tbuckley/cabot-search huggingface dataset:
Tumor Necrosis Factor Soluble Receptors in Patients With Various Degrees of Congestive Heart Failure
Authors: RobertoFerrari, TizianaBachetti, RobertaConfortini, CristinaOpasich, OresteFebo, AngeloCorti, GiovanniCassani, OdoardoVisioli
Journal: Circulation (1995)

Background Tumor necrosis factor alpha (TNF-α) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-α activity have been identified in human serum. These two soluble proteins are the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII, respectively). The determination of circulating sTNF-Rs could provide us with some additional information about the activation of this cytokine in CHF. Methods and Results This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-α in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-α increased (from 14.3±7.08 to 33.5±13.1 pg/mL, P<.001) in preterminal patients with severe CHF (New York Heart Association [NYHA] class IV). In these patients, sTNF-Rs were also increased (sTNF-RI from 1.17±0.43 to 4.43±2.14 ng/mL and sTNF-RII from 2.2±0.44 to 7.55±2.28 ng/mL, P<.001). When measured by...
Abstract 4322: Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling
Authors: Carla Danussi, Promita Bose, Pedro Silberman, John S. Van Arnam, Mark Vitucci, Oliver Tang, Adriana Heguy, Timothy A. Chan, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse
Journal: Cancer Research (2018)

Abstract Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. For instance, genetic inactivation of the SWI/SNF chromatin regulator ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in both adult and pediatric malignant glioma, and occurs frequently in other cancers as well. ATRX deficiency has been linked to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. However, the precise oncogenic mechanism(s) induced by ATRX deficiency remain unclear, particularly those involving epigenomic dysregulation. To model these events in putative glioma cells of origin, we inactivated Atrx in primary murine neuroepithelial progenitors (mNPCs). Atrx loss, especially when coupled with Tp53 inactivation, promoted mNPC motility while also modulating differentiation state and potential, effectively recapitulating characteristic disease phenotypes and molecular features. Moreover, these phenotypes correlated with altered gene expression profiles in functionally relevant molecular networks (e.g. cell differentiation and migration). Integrating these transcriptional changes with shifts in chromatin accessibility occurring with Atrx deficiency, along with genome-wide Atrx distribution as determined by ChIP-seq, revealed highly significant spatial correlations between differentially expressed genes, regions of altered chromatin compaction, and genomic sites normally occupied by Atrx. Finally, target genes mediating specific Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate cellular and molecular contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes. Citation Format: Carla Danussi, Promita Bose, Pedro Silberman, John S. Van Arnam, Mark Vitucci, Oliver Tang, Adriana Heguy, Timothy A. Chan, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse. Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling [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 4322.
Targeting 2A Protease by RNA Interference Attenuates Coxsackieviral Cytopathogenicity and Promotes Survival in Highly Susceptible Mice
Authors: SabineMerl, CorneliaMichaelis, BirgitJaschke, MarcVorpahl, StefanSeidl, RainerWessely
Journal: Circulation (2005)

Background— Enteroviridae such as coxsackievirus B3 (CVB3) are important infectious agents involved in viral heart disease, hepatitis, and pancreatitis, but no specific antiviral therapy is available. Methods and Results— The aim of the present study was to evaluate the impact of RNA interference on viral replication, cytopathogenicity, and survival. Small interfering RNA (siRNA) molecules were designed against the viral 2A region (siRNA-2A), which is considered to be highly conserved and essential for both virus maturation and host cytopathogenicity. siRNA-2A exhibited a significant protective effect on cell viability mediated by marked inhibition of CVB3 gene expression and viral replication. In highly susceptible type I interferon receptor–knockout mice, siRNA-2A led to significant reduction of viral tissue titers, attenuated tissue damage, and prolonged survival. Repeated siRNA-2A transfection was associated with a further improvement of survival. Various control siRNA molecules had no protective effe...
Abstract 4898: Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis
Authors: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li
Journal: Cancer Research (2018)

Abstract In the United States, over 80% of prostate cancer patients die with bone metastases. Second-line hormonal therapies, such as enzalutamide, only improve overall patient survival by a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance in order to provide better treatments for prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor. Our study showed that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted subcutaneously, it had no effect on the growth of C4-2B tumors in the bone or on the development of bone lesions. These data suggested a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. To dissect the role of enzalutamide on the bone microenvironment, we treated bone cells, both osteoblasts and osteoclasts, with enzalutamide. We found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer bone metastatic tissue microarray, in which we performed immunohistochemistry and found a significant decrease of TGFBR2 expression specifically in cancer-associated osteoblasts from patients who had undergone treatment with second-line hormonal therapies, either enzalutamide or abiraterone. Statistical analysis showed that the decrease of TGFBR2 in cancer-associated osteoblasts was a causative effect from the hormonal therapies. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that loss of TGFBR2 in osteoblasts significantly promoted prostate cancer bone metastasis. Together, our data showed for the first time that reduction of TGFBR2 in osteoblasts by enzalutamide causes resistance to the drug in prostate cancer bone metastasis. Citation Format: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li. Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis [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 4898.
Optoacoustic imaging identifies ovarian cancer using a microenvironment targeted theranostic wormhole mesoporous silica nanoparticle
Authors: Abhilash Samykutty, William E. Grizzle, Benjamin L. Fouts, Molly W. McNally, Phillip Chuong, Alexandra Thomas, Akiko Chiba, Dennis Otali, Anna Woloszynska, Neveen Said, Peter J. Frederick, Jacek Jasinski, Jie Liu, Lacey R. McNally
Journal: Biomaterials (2018)
Total Urinary Catechol Excretion in Cardiovascular and Other Clinical Conditions
Authors: Wilhelmraab, Wildagigee
Journal: Circulation (1954)

