tbuckley/cabot-search huggingface dataset:
Abstract LB-089: Targeting WNT signaling <i>in vivo</i>via Tankyrase inhibition
Authors: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Sukanya Goswami, Lukas E. Dow
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 95% of CRCs show hyperactive WNT signaling, yet there are no targeted therapies that effectively suppress the WNT pathway. The majority (~80%) of these tumors harbor a mutation in APC, a scaffold component of the ‘destruction complex', which is a critical negative regulator of WNT. Using genetically defined mouse models of CRC, we recently showed that restoring Apc function can induce WNT suppression, and rapid and sustained disease regression. While there is no way to restore normal APC protein in human CRCs, it may be possible to restore the function of the APC-associated destruction complex by inhibiting Tankyrase (TNKS) enzymes. Tankyrase inhibitors have been shown to stabilize AXIN, prevent degradation of the destruction complex, and decrease levels of WNT signaling. While in vitro studies have shown promise, it is unclear whether TNKS inhibition could provide a therapeutic benefit in vivo. Some published work reports significant anti-tumor activity, while others suggest overt dose-limiting toxicity. Thus, while TNKS inhibition holds significant potential, it is not clear whether TNKS enzymes are a viable target for CRC therapy. To circumvent the limitations of drug delivery, potency, and specificity, we generated mice with inducible, fluorescent reporter-linked shRNAs targeting Tnks and its redundant family member Tnks2. Here we show that potent, simultaneous shRNA-mediated knockdown of both genes is sufficient to stabilize Axin in vivo, similar to treatment with a pan-TNKS inhibitor, XAV939. We show that Tnks1/2 knockdown stabilizes Axin, suppresses WNT signaling, and blocks hyperproliferation driven by Apc loss. In contrast to current studies using small molecule TNKS inhibitors, our work suggests that there is a viable therapeutic window of TNKS1/2 inhibition in vivo, and that this strategy enables control of hyperactive WNT signaling in CRC and other WNT-associated cancers. Citation Format: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Sukanya Goswami, Lukas E. Dow. Targeting WNT signaling in vivovia Tankyrase inhibition [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 LB-089.
The Medial Wall of the Right Atrium
Authors: Robertwalmsley, Hamishwatson
Journal: Circulation (1966)

The correct orientation of the heart in situ has been stressed and the anatomic relationships of the medial wall of the right atrium have been described and illustrated. Each atrium lies behind and to the right of its corresponding ventricle and, as the plane of the septa is angled at approximately 45° to the median plane, the right atrium lies as much in front of the left atrium as alongside it. The area of overlap between the atria is small in both the anteroposterior and lateral views and the interatrial septum, which constitutes only the posterior half of the medial wall of the right atrium, is most accessible in the right anterior oblique projection. The anterior half of the medial wall of the right atrium is closely related from above downward to the first part of the aorta including the aortic valve, and to the left ventricular outflow tract through the membranous part of the interventricular septum. The right coronary artery and the right ventricular outflow tract are also important anterior relat...
Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial
Authors: Roser Pinyol, Robert Montal, Laia Bassaganyas, Daniela Sia, Tadatoshi Takayama, Gar-Yang Chau, Vincenzo Mazzaferro, Sasan Roayaie, Han Chu Lee, Norihiro Kokudo, Zhongyang Zhang, Sara Torrecilla, Agrin Moeini, Leonardo Rodriguez-Carunchio, Edward Gane, Chris Verslype, Adina Emilia Croitoru, Umberto Cillo, Manuel de la Mata, Luigi Lupo, Simone Strasser, Joong-Won Park, Jordi Camps, Manel Solé, Swan N Thung, Augusto Villanueva, Carol Pena, Gerold Meinhardt, Jordi Bruix, Josep M Llovet
Journal: Gut (2018)

Objective Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. Design Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. Results BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4 + T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. Conclusion In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. Trial registration number NCT00692770 .
Regulation of Cell Survival and Death by Pyridine Nucleotides
Authors: Shin-ichiOka, Chiao-PoHsu, JunichiSadoshima
Journal: Circulation Research (2012)

