tbuckley/cabot-search huggingface dataset:
Abstract A25: Elephant p53 (EP53) enhances and restores p53-mediated apoptosis in human and canine osteosarcoma
Authors: Lisa M. Abegglen, Cristhian Toruno, Lauren N. Donovan, Rosann Robinson, Mor Goldfeder, Genevieve Couldwell, Wendy K. Kiso, Dennis L. Schmitt, Aleah F. Caulin, Carlo C. Maley, Avi Schroeder, Joshua D. Schiffman
Journal: Clinical Cancer Research (2018)

Abstract Amplification of elephant p53 (EP53) was recently described as a potential mechanism for cancer resistance in elephants. Osteosarcoma is the most common pediatric bone tumor and also occurs frequently in pet dogs. Both human and canine osteosarcoma contain a very high rate of TP53 alterations leading to genomic instability. The purpose of our study was to determine if EP53 could enhance and/or restore p53 function in osteosarcoma and trigger p53-mediated cell death. We expressed various EP53 proteins in canine and human osteosarcoma cell lines (OSCA-40, U-2 OS, and Saos-2) by transfection or viral transduction. Expression of EP53 was confirmed by Western blot. Apoptosis of cells transfected/transduced with EP53 was compared to cells transfected/transduced with negative control vectors. Apoptosis was measured by fluorescence microscopy and caspase activity. We observed a significant increase in caspase activity (normalized to cell viability) of U-2 OS (TP53-wild type) cells expressing EP53 compared to negative control cells (p&amp;lt;0.0001). Saos-2 (TP53-null) and OSCA-40 cells underwent apoptosis as visualized by time-lapse fluorescence microscopy. Experiments to confirm these results with caspase activity assays are currently under way. Increased expression of p21, a direct p53 target, was observed in Saos-2 cells by Western blot. Taken together, our results indicate that EP53 enhances and restores p53-mediated apoptosis in osteosarcoma. These data suggest for the first time that EP53 can function in both human and canine osteosarcoma cells to promote cell death. Efforts to define the mechanism of action of EP53 in osteosarcoma cells are ongoing. Our results support further exploration of EP53-based osteosarcoma therapeutics for both humans and dogs. Citation Format: Lisa M. Abegglen, Cristhian Toruno, Lauren N. Donovan, Rosann Robinson, Mor Goldfeder, Genevieve Couldwell, Wendy K. Kiso, Dennis L. Schmitt, Aleah F. Caulin, Carlo C. Maley, Avi Schroeder, Joshua D. Schiffman. Elephant p53 (EP53) enhances and restores p53-mediated apoptosis in human and canine osteosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A25.
Inflammation in Atherosclerosis
Authors: Jun-oDeguchi, MasanoriAikawa, Ching-HsuanTung, ElenaAikawa, Dong-EogKim, VasilisNtziachristos, RalphWeissleder, PeterLibby
Journal: Circulation (2006)

Background— Matrix metalloproteinases (MMPs) in inflamed atherosclerotic plaques may contribute to extracellular matrix remodeling and the onset of acute thrombotic complications. Methods and Results— To test the hypothesis that optical molecular imaging with the use of an activatable near-infrared fluorescence (NIRF) probe can detect enzymatic action of MMP in atherosclerotic plaques, we used a NIRF substrate for gelatinases (MMP-2/gelatinase-A and MMP-9/gelatinase-B) in apolipoprotein E–deficient (apoE−/−) mice that consumed a high-cholesterol diet for 12 weeks and age-matched apoE+/+ mice as control. The aortas of apoE−/− mice at 24 hours after probe yielded intense NIRF signals, as detected by NIRF reflectance ex vivo, compared with negligible signals in aortas of apoE+/+ mice with/without probe administration or atherosclerotic apoE−/− aortas without probe. Gelatinase inhibitor treatment abolished NIRF signals in apoE−/− mouse aortas ex vivo. Sites of gelatinase activity visualized by NIRF colocalize...
Abstract 4660: Tumor multicomponent targeting nanoparticle library for personalized cancer therapy &amp; imaging
Authors: Samaresh Sau, Hashem Alsaab, Katyayani Tatiparti, Ketki Bhise, Arun Rishi, Arun K. Iyer
Journal: Cancer Research (2018)