Although colorimetry (method of Shaw) permits neither a differentiation of epinephrine and norepinephrine nor their separation from other catechols, it reveals the total urinary catechol excretion, including those portions which were inactivated in the body. No significant abnormalities were found in arterial hypertension, in congestive heart failure, after myocardial infarction and during emotional stress. Thoracolumbar sympathectomy depressed total catechol excretion temporarily. In renal uremia, the regularly demonstrable elevation of the blood catechols was paralleled by a diminution of the conjugated catechols in the urine. It appears to be due to renal retention.
Abstract 242: Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer
Authors: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon
Journal: Cancer Research (2018)

Abstract Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR &amp;lt; 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA. Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic 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 242.
Homocysteine Increases Nitric Oxide Synthesis in Cytokine-Stimulated Vascular Smooth Muscle Cells
Authors: UichiIkeda, MichiyoIkeda, SeijiMinota, KazuyukiShimada
Journal: Circulation (1999)

Background—Elevated plasma homocysteine levels have been reported to be an independent risk factor for vascular disease. However, there have been no reports concerning the effects of homocysteine on the production of nitric oxide (NO), another modulator of vascular function and proliferation, by the vascular smooth muscle. Methods and Results—We investigated the effects of homocysteine on NO synthesis by measuring the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells (VSMCs). Incubation of cultures with interleukin (IL)-1β 10 ng/mL for 24 hours caused a significant increase in nitrite generation. The IL-1β–induced nitrite production by VSMCs was significantly increased by homocysteine in a dose-dependent manner. This effect of homocysteine was significantly inhibited in the presence of NG-monomethyl-l-arginine or actinomycin D. The homocysteine-induced nitrite production was accompanied by increased inducible NO synthase mRNA and protein accumulation. Cysteine,...
Differential Activation of Cardiac c-Jun Amino-Terminal Kinase and Extracellular Signal-Regulated Kinase in Angiotensin II–Mediated Hypertension
Authors: MasahikoYano, ShokeiKim, YasukatsuIzumi, ShinyaYamanaka, HiroshiIwao
Journal: Circulation Research (1998)

Abstract—Two subgroups of mitogen-activated protein kinases, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng · kg−1 · min−1) infusion caused larger activation of left ventricular JNK than ERK, via the AT1 receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT1 receptor. The dose-response relationships for Ang II–induced rises i...
Abstract 3723: Nanoengineered mesenchymal stem cells successfully inhibit tumor progression in a syngeneic mouse model
Authors: Buddhadev Layek, Jayanth Panyam, Swayam Prabha
Journal: Cancer Research (2018)

Abstract Active tumor-targeted drug delivery holds great promise for enhancing therapeutic efficacy and mitigating toxic side effects resulting from nonspecific distribution of chemotherapeutic agents to healthy tissues. However, the majority of current drug delivery strategies depend on inefficient passive accumulation of the drug carrier in the tumor. We have developed a novel and truly active tumor-targeting approach that relies on the tumor tropism of mesenchymal stem cells (MSCs). Our work emphases nanoengineering of MSCs with paclitaxel-loaded nanoparticles to create cellular drug depots capable of selectively homing to tumor sites and releasing the drug over an extended duration. Paclitaxel-loaded PLGA nanoparticles (18.1 ± 1.9 % w/w paclitaxel; diameter of 282.5 ± 5.2 nm; and zeta potential of −18.4 ± 2.5 mV) were formulated by emulsion-solvent evaporation method. Nanoengineered MSCs were generated by incubating MSCs with 100 µg/mL paclitaxel-loaded nanoparticles for 4 hours at 37°C without altering their viability and migration potential. Anticancer efficacy of nanoengineered MSCs was evaluated in C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Despite significantly lower doses of paclitaxel (~2.5 mg/kg total dose for nanoengineered MSCs vs. 120 mg/kg for free- and nanoparticle-encapsulated drug), nanoengineered MSCs resulted in significant greater tumor inhibition and superior survival. Furthermore, administration of human MSCs did not elicit any overt immunologic responses in mice. In summary, our results demonstrate that nanoengineered MSCs can serve as an efficient carrier for tumor-specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy. Citation Format: Buddhadev Layek, Jayanth Panyam, Swayam Prabha. Nanoengineered mesenchymal stem cells successfully inhibit tumor progression in a syngeneic mouse model [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 3723.
Prognosis of breast cancer in patients with peritoneal metastasis.
Authors: Ibrahim Petekkaya, Veysel Ayyildiz, Cemal Kizilarslanoglu, Ugur Sahin, Gamze Gezgen, Emir C. Roach, Musturay Karcaaltincaba, Kadri Altundag
Journal: Journal of Clinical Oncology (2012)

