tbuckley/cabot-search huggingface dataset:
Abstract 3513: Curcumin induces a fatal energetic impairment by inhibiting ATP-synthase activity and decreasing ATP generation and oxygen consumption in <i>in vitro</i> and <i>in vivo</i> tumor models
Authors: Ulrich Pfeffer, Giovanna Bianchi, Silvia Ravera, Chiara Traverso, Adriana Amaro, Francesca Piaggio, Laura Emionite, Tiziana Bacchetti, Lizzia Raffaghello
Journal: Cancer Research (2018)

Abstract Curcumin has been reported to inhibit inflammation, tumor growth, angiogenesis and metastasis by decreasing cell growth and by inducing apoptosis mainly through the inhibition of nuclear factor kappa-B (NFkB), a master regulator of inflammation. Recent reports also indicate potential metabolic effects of the polyphenol and we therefore analyzed whether and how it affects the energy metabolism of tumor cells. We show that curcumin inhibits the activity of ATP-synthase in isolated mitochondrial membranes leading to a dramatic drop of ATP and a reduction of oxygen consumption in in vitro in several murine tumor cell lines (CT26 colon cancer, B16 melanoma, L1210 lymphocytic leukemia, 4T1 breast cancer) and in vivo in syngeneic tumor models. The effects of curcumin on ATP-synthase are independent of the inhibition of nuclear factor kB (NFkB) since the IkB Kinase inhibitor, SC-514, inhibits the expression of the NFkB target gene, BCL2, but does not affect the activity of the ATP-synthase. The activities of the glucose metabolism enzymes hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase are only slightly affected in a cell type specific manner. The energy impairment translates into decreased tumor cell viability. Apoptosis is induced by promoting the generation of reactive oxygen species and malondialdehyde (MDA), a marker of lipid oxidation. Tumor autophagy is induced by curcumin at least in part due to the activation of the AMP-activated protein kinase (AMPK). These activities translate into a significant delay of in vivo tumor growth likely due to a reduction of tumor angiogenesis since we observe reduced number and size of tumor vessels in vivo. These results establish the ATP-synthase, a central enzyme of the cellular energy metabolism, as a target of the anti-tumoral polyphenol leading to inhibition of cancer cell growth and a general reprogramming of tumor metabolism. Citation Format: Ulrich Pfeffer, Giovanna Bianchi, Silvia Ravera, Chiara Traverso, Adriana Amaro, Francesca Piaggio, Laura Emionite, Tiziana Bacchetti, Lizzia Raffaghello. Curcumin induces a fatal energetic impairment by inhibiting ATP-synthase activity and decreasing ATP generation and oxygen consumption in in vitro and in vivo tumor models [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 3513.
Abstract 1914: Elongation factor 2: A novel target for cancer progression
Authors: Beatrice Malacrida, Catríona M. Dowling, Rasmus K. Flygaard, Maeve Kiely, John C. Coffey, Lasse B. Jenner, Patrick A. Kiely
Journal: Cancer Research (2018)

Abstract Protein translation is one the most energy demanding and highly regulated processes in cells. For this reason, dysregulation of protein synthesis is linked with different types of disease, including cancer. The link between protein synthesis and cancer progression is becoming a central theme among cancer research. Although numerous studies have identified protein synthesis as a process central to cancer progression, further research is required to identify potential novel targets and/or biomarkers. Recently, RACK1 (Receptor for Activated C Kinase 1), a scaffold protein involved in many cell regulatory pathways including cell proliferation and migration, has been found to be part of the ribosomal machinery. Here, RACK1 is able to regulate the synthesis of particular sets of proteins and the translation itself. In fact, RACK1 is located close the mRNA exit channel where is able to recruit kinases, phosphatases and specific mRNA binding proteins. We have identified elongation factor 2 (eEF2) as novel RACK1 interacting protein in our two and three dimensional colon cancer models. Elongation factor 2 is one of the main proteins regulating the elongation phase of protein synthesis, responsible for the translocation of the mRNA along the ribosome. We have confirmed the binding between eEF2 and RACK1 by isolating and purifying a native human form of eEF2 and combining it with a purified human version of RACK1. Interestingly, we have demonstrated that stress conditions and IGF-1 stimulation modulate eEF2 activity in colon cancer cells. Moreover, we have examined the expression of EEF2 and have found that EEF2 gene is dysregulated in our cohort of matched normal and cancer colonic patient tissues. Interestingly, EEF2 expression is upregulated in mucinous cancers (a rare and aggressive type of colorectal cancer) compared to non-mucinous cancers and the expression of EEF2 is as well upregulated in cancers that have recurred within 2 to 3 years after the first surgery. We believe that eEF2 is playing an important role in cancer progression and migration especially by regulating and modulating protein synthesis in certain conditions. A better understanding of the role of this protein will help in the identification of novel targets that can be then translated into therapeutic strategies against colorectal cancer. Citation Format: Beatrice Malacrida, Catríona M. Dowling, Rasmus K. Flygaard, Maeve Kiely, John C. Coffey, Lasse B. Jenner, Patrick A. Kiely. Elongation factor 2: A novel target for cancer progression [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 1914.
Dependence of Wall Stress in the Human Thoracic Aorta on Age and Pressure
Authors: Hermannbader
Journal: Circulation Research (1967)