Pyridine nucleotides (PNs), such as NAD(H) and NADP(H), mediate electron transfer in many catabolic and anabolic processes. In general, NAD+ and NADP+ receive electrons to become NADH and NADPH by coupling with catabolic processes. These electrons are utilized for biologically essential reactions such as ATP production, anabolism and cellular oxidation-reduction (redox) regulation. Thus, in addition to ATP, NADH and NADPH could be defined as high-energy intermediates and “molecular units of currency” in energy transfer. We discuss the significance of PNs as energy/electron transporters and signal transducers, in regulating cell death and/or survival processes. In the first part of this review, we describe the role of NADH and NADPH as electron donors for NADPH oxidases (Noxs), glutathione (GSH), and thioredoxin (Trx) systems in cellular redox regulation. Noxs produce superoxide/hydrogen peroxide yielding oxidative environment, whereas GSH and Trx systems protect against oxidative stress. We then describe ...
Exercise Training Improves Left Ventricular Diastolic Filling in Patients With Dilated Cardiomyopathy
Authors: RomualdoBelardinelli, DemetriosGeorgiou, GiovanniCianci, NancyBerman, LeonardGinzton, AugustoPurcaro
Journal: Circulation (1995)

Background Patients with dilated cardiomyopathy (DCM) often have left ventricular (LV) diastolic dysfunction that can precede the development of systolic dysfunction. Recent reports showed that exercise training (ET) improves the exercise capacity of these patients. Although this improvement is primarily due to peripheral adaptations, the contribution of LV diastolic filling has not been well defined. The purpose of this study was to determine whether ET can induce changes in LV diastolic filling that can account for an increase in exercise capacity and whether these changes can influence prognosis. Methods and Results We prospectively studied 55 consecutive patients (mean age, 55±7 years) with DCM. Patients were randomized into a training group (36 patients) or a control untrained group (19 patients) and matched for clinical and functional characteristics. All patients underwent a pulsed Doppler echocardiographic study, a radionuclide angiographic study, and a cardiopulmonary exercise test before and aft...
Abstract 15209: Endotoxemia as Mechanism for Platelet Aggregation in Patients With Pneumonia
Authors: CristinaNocella, RobertoCarnevale, SimonaBartimoccia, DanielePastori, PasqualePignatelli, FranecescoVioli
Journal: Circulation (2015)

Introduction: Patients with community-acquired pneumonia (CAP) are at increased risk of cardiovascular events; platelet activation has been suggested to play a role but the underlying mechanism is still unclear. Hypothesis: Our study hypothesis was that endotoxins (bacterial lipopolysaccharide, LPS) might play a role. Methods: Patients (n=100) with diagnosis of community-acquired pneumonia (CAP) through the emergency department (ED) and healty subjects (n=50) were consecutively recruited. Categorical variables were reported as counts (percentage) and continuous variables as means ± standard deviation (SD). The study was comprised 3 parts: 1) analysis of serum endotoxins in CAP patients versus controls; 2) ex vivo platelets aggregation in CAP patients and controls; 3) in vitro experiments to assess if LPS, in a range of concentrations detected in the blood of CAP patients, was capable of activating platelets. Results: CAP patients showed higher serum LPS and ex vivo platelet aggregation (PA) compared to co...
Abstract 19210: Remote Ischemic Conditioning, Applied During Recurrent Coronary Thrombosis Mimicking Unstable Angina, Improves Coronary Patency
Authors: KarinPrzyklenk, PeterWhittaker
Journal: Circulation (2014)