Abstract The fundamental limitations of conventional cancer treatment have promoted the development and application of nanoengineering platforms for achieving effective patient outcomes. Over a time, considerable clinical success has been accomplished in nanotechnology field but there are many challenges limiting the progress of nanomedicine from bench to the beside. The highly heterogeneous tumor environment, an inadequate understanding of interactions between tumor biomarkers and nanomedicine, and reproducibility in synthesis required for clinical translation are some of the major challenges. Thus, there is an urgent need to redirect our focus of nano-drug carrier that can target multiple components of tumor including, tumor epithelial cells, tumor angiogenic vessels, tumor hypoxia and stromal cells. To achieve this, we developed a library of various tumor biomarker targeting ligands, and drug and imaging agents encapsulated in nanoparticles (NPs). Finally, the library of targeting ligands was conjugated with NPs using reagent free ‘click' chemistry. This strategy will serve as an “off-the-shelf ready to configure drug formulation" that can be engineered based on a mix-and-match strategy for individual patient needs. It is envisaged that the patient can walk in the clinic and be given the targeted drug that is personalized to their need. For the proof-of-concept, we evaluated tumor selectivity of multiple cancer biomarker targeting oligo-micelles (OMs), iron oxide and lipid NPs in various patient derived tumor xenograft (PDx) models, such as non-small cell lung and triple negative breast cancer. We observed that the dual tumor hypoxia and cancer stem cell (CSC) targeting rod shaped OM has 8-fold higher tumor core penetration compared to non-targeted OM in these PDx tumors, as obtained from NIR-fluorescence imaging. This OM has significantly higher tumor vs. liver ratio and they follow tumor specific receptor competition. The tumor growth inhibition of drug loaded OM is superior compared to free drug. This approach demonstrated significant improvement of tumor stroma penetration with low healthy organ uptake of NPs portending more promising potentials for selective cancer treatment. Citation Format: Samaresh Sau, Hashem Alsaab, Katyayani Tatiparti, Ketki Bhise, Arun Rishi, Arun K. Iyer. Tumor multicomponent targeting nanoparticle library for personalized cancer therapy &amp; imaging [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 4660.
Abstract LB-097: Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses
Authors: Qiuhui Li, Xin Chen, Qu Deng, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Ruizhe Zhao, Kiera Rycaj, Dean G Tang
Journal: Cancer Research (2018)

Abstract Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity in regulating PCa biology and response to androgen/AR-targeted therapies remains unclear. Screening of ~200 castration-resistant PCa (CRPC) cores identified 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling demonstrated that, although the AR+ CRPC responded to Enzalutamide, the AR-/lo CRPC was completely refractory to Enzalutamide. Genome editing-derived isogenic AR+ and AR-KO (knockout) PCa cells showed contrasting tumor-regenerating capacities and responses to castration and Enzalutamide. Whole-genome RNA-Seq and biochemical analyses coupled with experimental combinatorial therapy identified novel signaling pathways and BCL-2 as a critical therapeutic target in both AR+ and AR-/lo CRPC. Our study links AR heterogeneity to distinct castration/Enzalutamide responses and suggests the urgency in developing therapeutics to target AR-/lo PCa cells/clones. Citation Format: Qiuhui Li, Xin Chen, Qu Deng, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Ruizhe Zhao, Kiera Rycaj, Dean G Tang. Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses [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-097.
Analyzing excess mortality from cancer among individuals with mental illness.
Authors: Jackson S. Musuuza, Marion E. Sherman, Kraig J. Knudsen, HelenAnne Sweeney, Carl V Tyler, Siran M. Koroukian
Journal: Journal of Clinical Oncology (2012)