The tangential wall stress and the tangential elasticity modulus at pressures from 0 to 200 mm Hg were calculated from pressure-volume diagrams of 27 human thoracic aortas aged 22 to 85 years. The relative volume increase of the aortas between 0 and 100 mm Hg decreased linearly from about 190% at age 20 to about 40% at age 85, whereas the elasticity modulus at 100 mm Hg increased linearly from 10 kg/cm2 at age 20 to 42.5 kg/cm2 at age 85. The decrease of the distensibility of the aortic wall with age was partly compensated by an increase of the internal volume of the aorta but at higher ages the distensibility was less than the theoretical values necessary for a proper buffering chamber activity. The tangential wall stress decreased linearly with age from about 2.5 kg/cm2 at age 20 to about 1.2 kg/cm2 at age 85. Since the pressoreceptors in the wall of the elastic vessels respond to the wall stress, this result means either that smooth muscles must increase the stress of the elastic fibers continuously, o...
B lymphocyte–induced maturation protein 1 controls TH9 cell development, IL-9 production, and allergic inflammation
Authors: Luciana Benevides, Renata Sesti Costa, Lucas Alves Tavares, Momtchilo Russo, Gislâine A. Martins, Luis Lamberti P. da Silva, L. Karla Arruda, Fernando Q. Cunha, Vanessa Carregaro, João Santana Silva
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 2910: Identification of URST1 as a novel prognostic biomarker and therapeutic target for various subtypes of breast cancer
Authors: Masako Nakamura, Atsushi Takano, Phung Manh Thang, Yohei Miyagi, Yataro Daigo
Journal: Cancer Research (2018)

Abstract Breast cancer is one of the most common causes of cancer death for women worldwide. To identify diagnostic and therapeutic targets for breast cancer, we screened molecules that were highly expressed in the majority of breast cancers by our gene expression profile database. During this process, we identified URST1 (up-regulated in solid tumor 1) as a candidate. Immunohistochemical analysis showed that URST1 was expressed in 195 of 257 (75%) breast cancer cases (69% in luminal type, 88% in HER2-positive cancer, 86% in Triple-negative cancer) that had undergone curative surgery, whereas no staining was observed in adjacent normal breast tissues. URST1 expression was significantly related to poor clinical outcome for breast cancer patients (P = 0.01, Log-rank test) and multivariate analysis showed that it was an independent prognostic factor. Knockdown of endogenous URST1 expression by siRNAs against URST1 or treatment with URST1 inhibitor significantly inhibited the growth of breast cancer cells through cell cycle arrest at G2/M phase. Our data suggest that URST1 is likely to be a prognostic biomarker and therapeutic target for various subtypes of breast cancers. Citation Format: Masako Nakamura, Atsushi Takano, Phung Manh Thang, Yohei Miyagi, Yataro Daigo. Identification of URST1 as a novel prognostic biomarker and therapeutic target for various subtypes of breast 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 2910.
Abstract 12272: Sphingosine-1-phosphate Reverts the Mechanism of Flow Induced Dilation to Nitric Oxide in Diseased Human Arterioles
Authors: Julie K Freed, Joseph C Hockenberry, David D Gutterman
Journal: Circulation (2015)