Evidence from our group revealed that the benefits of preconditioning ischemia extend beyond infarct size reduction via up-regulation of cardioprotective signaling. We found that brief antecedent ischemia: i) attenuates molecular indices of platelet activation-aggregation (i.e., P-selectin expression, fibrinogen binding); and thus ii) improves arterial patency in models mimicking unstable angina. However, two issues limit potential translation of this endogenous anti-platelet effect: the conditioning stimulus was applied directly to the heart, as a pretreatment. Our current aim was to establish whether brief ischemia applied at a remote site (skeletal muscle), after the onset of recurrent coronary thrombosis, would improve subsequent coronary patency. Methods: Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h after injury + stenosis, dogs received: i) remote ischemic conditioning (RIC: 4 5-min episodes of bila...
FDA analysis of patients with baseline autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents.
Authors: Chana Weinstock, Harpreet Singh, Virginia Ellen Maher, Geoffrey Kim, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

3018 Background: With FDA approval of three novel agents targeting the PD-L1/PD-1 checkpoint pathway in multiple tumor types, use of these agents in the clinical setting is becoming increasingly common. However, little is published on their use in patients with a history of autoimmune diseases. We therefore aimed to collect safety data on patients with a history of autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents in a clinical trial setting. Methods: Data on patients with a history of autoimmune disease were collected for four different PD-1/PD-L1 immunotherapy agents. Information collected included name of autoimmune disease, corticosteroid dependency at baseline, duration of dosing, immune-related adverse events (iRAEs) and worsening of underlying autoimmune disease. Results: In total, 552 patients enrolled in 22 clinical trials of PD-1/PD-L1 immunotherapy agents were identified with a history of autoimmune disease. None were known to be dependent on systemic corticosteroids at baseline. The most common autoimmune diseases identified were thyroid disorder (n = 188), psoriasis (n = 70), and vitiligo (n = 44). For the four agents identified, mean duration of dosing was 183, 187, 196, and 145 days. Worsening of underlying autoimmune disease occurred in 16%, 6%, 13% and 6%. There were two grade 4 cases of hyperglycemia in patients with diabetes, three cases each of grade 3 AEs related to the underlying disorder in patients with psoriasis, interstitial lung disease, and hypothyroidism, and one grade 3 AE in a patient related to ankylosing spondylitis.For two of these agents, data were available on the development of grade 1-4 irAEs (per investigator) that required treatment with systemic steroids, which occurred in 8% and 9% of patients. Conclusions: Clinical trial data demonstrates relative safety of the use of PD-1/PD-L1 immunotherapy agents in patients with a history of autoimmune disease compared to their use in patients without such history. No consistent pattern of worsening of baseline autoimmune disease was identified. These results should be interpreted with caution, as diagnostic method and clinical manifestations of reported baseline autoimmune conditions are not known.
Abstract 3197: Beta-Apopicropodophyllin, a derivative of podophyllotoxin, has a function as anticancer drug and radiosenstizer against non-small cell lung cancer cells
Authors: Ju Yeon Kim, Jeong Hyun Cho, Sang-Gu Hwang, Jie-Young Song, EunAh Lee, Hong-Duck Um, Jong Kuk Park
Journal: Cancer Research (2018)

Abstract We have synthesized new 32 derivatives of podophyllotoxin and screened candidate showed anti-cancer effect. Among these derivatives, we found beta-Apopicropodophyllin (APP) is candidate derivative inducing cell death against non-small cell lung cancer (NSCLC) cell lines: A549, NCI-1299 and NCI-460 (IC50 values =16.9, 13.1 and 17.1 nM, respectively). We also analyzed MOA (mode of action) of APP and found APP induced cell death via various mechanisms. Firstly, APP inhibits the polymerization of microtubule and induces G2/M phase arrest as well as DNA damage. APP treatment induces expressions of mitosis-related proteins, phospho-ATM, γ-H2AX and p21. Next, the intrinsic and extrinsic apoptotic pathways by APP are activated as shown in the activations of caspase-3, -8 and -9. APP also induces pro-apoptotic ER stress signaling pathway as indicated by elevated expression levels of BiP, phospo-eIF2α, CHOP and ATF4. Additionally, APP also showed radiosensitizer function. Combination of APP and gamma-ionizing radiation (IR) enhanced apoptotic cell death of NSCLC cell via amplification of ER stress. Taken together, these results implied APP might be a potent anti-cancer drug candidate inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress. Citation Format: Ju Yeon Kim, Jeong Hyun Cho, Sang-Gu Hwang, Jie-Young Song, EunAh Lee, Hong-Duck Um, Jong Kuk Park. Beta-Apopicropodophyllin, a derivative of podophyllotoxin, has a function as anticancer drug and radiosenstizer against non-small cell lung cancer cells [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 3197.
Abstract 2405: P53-dependent mitophagy controls glycolytic shift in radioresistant head and neck cancer cells
Authors: Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Hae Yun Nam, Myungjin Lee, Won Hyeok Lee, Song Hee Kim, Da Seul Seong, Myung Woul Han, Jong Cheol Lee, Jung Je Park, Ji-hyun Seo, Seong Who Kim, Sang Yoon Kim
Journal: Cancer Research (2018)

