HMGA2 and JunD/ROS for the first time, and data that wild-type and truncated HMGA2 may have differing functions that converge to increase cell proliferation and migration, and may in future instruct on more precise therapeutic targeting in patients with these isoforms. GRANT SUPPORT: NIH 1P20MD002285 and NIH/NCRR/RCMI G12RR003062-22 Citation Format: Ohuod A. Hawsawi, Liza Burton, Jodi Dougan, Ana Cecillia Millena, Peri Nagappan, Shafiq Khan, Valerie Odero-Marah. Role of high mobility group A2 (HMGA2) in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1089.
Abstract 17158: Intraoperative Electroanatomical Mapping and Histopathological Examination Revealed Mechanism of Monomorphic Ventricular Tachycardia associated with Primary Cardiac Tumor
Authors: Hiroshige Murata, Yasushi Miyauchi, Takashi Nitta, Kenta Takahashi, Ippei Tsuboi, Hiroshi Hayashi, Shunsuke Uetake, Kenji Yodogawa, Yu-ki Iwasaki, Meiso Hayashi, Shun-Ichiro Sakamoto, Shinobu Kunugi, Wataru Shimizu
Journal: Circulation (2014)

Introduction: Ventricular tachycardia (VT) associated with a primary cardiac tumor is extremely rare. Complete resection of a tumor was reported to be effective in a treatment of this VT. However, the mechanism of the cardiac tumor-related VT (CT-VT) is still unknown, and the therapeutic strategy of the VT in patients with unresectable tumor is not determined. Methods and Results: Four patients (20 ± 15 years, 3 males) with CT-VT (fibroma in 2, lipoma in 1, and hemangioma in 1 patient) were investigated. All four patients developed repetitive forms of monomorphic VTs, which were reproducibly induced by programmed ventricular stimulation and terminated by burst pacing. These VTs exhibited a right bundle branch block QRS morphology (QRS duration, 160 ± 28 ms) with a pseudo-delta wave (75 ± 10 ms) at a cycle length of 330 ± 86 ms. Intraoperative electroanatomical mapping showed a radially spreading activation pattern originating from the epicardial border of the tumor, where fractionated and late potentials were detected during sinus rhythm. Histopathological studies of the sections from this border area revealed tumor infiltration to the surrounding myocardium and myocardial cell disorganization exhibiting myocardial disarray. In 2 patients in whom the cardiac tumor was completely resected, cryoablation was added to the resection line. In the remaining 2 patients in whom complete resection of the tumor was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing their VTs. Conclusions: The mechanism of CT-VT is reentry localized at the epicardial border of the tumor. Myocardial disarray associated with infiltration of the cardiac tumor may be a substrate of this VT. Encircling cryoablation along the border of the tumor may be a therapeutic option for an unresectable CT-VT.
THU0626 Correlation among serum amyloid a levels, clinical manifestations, treatment and disease activity in patients with behÇet’s disease
Authors: J. Sota, A. Vitale, O.M. Lucherini, R. Franceschini, B. Frediani, I. Orlando, M. Galeazzi, C. Fabiani, G.M. Tosi, L. Cantarini
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Behçet's disease (BD) is an inflammatory disorder potentially leading to life- and sight-threatening complications: no laboratory marker correlating with disease activity or predicting the occurrence of disease manifestations is currently available in the clinical practice. <h3>Objectives</h3> To search for a correlation between serum amyloid-A (SAA) levels and disease activity evaluated via BD current activity form (BDCAF), to assess disease activity in relationship with different SAA thresholds, to examine the association between single organ involvements and the overall major organ involvement with different SAA thresholds, and to assess the influence of biologic therapy on SAA levels. <h3>Methods</h3> Ninety-five serum samples were collected from 64 BD patients, and their related demographic, clinical and therapeutic data were retrospectively collected. <h3>Results</h3> No correlation was identified between SAA levels and BD disease activity (Spearman <i>rho</i>=0.085; p=0.411), while a significant difference was found in the mean BDCAF score between patients presenting SAA levels&lt;200 mg/L and those with SAA levels&gt;200 mg/L (p=0.027). SAA levels higher than 200 mg/L were significantly associated with major organ involvement (p=0.008). A significant association was found between SAA levels&gt;150 mg/dl and ocular (p=0.008), skin (p=0.002) and mucosal manifestations (p=0.012). Patients undergoing biologic therapies were significantly associated with SAA levels&lt;200 mg/L compared with patients who were not treated with biologics (p=0.012). <h3>Conclusions</h3> SAA level does not represent <i>per se</i> a biomarker of disease activity, but might be useful as a predictor of major organ involvement and ocular disease relapse at certain thresholds in patients with BD. <h3>Disclosure of Interest</h3> None declared
Abstract 9516: Chronic and Continuous Use of Adaptive Servo-Ventilation Improves and Keeps Cardiac Function in Patient With Heart Failure With Central Sleep Apnea
Authors: TatsunoriIkeda, ManabuFujimoto, KazuyasuOkeie, MasakazuYamamoto, HisayoshiMurai, SoichirouUsui, MasayukiTakamura, ShuichiKaneko
Journal: Circulation (2014)