1598 Background: Previous studies have documented higher cancer-related mortality in individuals with mental illness, compared to their healthier counterparts. The aim of this study was to identify the anatomic cancer sites for which mortality is higher in individuals with mental illness. Methods: We used a linked dataset comprised of death certificate data for the state of Ohio for the years—2004-2007 and data from the publicly funded mental health system in Ohio. Decedents with mental illness were those identified concomitantly in both data sets. We used age-adjusted standardized mortality ratios (SMRs) in race- and sex-specific strata to estimate excess deaths for each of the anatomic cancer sites. Results: Overall, there was excess mortality from cancer associated with having mental illness in Non-Black men and women (SMR: 1.14 (95% confidence interval [CI] = 1.05-1.22), and 1.13 (95% CI= 1.05-1.20, respectively), but lower mortality in Black men, likely due to premature mortality from other causes (0.71 (95% CI= 0.61-0.83). In Black women, we observed no excess mortality from cancer that was associated with having mental illness. There was excess mortality from hepatobiliary cancer in Non-Black men (SMR= 1.65; 95% CI =1.15-2.29), but not in any other sex- and race- stratum. In addition, we observed excess mortality from lung and laryngeal cancers among Non-Black men and women (SMRs for lung cancer of 1.28 (95% CI= 1.13-1.45), and 1.45 (95% CI= 1.29-1.62), respectively; and for laryngeal cancer (2.01 (95% CI= 1.19-3.18 for men, and 2.47 (95% CI= 1.08-4.89) for women). Black women experienced excess mortality from cancer of the kidney and renal pelvis (SMR= 2.91; 95% CI =1.53-5.06), while Non-Black women experienced excess mortality from urinary bladder cancers (SMR=1.89; 95% CI=1.15- 2.92). Conclusions: Compared to the general population in Ohio, individuals with mental illness experienced excess mortality from certain cancers. In part, this excess mortality may be mediated by a higher prevalence of smoking or substance abuse in individuals with mental illness. Further investigation is needed to explain the observed racial variation in cancer mortality, and to examine mortality for specific cancers based on severity of mental illness.
Abstract 4502: Cxcl-12-cxcr4 inhibition enhances immune response in pancreatic ductal adenocarcinoma
Authors: Bharti Garg, Anthony Ferrantella, Bhuwan Giri, Shrey Modi, Vrisketan Sethi, Saba Kurtom, Sulagna Banerjee, Ramakrishnan Sundaram, Eli Gilboa, Ashok Saluja, Vikas Dudeja
Journal: Cancer Research (2018)

Abstract Introduction: Pancreatic ductal adenocarcinoma, one of the most aggressive malignancies and is refractory to Immunotherapy. This, in part, is mediated by the fibrotic stroma, creating an immune-suppressive microenvironment. CXCL12/SDF-1 has been shown to act as a chemo-repellant in several cancers. Therefore, we evaluated the role of stromal CXCL-12 in mediating an immunosuppressive phenotype within the pancreatic tumor. Methods: Pancreatic cancer cells harvested from KPC, a genetically engineered mouse model for PDAC, were either injected or alone or co-injected with pancreatic stellate cells (PSCs) extracted from WT (C57/BL6) mice to induce tumors. SDF-1 expression levels were detected by IF and q-RT PCR in tumor sections. An SDF-1 inhibitor, AMD3100 (2mg/kg), or vehicle was administered i.p for 21 days in tumor bearing mice and tumor growth and immune infiltration were assessed as an end point by flow cytometry. To evaluate the T cell migration in vitro, PSCs were pre-treated with SDF-1 neutralizing antibody, educated with KPC cancer cells and further co-cultured with splenic CD3+ T cells extracted from KPC mice. Results: In vitro results showed markedly increased secretion of SDF-1 by PSCs and neutralization of SDF-1 led to increased T-cell migration when cultured with cancer cells alone. We also evaluated the effect of inhibition of SDF-CXCR4 axis on tumor growth. Co-injection of KPC with WT PSC formed larger tumors with increased section of CXCL-12 as compared to when KPC cells were injected alone. Interestingly, Inhibition of SDF-1-CXCR4 interaction with AMD3100 led to reduced tumor growth with increased infiltration of activated CD8+ cytotoxic T cells as compared to the saline-treated mice. Conclusion: Our results indicate that stromal cells contribute to tumor progression by blocking the infiltration of cytotoxic T cells via secretion of CXCL-12. Targeting CXCL-12 could pave the way for designing better therapeutic interventions against pancreatic cancer. Citation Format: Bharti Garg, Anthony Ferrantella, Bhuwan Giri, Shrey Modi, Vrisketan Sethi, Saba Kurtom, Sulagna Banerjee, Ramakrishnan Sundaram, Eli Gilboa, Ashok Saluja, Vikas Dudeja. Cxcl-12-cxcr4 inhibition enhances immune response in pancreatic ductal adenocarcinoma [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 4502.
Abstract 1402: Silencing of B4GALT1 inversely regulates malignant phenotypes of hepatocellular carcinoma cells
Authors: Po-Da Chen, Ai-An Chang, Yao-Ming Wu, Min-Chuan Huang
Journal: Cancer Research (2018)