Abstract P53 is an important biomarker in response to genotoxic stress, but it is also known to plays a key role in the regulation of metabolic homeostasis. The loss of p53 is a well-established contributor to the malignant transformation and glycolytic phenotype acquisition of cells during cancer development. However, the role of p53 in genotoxic therapy-induced metabolic shift in cancers remains unclear. Here, we attempted to elucidate how p53 participates in the glycolytic shift of head and neck cancer cell lines following irradiation. We established a stable radioresistant head and neck cancer cells (HN30-R; p53 wild type and UMSCC1-R; p53 null type) through cumulative irradiation and then analyzed their glucose metabolic profiles and mitochondria respiration. As a result, the metabolic analysis revealed no changes glycolysis of HN30-R cells, but UMSCC1-R cells exhibited increased glycolysis through increased glucose uptake and lactate production and glycolytic intermediates as well as related glycolytic enzymes, compared to UMSCC1 cells. Also, we confirmed that the mitochondrial respiration was reduced by the maximal respiration parameters of oxygen consumption rate (OCR) and that abnormal mitochondria were accumulated by electron microscopy in UMSCC1-R cells. Thus, UMSCC1-R cells exhibited an increased sensitivity to glycolysis-targeting drugs such a hexokinases inhibitor (2-deoxy-D-glucoes; 2-DG) and a lactate dehydrogenase-A inhibitor (AT101), but HN30-R cells did not shown any changes. Moreover, we identified that mitophagy limits glycolytic shift through the p53-dependent clearance of abnormal mitochondria. Taken together, these results suggest that p53 null type cells increased aerobic glycolysis to overcome the accumulation of abnormal mitochondria in radioresistnat cells. Conversely, p53 wild type cells inhibited the glycolytic shift by regulating a integrity through p53-dependent mitophagy. Thus, glycolysis-targeted drugs could be an alternative strategy for overcoming recurrent cancers after radiotherapy, and p53 status could be a biomarker for selecting participants for clinical trials. Citation Format: Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Hae Yun Nam, Myungjin Lee, Won Hyeok Lee, Song Hee Kim, Da Seul Seong, Myung Woul Han, Jong Cheol Lee, Jung Je Park, Ji-hyun Seo, Seong Who Kim, Sang Yoon Kim. P53-dependent mitophagy controls glycolytic shift in radioresistant head and neck cancer cells [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 2405.
Abstract 1448: Integrated molecular analysis reveals novel SPARC-regulated metabolic programming in ovarian cancer
Authors: Christine Naczki, Bincy John, Chirayu Patel, Ashlyn Lafferty, Alia Ghoneum, Hesham Afify, Amanda Davis, Guangxu Jin, Neveen Said
Journal: Cancer Research (2018)