Central sleep apnea (CSA) is closely associated with poor prognosis in heart failure (HF) patient. Adaptive servo-ventilation (ASV) is a new treatment for HF with CSA patient. However, there is little evidence in chronic use. We examined 70 HF with CSA patients treated with ASV seen between May 2008 and November 2012 in our hospital, retrospectively, who had not been admitted to the hospital due to worsening HF in the 6 months before initiating ASV therapy. We divided it into 2 groups: (A) non-continues-ASV-treated patients; (B) continues-ASV-treated patients. 18 patients (group A) used ASV only in the hospital and could not continue because of its discomfort. 52 patients (group B) could continue to night time use the ASV device after leaving the hospital. The median follow up time was 364 days after leaving hospital. There were almost no significant differences in the baseline characteristics between two groups. In group B, during 6, 12, 24 months observation, left ventricular ejection fraction (45.5 +/-...
Abstract 5059: Comprehensive molecular profiling of HPV-induced transformation over time
Authors: Iris Babion, Viktorian Miok, Annelieke Jaspers, Wessel N. van Wieringen, Renske D. Steenbergen, Saskia M. Wilting
Journal: Cancer Research (2018)

Abstract Although persistent infection with high-risk human papillomavirus (HPV) is generally acknowledged as necessary cause for cervical cancer, additional molecular changes are required for the development of cancer. Those changes include chromosomal aberrations that result in deregulated expression of coding and non-coding RNAs. In this study we performed a comprehensive and longitudinal molecular characterization of HPV-transformed keratinocyte cell lines, to identify the sequential order and relevance of these molecular alterations for HPV-induced transformation. Genome-wide chromosomal, mRNA and miRNA expression profiles were generated from 4 HPV-transformed keratinocyte cell lines at 8 different passages representing progressive stages of transformation. Unsupervised hierarchical clustering of DNA copy number, mRNA and miRNA profiles revealed that in all 4 cell lines most pronounced changes were associated with the acquisition of anchorage independence, a hallmark of transformation. Approximately one third of differentially expressed mRNAs and miRNAs was directly attributable to DNA copy number alterations. Focal adhesion, TGF-β signalling and mTOR signalling pathways were enriched among these genes. In addition, longitudinal analysis identified more than 600 potential miRNA-mRNA interactions that were negatively correlated during passaging. Four interactions were also predicted by 3 independent prediction algorithms, and have in part already been functionally validated, thereby demonstrating the validity of our approach. In conclusion, integrated longitudinal analysis of our HPV-induced transformation model enabled us to pinpoint relevant interconnected molecular changes and affected signalling pathways. Increased understanding of the interplay between different molecular alterations and affected pathways will be of importance for the clinical management of patients diagnosed with HPV-induced (pre)cancerous lesions. Citation Format: Iris Babion, Viktorian Miok, Annelieke Jaspers, Wessel N. van Wieringen, Renske D. Steenbergen, Saskia M. Wilting. Comprehensive molecular profiling of HPV-induced transformation over time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5059.
Colocalization of CPP-32 With Apoptotic Cells in Human Atherosclerotic Plaques
Authors: ZiadMallat, JeannyOhan, GuyLesèche, AlainTedgui
Journal: Circulation (1997)

Background Apoptosis that has been reported in human atherosclerosis may contribute to the remodeling of atherosclerotic plaques. The identification of specific markers for apoptosis in these plaques would permit the development of specific therapeutic strategies to limit their progression. Cysteine protease CPP-32 is essential for apoptotic death in mammalian cells and appears to be an attractive candidate. Methods and Results We studied 12 atherosclerotic plaques from 12 patients who underwent carotid endarterectomy. Apoptosis was analyzed by in situ end labeling of fragmented DNA (TUNEL method) and corroborated by the presence of DNA fragmentation in agarose gel electrophoresis. CPP-32 was detected with the use of a specific monoclonal antibody, and its expression was compared with that of interleukin-1β–converting enzyme (ICE). We showed that CPP-32 was highly expressed in 10 of 12 atherosclerotic plaques and that it colocalized with apoptotic cells. Expression of ICE generally paralleled that of CPP-...
Abstract 13441: The QTc Interval Does Not Predict Mortality at the Emergency Department
Authors: Bert Vandenberk, Caroline Siau, Eline Vandael, Veerle Foulon, Sandra Verelst, Rik Willems
Journal: Circulation (2016)