Abstract Identifying molecular targets for hepatocellular carcinoma (HCC) is an urgent need to overcome the treatment failure and death from cancer cell invasion and metastasis. Beta-1,4-galactosyltransferase 1 (B4GALT1) has been documented as the key enzyme in morphogenesis and cellular adhesion, for it adds galactose to N-acetylglucosamine residues of glycoprotein carbohydrate chains; whereas abnormal B4GALT1 expression is associated with tumor progress in many cancers. However, functional roles of B4GALT1 in HCC remains unclear. With clinical correlation, the immunohistochemistry confirmed that lower expression of B4GALT1 in cancer tissue is associated with higher ratio of vascular invasion and worse overall survival. Consistently, stable knockdown of B4GALT1 regarding HCC cell lines promoted cell migration, and invasion; as the overexpressed B4GALT1 inhibited cell migration and invasion of HCC cell lines. Moreover, our data suggested that down-regulated B4GALT1 modified LEL lectin, and interfered hepatocyte growth factor receptor (HGFR), Epidermal growth factor receptor (EGFR), and Axl signaling. Given that, B4GALT1 is sufficient to inversely regulate malignant behaviors of HCC cells with a significant correlation between gene expression and clinical prognosis, implying that B4GALT1 played a crucial role in cancer progress of HCC. Citation Format: Po-Da Chen, Ai-An Chang, Yao-Ming Wu, Min-Chuan Huang. Silencing of B4GALT1 inversely regulates malignant phenotypes of hepatocellular carcinoma 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 1402.
Oxidative Stress and Diabetic Complications
Authors: FerdinandoGiacco, MichaelBrownlee
Journal: Circulation Research (2010)

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that dr...
Abstract 3504: A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition
Authors: Christopher Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Anil Padyana, Stefan Gross, Sebastian Hayes, Zi Peng Fan, Gabrielle McDonald, Yu Chen, Joshua Murtie, Giovanni Cianchetta, Raj Nagaraja, Rohini Narayanaswamy, Sung Choe, Stuart Murray, Shengfang Jin, Scott Biller, Thomas Roddy, Gromoslaw A. Smolen
Journal: Cancer Research (2018)