e11509 Background: Distant spread from breast cancer is commonly found in bones, lungs, liver, and central nervous system. However, peritoneal involvement is unusual and unexpected. The aim of the study was to perform a comprehensive analysis of breast cancer patients with peritoneal metastases. Methods: Twenty-one (0.9% of the cohort) breast cancer patients with peritoneal metastases were detected out of a database of 2,219 breast cancer patients treated in Hacettepe University Medical Oncology Department. Clinical characteristics, follow up times and survival rates were analyzed. Results: The mean age of the 21 patients at the time of peritoneal metastasis was 56 years (38-71). 12 (57.1%) patients were post-menopausal, 6 (28.6%) patients were pre-menopausal. Numbers of deceased patients were 7 (33.3%). Seven (33.3%) patients’ histological subtypes were invasive ductal carcinoma (IDC), five (23.8%) patients’ were invasive lobular carcinoma (ILC) and three (14.3%) patients’ were mixed (IDC and ILC). Numbers of luminal A patients were 8 (38.1%), luminal B were 5 (23.8%), triple negative were 2 (9.5%). There was no Her-2 overexpressing patient and numbers of unknown molecular subtype patients were 6 (28.6%). The median follow up times after peritoneal disease in patients deceased and living were 9.3 (range: 0.4-23.3) months and 15.6 (range: 0.3-40.4) months, respectively. Median follow up time after peritoneal metastasis of ER positive patients was 13.7 months, and it was longer than ER negative patients (4.4 months). Six months and one year survival rates after peritoneal metastasis were 83.3% and 73.3%, respectively. Disease free, progression free and overall survival data could not be obtained due to inadequate number of events. Conclusions: Peritoneal metastasis of breast cancer is very rare and median survival time is controversial in literature. Despite of a small cohort, we found the patients’ follow up times longer than reported before. Especially, ER positive patients have longer survival time than ER negative, and this result highlights the importance of hormonotherapies.
Stephen William Valentine Coppinger
Authors: Christopher Mitchell
Journal: BMJ (2018)

Stephen William Valentine Coppinger (“Steve”) was born in Vancouver, Canada. His father served in the Canadian Army as a gynaecologist and obstetrician, and Steve spent part of his childhood at Fort Churchill, on the shores of Hudson’s Bay. This early experience of the wilderness left a lasting impression on him, and he acquired a lifelong love of the outdoors. He subsequently worked in northern Canada as a professional guide.

He was educated at Ridley College in Canada (1967-72) and at the University of Western Ontario (1972-74). In 1974 …
Abstract 4264: Mathematical modeling of differential effects of sunitinib on primary tumor and metastatic growth
Authors: Chiara Nicolò, Michalis Mastri, Amanda Tracz, John M. Ebos, Sébastien Benzekry
Journal: Cancer Research (2018)

Abstract Sunitinib is a drug with anti-angiogenic activity used in the treatment of patients with metastases from renal cell carcinoma or gastrointestinal tumors. However, despite clear efficacy in reducing established tumor growth, recent preclinical studies have shown limited, or even opposing, efficacies in preventing metastatic spread. In this work, we evaluated a mathematical metastatic model to describe primary tumor and metastatic dynamics in response to sunitinib in a clinically relevant mouse model of spontaneous metastatic breast cancer that develops after surgical removal of an orthotopically implanted primary tumor. Mice received either vehicle or sunitinib in the neoadjuvant (presurgical) setting according to different schedules. The experimental dataset comprises measurements of primary tumor kinetics, metastatic burden and pre-surgical molecular and cellular biomarkers, including vascular cell Ki67 and CD31 expression, circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs). Estimation of the model's parameters was performed using a mixed-effects population approach. To describe tumor growth under sunitinib treatment, a simple ordinary differential equation model of tumor growth inhibition was used. Population fits obtained modeling the effect of treatment only on primary tumor growth described well the experimental data of all the treated groups considered. On the contrary, simulations of treatment also on metastasis could not reproduce the behavior of the data. By inserting in the model the available biomarkers as covariates, through a Wald-test, measurements of Ki67+/CD31+, CTCs and granulocytic MDSCs were found significantly correlated with the model parameter expressing the metastatic aggressiveness of the tumor. Together, these mathematical models confirm a differential effect of sunitinib on primary (localized) tumors compared to secondary (metastatic) disease. Our results suggest that Ki67+/CD31+, CTCs and MDSCs measurements might help in predicting metastatic potential and thus aid in predicting benefit in overall survival for preoperative antiangiogenic treatments. Citation Format: Chiara Nicolò, Michalis Mastri, Amanda Tracz, John M. Ebos, Sébastien Benzekry. Mathematical modeling of differential effects of sunitinib on primary tumor and metastatic growth [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 4264.