tbuckley/cabot-search huggingface dataset:
Abstract 141: HEY1-mediated inhibition of glioma stem cell proliferation is associated with restoration of glioma stem cell division asymmetry and transcriptional repression of PDGFRA
Authors: Damian A. Almiron Bonnin, Jaclyn Sullivan, Mark A. Israel, Matthew Havrda C. Havrda
Journal: Cancer Research (2018)

Abstract Emerging evidence suggests that deregulation of cell-fate regulatory mechanisms in subpopulations of stem-like tumor cells can contribute to the initiation, progression, and recurrence of glioma. In this study, we report that Hey1 expression suppresses the expansion of oligodendroglial progenitor (OPC)-like glioma stem cells, which are a putative cell of origin for high-grade gliomas. We found that Hey1 expression reduced the proliferation of primary neural progenitor cells isolated from mice without the tumor suppressor Tp53, and OPC-like glioma stem cell cultures isolated from a mouse model of glioma driven by an EGFR gain-of-function mutation and Tp53 loss (v-ErbB/p53-/-). Further analysis of these cultures revealed that Hey1-mediated reductions in proliferation were associated with suppression of self-renewal and a reduced percentage of symmetric cell divisions. Mechanistically, we found that HEY1 directly bound to novel promoter elements and repressed the mRNA expression of a key marker and mitogenic driver of OPCs, the PDGF Receptor A (Pdgfra). Furthermore, Hey1-mediated of Pdgfra expression was associated with inactivation of the canonical PDGF/PDGFRA downstream target, extracellular signal-regulated kinases (ERK), in v-ErbB/p53-/- glioma stem-like cells. Key findings made in the murine system were validated in patient-derived glioma stem-like cells. Moreover, analyzing publicly available databases, we found that the subset of glioma patients with high levels of HEY1 expression had improved survival compared to patients with tumors expressing low levels of HEY1. Further supporting a role for HEY1 in the regulation of the oligodendroglial lineage, ontologic analysis revealed that the subset of patients with high levels of HEY1 expression were also characterized by the expression of gene sets associated with oligodendroglial differentiation. These cellular, molecular and genetic findings provide support for a model in which HEY1 functions to suppress glioma progression by inhibiting the expansion of glioma stem cells. Citation Format: Damian A. Almiron Bonnin, Jaclyn Sullivan, Mark A. Israel, Matthew Havrda C. Havrda. HEY1-mediated inhibition of glioma stem cell proliferation is associated with restoration of glioma stem cell division asymmetry and transcriptional repression of PDGFRA [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 141.
Low Referral Rate for Genetic Testing in Racially and Ethnically Diverse Patients Despite Universal Colorectal Cancer Screening
Authors: Charles Muller, Sang Mee Lee, William Barge, Shazia M. Siddique, Shivali Berera, Gina Wideroff, Rashmi Tondon, Jeremy Chang, Meaghan Peterson, Jessica Stoll, Bryson W. Katona, Daniel A. Sussman, Joshua Melson, Sonia S. Kupfer
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 891: A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia
Authors: Alexander Richard, Hamdy M. Abdel-Rahman, Jung Hyun Kim, Lana Vukadin, Gary A. Piazza, Eun-Young E. Ahn
Journal: Cancer Research (2018)