Abstract Numerous reports have described the differential metabolism of cancer cells as compared to their normal counterparts. However, only relatively few metabolic genes with cancer-specific mutations have been reported and the identification of cancer subsets with particular metabolic vulnerabilities remains a challenge. To explore potential cancer-specific dependencies, we conducted a chemical biology screen utilizing a collection of small molecule inhibitors targeting diverse metabolic pathways in a large panel of cancer cell lines. A subset of neuroendocrine tumors, particularly small cell lung cancers (SCLC), displayed a striking dependence on squalene epoxygenase, SQLE, an enzyme in the cholesterol biosynthetic pathway. To develop further confidence in these findings, we have determined the first three-dimensional SQLE structure and further advanced a pharmacological toolbox for SQLE. Using these tools, we showed that the observed effects are on target and that the patterns of cellular sensitivity observed in vitro display excellent translation to in vivo xenografts studies. Interestingly, using a variety of orthogonal approaches, we demonstrated that SQLE sensitivity appears not to be related to overall inhibition of the cholesterol pathway but rather to specific and toxic accumulation of the SQLE substrate, squalene. Collectively, these findings highlight the utility of chemical biology screens and identify SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly SCLC. Citation Format: Christopher Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Anil Padyana, Stefan Gross, Sebastian Hayes, Zi Peng Fan, Gabrielle McDonald, Yu Chen, Joshua Murtie, Giovanni Cianchetta, Raj Nagaraja, Rohini Narayanaswamy, Sung Choe, Stuart Murray, Shengfang Jin, Scott Biller, Thomas Roddy, Gromoslaw A. Smolen. A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE 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 3504.
Anti-Ischemic and Anti-Anginal Effects of Thoracic Epidural Anesthesia Versus Those of Conventional Medical Therapy in the Treatment of Severe Refractory Unstable Angina Pectoris
Authors: KarinOlausson, HelgaMagnusdottir, LeonLurje, BertilWennerblom, HåkanEmanuelsson, Sven-ErikRicksten
Journal: Circulation (1997)

Background Cardiac sympathetic blockade by thoracic epidural anesthesia (TEA) dilates stenotic coronary arteries and has been used to control pain in patients with unstable angina. The aim of the present study was to evaluate the potential anti-ischemic effects of cardiac sympathetic blockade by TEA in severe, refractory, unstable angina. Methods and Results Forty patients with unstable angina refractory to standard anti-anginal therapy were randomized to receive either continuous epidural infusion of bupivacaine (TEA, Th1 to Th5) or to standard anti-anginal therapy including β-blockers, calcium antagonists, aspirin, heparin, and nitroglycerin infusion (control group). The primary end points were number of anginal attacks and severity of myocardial ischemia assessed by 48-hour ambulatory Holter monitoring. The incidence of myocardial ischemia was lower in the TEA group (22% versus 61%; P<.05). The number of ischemic episodes per patient was 1.0±0.6 in the TEA group and 3.6±0.9 in the control group (P<.05)...
Abstract 312: Emodin inhibits colon cancer by modulating apoptotic and cell survival signals
Authors: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh
Journal: Cancer Research (2018)

Abstract Colon cancer remains a formidable health care concern and is the third most common cancer among men and women. Late diagnosis and development of resistance to chemotherapeutic regimens significantly impact overall outcome and survival. Various phytochemicals have been shown to have promising anti-cancer properties. Consequently, such natural agents are emerging as an alternative treatment modality for various cancers, including colon cancer. In this study, we have tested the effect of Emodin, an anthraquinone derivative of rhubarb, on human colon cancer cell lines. Our antibody microarray data and pathway analysis indicated that Emodin induced apoptosis in colon cancer cells by triggering both intrinsic and extrinsic apoptotic pathways. These effects of Emodin were associated with modulation of death receptor expression, changes in mitochondrial membrane integrity, and DNA degradation. Further, western blot analysis confirmed that Emodin significantly increased pro-apoptotic proteins (Bak, Bax, Bad) as well as activated caspase-3 and -8. Additionally, Emodin reduced ERK1/2, NF-κB, and STATs at transcript and protein levels, suggesting it also interferes with cell survival. Hence, the ability of Emodin to induce apoptosis and inhibit cell survival by altering molecular pathways underscore its potential as chemo-preventive as well as -therapeutic agent in combination with conventional chemotherapy. Citation Format: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh. Emodin inhibits colon cancer by modulating apoptotic and cell survival signals [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 312.
Rationale and Application of the Protocol S Anti–Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy
Authors: Jennifer K. Sun, Adam R. Glassman, Wesley T. Beaulieu, Cynthia R. Stockdale, Neil M. Bressler, Christina Flaxel, Jeffrey G. Gross, Michel Shami, Lee M. Jampol
Journal: Ophthalmology (2018)