Abstract We have reported a tumor suppressor effect of SPARC in ovarian cancer as both host and tumor SPARC are implicated in anti-proliferative, anti-adhesive effects as well as normalization of the peritoneal tumor microenvironment. Herein, we extend our studies using a syngeneic model of peritoneal ovarian carcinomatosis to gain comprehensive insight on the effect of SPARC on metabolic programming of the ovarian cancer ecosystem. We performed comprehensive metabolomic and transcriptomic profiling of micro-dissected ID8 omental tumors that developed after intra-peritoneal injection in SP-/- and SP+/+ mice. Integrated analysis revealed that the accelerated growth of ID8 tumors in SP-/- mice was associated with metabolic programming of cancer cells with up-regulation of the genes involved in glycolysis, fatty acid oxidation, and oxidative phosphorylation. Tumors also exhibited perturbed redox homeostasis, as well as mitochondrial and ribosomal biogenesis. Comparative analysis of the syngeneic tumors with human high grade serous ovarian cancer (HGSC) revealed upregulation of the same genes involved in metabolic programming with inverse correlation with SPARC transcript expression, implying a role of stromal-SPARC in the metabolic programming of HGSC. Bio-energetic studies revealed that SPARC inhibits basal glycolysis, glycolytic reserve, oxygen consumption rate and mitochondrial ATP synthesis. To the best of our knowledge this is the first study that characterizes the metabolic programming of the ovarian cancer ecosystem by host-SPARC. Citation Format: Christine Naczki, Bincy John, Chirayu Patel, Ashlyn Lafferty, Alia Ghoneum, Hesham Afify, Amanda Davis, Guangxu Jin, Neveen Said. Integrated molecular analysis reveals novel SPARC-regulated metabolic programming in ovarian 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 1448.
Abstract 17303: Protective Roles of Corin Against High Salt-induced Renal Damage
Authors: Jiao Zhang, Yanjun Yin, Yang Wang, Yongbo Lu, Chao Chu, Yifei Miao, Marcy Martin, Zuyi Yuan, John Y Shyy, Jianjun Mu
Journal: Circulation (2016)

Introduction and Hypothesis: Dietary sodium and potassium affect the fluctuation of blood pressure and renal function. With its activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, corin regulates blood pressure, cardiac and renal functions. We hypothesize that corin plays an essential role in ameliorating the high salt-induced renal damage through its regulation of salt and water homeostasis. Methods and Results: Forty-two volunteers (28-65 years of age) were intervened with three sequential diets: a low salt diet (3.0 g/day NaCl) for 7 days, a high salt (HS) diet (18.0 g/day NaCl) for 7 days, followed by a high salt diet with potassium supplementation (18.0 g/day NaCl and 4.5 g/day KCl) for 7 days. The systolic blood pressure and urinary microalbumin level (U-MALB) of the 42 subjects were augmented in the period of HS diet compared to those at the baseline level (117.3±2.7 mmHg vs. 108.7±1.8 mmHg, p<0.05; 8.21±0.89 mg/day vs. 4.89±0.34 mg/day, p<0.05). Such changes we...
Ribozyme-Mediated Inhibition of Expression of Leukocyte-type 12-Lipoxygenase in Porcine Aortic Vascular Smooth Muscle Cells
Authors: Jia-LiGu, DangeVeerapanane, JohnRossi, RamaNatarajan, LisaThomas, JerryNadler
Journal: Circulation Research (1995)

Abstract Activation of a leukocyte-type 12-lipoxygenase (12-LO) has been proposed to be an important mechanism for angiotensin II– and glucose-induced vascular smooth muscle cell growth. Currently, no specific pharmacological inhibitors for the leukocyte-type 12-LO are available to test this hypothesis. We have therefore designed a chimeric DNA-RNA hammerhead ribozyme to produce cleavage at the first GUC sequence at nucleotide 7 of porcine leukocyte 12-LO mRNA. The ribozyme was tested in vitro with a 206-base 12-LO mRNA as substrate. We observed that the ribozyme specifically and dose-dependently cleaved porcine leukocyte 12-LO mRNA at the predicted site under physiological temperature. Furthermore, we also efficiently delivered the ribozyme into porcine aortic vascular smooth muscle cells by transfection with cationic liposomes. The ribozyme caused a dose-dependent decrease in levels of porcine leukocyte-type 12-LO mRNA in these cells and was more potent than an antisense oligonucleotide directed against...