Abstract Cyclic adenosine monophosphate (cAMP) is a secondary messenger that regulates cell proliferation, differentiation, and apoptosis. Phosphodiesterases (PDEs) are enzymes that catabolize cyclic nucleotides to relay cellular signals. Among them, PDE4 is a cAMP-specific PDE isozyme family and several PDE4 inhibitors have been developed to treat a diverse group of diseases, such as asthma and chronic obstructive pulmonary disease. Although PDE4 inhibitors have been demonstrated to induce cell death in solid tumors, their therapeutic potential in treatment of hematopoietic malignancies has not been well studied. Our analysis on the expression pattern of PDE family demonstrated that PDE4B is abundantly expressed in blood cancers compared to other solid tumors, implicating PDE4 as a potential therapeutic target for leukemia. N-acylhydrazone and nitraquazone are potent PDE inhibitors that are structurally unrelated to rolipram, a prototypical PDE4 inhibitor. To develop novel PDE4 inhibitors with increased scaffold rigidity, we hybridized N-acylhydrazone with Nitraquazone, and designed a series of quinazolin-4(3H)-one/schiff base hybrid compounds. Among those, compound 23 (CPD23) showed the best activity in PDE4B inhibition, and was selected for further studies. Our results showed that CPD23 treatment leads to growth inhibition and cell cycle arrest of several human leukemia cell lines. Since cAMP is a well-studied secondary messenger for megakaryopoesis and apoptosis, we continued to elucidate CPD23's mechanism of action in several megakaryoblastic leukemia cell lines. While other well-known PDE4 inhibitors, such as rolipram, did not show any effect in cell viability, CPD23 significantly decreases the viability of megakaryoblastic cell lines. Further studies on molecular actions revealed that CPD23 caused double-stranded DNA breaks, which was detected by increased ϒH2AX levels. Quantitative RT-PCR experiments also demonstrated that CPD23 induces transcriptional activation of megakaryocytic differentiation markers, such as CD61, in selective cell lines. Taken together, our study shows that CPD23, synthesized as a quinazolin-4(3H)-one/schiff base hybrid PDE4 inhibitor, decreases proliferation, induces double-stranded DNA breaks, and differentiation in megakaryoblastic leukemia cell lines. Further studies will enhance our knowledge on detailed molecular actions of CPD23 and its therapeutic value for leukemia. Citation Format: Alexander Richard, Hamdy M. Abdel-Rahman, Jung Hyun Kim, Lana Vukadin, Gary A. Piazza, Eun-Young E. Ahn. A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia [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 891.
Abstract 12320: Inhibition of DNA Methylation and Histone Acetylation Changes the Macrophage Polarization During Endotoxemia-induced Lung Injury
Authors: Saheli Samanta, Sheeja Rajasingh, Urmi Patel, Buddhadeb Dawn, Johnson Rajasingh
Journal: Circulation (2015)

Introduction: Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. The exact molecular mechanism for ALI is poorly understood. Although chemical epigenetic modifiers can potentially limit lung inflammation, to date no study has examined the efficacy of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor Trichostatin A (TSA) combination therapy (Aza+TSA) on the polarization of macrophages. Hypothesis: We hypothesized that therapy with Aza+TSA would reduce inflammation in ALI and will stimulate the production of M2 macrophages. Methods and Results: In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung inflammation and histopathological changes. Flow cytometry data showed a significant decrease in expression of CD14 and CD40, and increased expression of CD23 and CD124 in Aza+TSA-treated cells compared with untreated LPS-induced primary bone marrow derived macrophages (BMDMs) or LPS-induced BMDMs treated with either drug alone (Fig panel A). This was further confirmed by Western analysis for M1 marker NOS2 and M2 marker CD206. Our data showed lesser expression of NOS2 (Fig panel B) and higher expression of CD206 (Fig panel C) in LPS-challenged BMDMs treated with Aza+TSA than in the BMDMs treated with either Aza or TSA alone. These data support that Aza+TSA treatment promotes an M2 phenotype in LPS-stimulated macrophages, which secrete anti-inflammatory cytokines. Conclusions: This novel treatment with combined epigenetic modifiers has therapeutic potential for patients with sepsis-induced ALI by reducing inflammation and generation of alternatively activated M2 macrophages with more abilities of pathogen clearance.
Endothelial Dysfunction and Subsequent Decline in Glomerular Filtration Rate in Hypertensive Patients
Authors: FrancescoPerticone, RaffaeleMaio, MariaPerticone, AngelaSciacqua, ErmalShehaj, PaolaNaccarato, GiorgioSesti
Journal: Circulation (2010)

Background— Chronic kidney disease is a risk factor for cardiovascular disease, increasing all-cause mortality. Some evidence suggests that endothelial dysfunction is present in the early stages of renal insufficiency, but no data exist about its possible role in the progression of renal disease. Thus, we prospectively evaluated the effect of endothelial function on estimated glomerular filtration rate (eGFR) in essential hypertension. Methods and Results— We enrolled 500 never-treated uncomplicated hypertensive subjects with serum creatinine ≤1.5 mg/dL. Endothelial function was measured by strain-gauge plethysmography during intra-arterial infusion of acetylcholine and sodium nitroprusside. eGFR was calculated by use of the Chronic Kidney Disease Epidemiology Collaboration equation. The annual rate of decline of eGFR (ΔeGFR/y) was determined as the difference between the follow-up and baseline eGFR values, with this value divided by the time interval in years. During follow-up (92.3±36.2 months), mean Δe...
Effect of Pacing Chamber and Atrioventricular Delay on Acute Systolic Function of Paced Patients With Congestive Heart Failure
Authors: AngeloAuricchio, ChristophStellbrink, MichaelBlock, StefanSack, JürgenVogt, PatriciaBakker, HelmutKlein, AndrewKramer, JiangDing, RodneySalo, BruceTockman, ThierryPochet, JulioSpinelli
Journal: Circulation (1999)