Introduction: The Bazett corrected QT interval (QTcB) has been shown a predictor of outcome at the Emergency Department (ED). Since the known limitations of QTcB at higher heart rates, we investigated the use of a recently proposed QRS width dependent QTc algorithm (QTcA) at the ED. Methods: We performed a retrospective age- and sex-matched cohort study, powered to detect mortality differences between normal and prolonged (&gt; 450/470 ms in men and women respectively) QTcB at the ED. QTcA, Fridericia formula is used when QRS&lt;120ms and Rautaharju when ≥120ms, was compared with QTcB. Cox regression modeling for in-hospital mortality was performed. Results: In total 1930 patients, age 72 ± 16 y, 63% male and mean triage code 2.5 ± 0.6, were included. The mean heart rate was 81 ± 22 bpm. 18% patients had a QRS duration ≥120ms and 81% had sinus rhythm. In-hospital mortality was 4.4% and 1 y mortality was 19.5%. Using QTcB, 50% of patients had prolonged QTc, whereas only 17.4% using QTcA. In-hospital mortality in the prolonged QTcB group was significantly higher (6.0%) compared to the control group (2.8%, p&lt;0.001), whereas with QTcA mortality rates were similar (5.4% vs 4.2% respectively, p=0.349). Also, 1 y mortality was significantly higher in patients with prolonged QTcB (22.6% vs 16.4%, p=0.001), while prolonged QTcA showed only a trend to worse survival (22.9% vs 18.8%, p=0.080). In univariate Cox regression for in-hospital mortality, QTcB was a predictor of mortality (HR 1.004, 95%CI 1.000 - 1.009), while QTcA was not (HR 1.001, 95%CI 0.995 - 1.008). After multivariate analysis QTcB did not remain as independent predictor of mortality. Independent predictors were heart rate (HR 1.02, 95%CI 1.01-1.03), history of cardiovascular disease (HR 1.66, 95%CI 1.00-2.76), witnessed arrhythmia requiring CPR (HR 3.79, 95%CI 1.66-8.67), neurological events (CVA, epileptic insult, IC bleeding or hematoma) (HR 3.51, 95%CI 1.91-6.43), age-adjusted Charlson Comorbodity Index (HR 1.18, 95%CI 1.10-1.27), lower eGFR (HR 0.99, 95%CI 0.98-1.00) and higher leukocyte count (HR 1.02, 95%CI 1.01-1.03). Conclusion: Several easily obtainable parameters and risk factors can be useful for risk stratification at the ED, however adequate corrected QT was not an independent predictor of mortality.
Reduced Myocardial Sarcoplasmic Reticulum Ca2+-ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy
Authors: FujiSomura, HideoIzawa, MitsunoriIwase, YasushiTakeichi, RyojiIshiki, TakaoNishizawa, AkikoNoda, KohzoNagata, YoshijiYamada, MitsuhiroYokota
Journal: Circulation (2001)

Background— The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca2+-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results— We calculated the maximum first derivative of LV pressure (LV dP/dtmax) and the LV pressure half-time (T1/2) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction >55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na+/Ca2+ exchanger were quantified by use of a real-time quantitative reverse transcription—polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dtmax with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate—LV dP/dtmax relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertr...
Abstract 3131: Acute myeloid leukemia derived SDF1 repels tumor infiltrating lymphocytes in the bone marrow microenvironment
Authors: Manar S. Shafat, Amina A. Abdul-Aziz, Christopher Marlien, Rachel Piddock, Kristian M. Bowles, Stuart A. Rushworth
Journal: Cancer Research (2018)

Abstract Introduction: Acute myeloid leukaemia (AML) is an age-related disease with a median age at diagnosis of 71. Combined with co-morbidities, survival of patients with AML above this age bracket is poor with 90% of older adults dying of their disease. Even in younger patients who achieve remission with chemotherapy, relapse is common and occurs from minimal residual disease sequestered in protective niches in the bone marrow microenvironment (BMM). AML as a disease is highly dependent on the bone marrow microenvironment and accordingly it is envisaged that improved outcomes will come from novel treatment strategies derived from an improved understanding of the biology of AML within the bone marrow and their interaction with the immune cells therein. Objective: Here, we investigate a possible immune evasive mechanism imparted by AML blasts attributed to their localization within the BMM. Methods and Results: Using RNA-seq data generated from bone marrow derived AML (BM-AML) compared to peripheral blood derived AML (PB-AML) (GEO ID: GSE49642, GSE48846) we identified SDF-1 as the most differentially expressed in favour of BM-AML. Further investigation using matched primary clinical samples (BM verses PB) by real-time PCR analysis and ELISA confirmed the in-silico findings. In addition, primary AML engrafted into NSG mice demonstrated high SDF-1 in the BM derived AML blasts compared to AML blasts derived from the spleen. Lentiviral knock-down of SDF-1 in the AML blasts impaired blast engraftment and prolonged survival of the animals. SDF1-mediated migration of T-cell subsets have been previously identified using varying concentrations of SDF1. We therefore, investigated the migration of CD8+ T cells when co-cultured with AML. We show that CD8+ T-cells migrate away from AML when in culture and this fugetaxis is reduced by the knock-down of SDF1 in the blasts. Conclusion: We conclude that SDF-1 is secreted by the AML blasts within the BMM contributing to fugetaxis of CD8+ cells away from the blasts. Implications of these finding suggest a possible immune evasive mechanism by the blasts that can be manipulated to potentiate CD8+ infiltration into the AML bone marrow. Citation Format: Manar S. Shafat, Amina A. Abdul-Aziz, Christopher Marlien, Rachel Piddock, Kristian M. Bowles, Stuart A. Rushworth. Acute myeloid leukemia derived SDF1 repels tumor infiltrating lymphocytes in the bone marrow microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3131.