Background—Previous studies of pacing therapy for dilated congestive heart failure (CHF) have not established the relative importance of pacing site, AV delay, and patient heterogeneity on outcome. These variables were compared by a novel technique that evaluated immediate changes in hemodynamic function during brief periods of atrial-synchronous ventricular pacing. Methods and Results—Twenty-seven CHF patients with severe left ventricular (LV) systolic dysfunction and LV conduction disorder were implanted with endocardial pacing leads in the right atrium and right ventricle (RV) and an epicardial lead on the LV and instrumented with micromanometer catheters in the LV, aorta, and RV. Patients in normal sinus rhythm were stimulated in the RV, LV, or both ventricles simultaneously (BV) at preselected AV delays in a repeating 5-paced/15-nonpaced beat sequence. Maximum LV pressure derivative (LV+dP/dt) and aortic pulse pressure (PP) changed immediately at pacing onset, increasing at a patient-specific optimal...
Abstract 2420: Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress
Authors: Lei Jin, Jiayu Wang, Guangzhi Liu, James S. Wilmott, Xu Guang Yan, Rick F. Thorne, Richard A. Scolyer, Xu Dong Zhang
Journal: Cancer Research (2018)

Abstract MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Citation Format: Lei Jin, Jiayu Wang, Guangzhi Liu, James S. Wilmott, Xu Guang Yan, Rick F. Thorne, Richard A. Scolyer, Xu Dong Zhang. Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress [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 2420.
Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria
Authors: TakeshiYamashita, AkikoSekiguchi, Yu-kiIwasaki, KouichiSagara, SeijiHatano, HiroyukiIinuma, TadanoriAizawa, Long-TaiFu
Journal: Circulation (2003)

Background— Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF. Methods and Results— The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analys...
Stenting of the Arterial Duct and Banding of the Pulmonary Arteries
Authors: HakanAkintuerk, InaMichel-Behnke, KlausValeske, MatthiasMueller, JosefThul, JuergenBauer, Karl-JuergenHagel, JoachimKreuder, PaulVogt, DietmarSchranz
Journal: Circulation (2002)

Background— Outcome of patients with hypoplastic left heart (HLH) is mainly influenced by the successful first-step palliation according to the Norwood procedure. An alternative approach is heart transplantation (HTX). The feasibility of ductal stenting in newborns with duct-dependent systemic blood flow and bilateral pulmonary artery banding has been reported. But it remains to be elucidated whether this approach allows a new strategy for patients with HLH. Methods and Results— In patients with various forms of HLH (n=11) and prostaglandin E-1 administration, ductal stenting was performed with balloon expandable Jo stents or Saxx stents. Bilateral pulmonary artery banding was surgically accomplished 1 to 3 days after the transcatheter procedure. Unrestricted blood flow through the interatrial septum was secured by balloon dilatation atrial septotomy, as required. Interventional procedures were performed with no mortality. Stent and ductal patency were achieved for up to 331 days. Two patients underwent H...
Clinical implications of muscle mass and quality in early-stage colorectal cancer (CRC).
Authors: Jessica Hopkins, Vickie E Baracos, David Bigam, Dean Eurich, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2018)

648 Background: Body composition has emerged as a potential prognostic factor for outcomes in early-stage CRC. Specifically, muscle mass and quality and visceral fat have been shown to be related to overall survival (OS) and disease-free survival (DFS). The objective of this study was to determine associations of sarcopenia, reduced skeletal muscle radiodensity (SMR) and visceral obesity (VO) with 5-year OS and DFS. Methods: Muscle and visceral fat at the time of diagnosis were quantified in a retrospective cohort of consecutive, early-stage CRC patients (pts), identified from a prospectively collected cancer database. Skeletal muscle area on computed tomography (CT) was measured and normalized by height (m 2 ) in order to compare skeletal muscle index (SMI) between pts. Mean SMR and visceral fat area were measured. All parameters were analyzed using Kaplan-Meier curves and univariate Cox regression. Sarcopenia was defined as SMI &lt; 41 cm 2 /m 2 in females and &lt; 43 cm 2 /m 2 in males with BMI &lt; 25 kg/m 2 and &lt; 53 cm 2 /m 2 with BMI &gt; 25 kg/m 2 . Reduced SMR was defined as &lt; 41 HU if BMI &lt; 25 kg/m 2 and &lt; 33 HU if BMI &gt; 25 kg/m 2 . VO was defined as VAT &gt; 160cm 2 in males and &gt; 80cm 2 in females. Results: We identified 968 pts with available CTs and anthropometric data. Prevalence of sarcopenia was 44.5% in males and 59.6% in females. Myosteatosis was present in 60.9% of pts. The mean length of follow up was 5.0 years, with 254 patients developing recurrent disease and 351 deaths. Males with sarcopenia and myosteatosis had worse overall survival (HR, 0.69, p = 0.005; HR 0.49, p &lt; 0.001) but no difference in DFS. Presence of VO was not associated with worse OS or DFS. There was no difference in OS for females with sarcopenia or VO, but myosteatosis predicted reduced OS (HR 0.53, p = 0.004). There was no difference in DFS for females by presence of sarcopenia, myosteatosis or VO. Conclusions: Body composition, specifically sarcopenia and myosteatosis, are highly prevalent in CRC pts treated with curative intent, and their presence is associated with reduced OS. Therefore, skeletal muscle mass and radiodensity are important prognostic factors in CRC outcomes, which are easily attained in a clinical setting.
Abstract 1170A: Organoids: A new tool for the prediction of breast cancer patients' outcome
Authors: Giuseppina Roscigno, Assunta Cirella, Alessandra Affinito, Francesco Palma, Maurizio Albero, Martina Messere, Martina Gelormini, Lorenza Cocca, Renato Thomas, Gerolama Condorelli
Journal: Cancer Research (2018)

Abstract Breast cancer is one of the leading causes of cancer mortality among women. The main causes of death are related to recurrence and metastasis. One major limitation in the breast cancer research field is that there are few in vitro models of breast cancer able to predict clinical patients' outcome. The main reason of this failure is that the present models do not take complexity or heterogeneity into account. Therefore, innovative models are now required to better represent tumor fidelity. To address this issue, we developed an in vitro 3D organoid culture system using primary human breast cancer tissue. Organoids are miniature forms of tissues that exhibit three-dimensional architecture and are able to maintain phenotypical properties cultured in a dish. Therefore, they could be used as models for diseases, including cancer. A major difficulty in the development of such models is to identify in vitro conditions that preserve the breast cancer phenotypes observed in vivo. For this reason, we isolated organoids from breast cancer patients and optimized the organoids growing conditions. We used a specialised medium and matrix (Cultrex Trevigen) required for supporting cell growth as it occurs in the human body. Then, we decided to test whether the obtained organoids could be used as an in vitro prediction tool. First, we performed immunofluorescence assay to assess the preservation of patient architecture (CK14, CK18 and E cadherin) and clinical phenotype (HER2, ER, PR). Then, we used an innovative chemotaxis assay in 3D collagen gels for analysing organoids cell invasion. It is based on a chamber in which a chemoattractant gradient is generated by diffusion through a porous membrane for mimicking blood microenvironment. Then we analysed the morphological changes after chemotherapeutics treatment to correlate the organoids response with patient tumor behaviour. Thus, organoids can be considered as a new tool for studying breast cancer and developing personalized medicine approaches for this disease. Citation Format: Giuseppina Roscigno, Assunta Cirella, Alessandra Affinito, Francesco Palma, Maurizio Albero, Martina Messere, Martina Gelormini, Lorenza Cocca, Renato Thomas, Gerolama Condorelli. Organoids: A new tool for the prediction of breast cancer patients' outcome [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 1170A.
Addressing Barriers to Inclusion of Pregnant Women in Clinical Trials
Authors: Rita Rubin
Journal: JAMA (2018)

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Cardiac Autonomic Dysfunction in Brugada Syndrome
Authors: ThomasWichter, PeterMatheja, LarsEckardt, PeterKies, KlausSchäfers, EricSchulze-Bahr, WilhelmHaverkamp, MartinBorggrefe, OtmarSchober, GünterBreithardt, MichaelSchäfers
Journal: Circulation (2002)

Background— Patients with Brugada syndrome present with characteristic ECG abnormalities (atypical right bundle-branch block and ST-segment elevation) and life-threatening ventricular tachyarrhythmias despite structurally normal hearts. Involvement of the autonomic nervous system is suggested by the occurrence of ventricular tachyarrhythmias and sudden death at rest or during sleep and by changes of typical ECG signs under pharmacological modulation of the myocardial autonomic tone. Methods and Results— This study investigated the presynaptic cardiac neuronal reuptake of norepinephrine (uptake 1) in 17 patients with Brugada syndrome and 10 age-matched control subjects with the use of the norepinephrine analogue [123I]m-iodobenzylguanidine (123I-MIBG), single-photon emission CT (SPECT), and quantitative 33-segment bull’s-eye analysis. Regionally reduced 123I-MIBG uptake was present in 8 (47%) of 17 patients with Brugada syndrome but in none of the control subjects. Quantitative analysis showed segmental re...