Impairment of flow-induced dilation (FID; the ability of the vasculature to dilate to increased shear stress in an endothelium-dependent manner) is predictive for future cardiovascular events. Recent discoveries in our laboratory have shown that increases in ceramide, through inhibiting its catabolism or exogenous administration, transitions the mediator of FID from NO to mitochondrial-derived H2O2, the same transition that occurs between health and disease. Ceramide can also undergo transformation to sphingosine, the backbone of all sphingolipids, and eventually phosphorylated to sphingosine-1-phosphate (S1P), known to have beneficial effects within the endothelial cell. We tested the hypothesis that exogenous administration of S1P will revert the mediator of FID back to NO in vessels from patients with CAD. Small adipose arterioles (100-200μm) from patients with CAD were prepared for videomicroscopy and constricted with endothelin-1. Changes in internal diameter to flow were recorded. The presence of PEG-Catalase (500U/ml) did not affect FID in CAD arterioles pre-treated with S1P (1μM, 16-20hrs) (82.4%±5.4 of maximal dilator capacity, n=7) compared to control (81.7%±2.9, n=4), however dilation was significantly impaired in the presence of L-NAME (100μM) (0.3%±2.0, n=8, p&lt;0.01, one-way ANOVA). Dilation with S1P alone was no different from control (80.6%±3.8, n=8, versus 81.7%±2.9, n=4, respectively). Together these data suggest that S1P is critical in regulating the mediator of FID and promotes vasodilation through the NO pathway as opposed to H2O2. We conclude that the ceramide-sphinogsine-S1P balance has a significant influence in determining the primary mediator of FID.
Donor, Recipient, and Operative Factors Associated with Graft Success in the Cornea Preservation Time Study
Authors: Mark A. Terry, Anthony J. Aldave, Loretta B. Szczotka-Flynn, Wendi Liang, Allison R. Ayala, Maureen G. Maguire, Christopher Croasdale, Yassine J. Daoud, Steven P. Dunn, Caroline K. Hoover, Marian S. Macsai, Thomas F. Mauger, Sudeep Pramanik, George O.D. Rosenwasser, Jennifer Rose-Nussbaumer, R. Doyle Stulting, Alan Sugar, Elmer Y. Tu, David D. Verdier, Sonia H. Yoo, Jonathan H. Lass
Journal: Ophthalmology (2018)
Abstract 17218: Radiation Therapy is not Associated With Incident Atrial Fibrillation in Patients With Thoracic Cancer
Authors: Robert Lentz, Brandon Chalazan, Matthew Kolek, Eric Farber-Eger, Quinn Wells, Javid Moslehi, Dawood Darbar
Journal: Circulation (2015)

Introduction: Radiotherapy for thoracic cancer causes incidental cardiac exposure and increases risk of ischemic heart disease. Less clear is whether radiotherapy similarly increases risk of arrhythmias. Radiotherapy induces cardiac inflammation and fibrosis, which are risk factors for atrial fibrillation (AF). Hypothesis: In patients with thoracic tumors, radiotherapy is associated with incident AF. Methods: We conducted a retrospective study of electronic medical records (EMR) of patients who had a primary tumor of the breast, lung, mediastinum, or esophagus diagnosed between 1994 and 2014, did not have AF at time of diagnosis, and did not have previous thoracic radiotherapy. Patients were followed for incident AF until the end of the EMR or death. Incident AF was determined using a validated algorithm with a positive predictive value of 95.6%. After multiple imputation of missing variables, the association between radiotherapy and incident AF was assessed using Cox proportional hazards models. Results: 4163 patients were included in the analysis. Mean (SD) age was 61.2 (13.3) years and 71% were women; 600 underwent radiotherapy. After a median (25 th -75 th percentile) 796 (255-2032) days of follow-up, the incidence of AF was 6.8% with and 6.2% without radiotherapy (P=0.538). After adjustment for potential confounders, radiotherapy was not associated with incident AF [hazard ratio (HR): 1.02, 95% confidence interval: 0.72-1.44]. Age [HR (per year): 1.05 (1.04-1.06), P=6.0*10 -15 ], male sex [HR: 2.44 (1.80-3.30), P=9.5*10 -9 ], coronary artery disease [HR: 1.42 (1.06-1.92), P=0.02], hypertension [HR: 6.44 (2.04-20.3), P=0.001], and heart failure [HR: 3.20 (2.31-4.44), P=3.4*10 -12 ] were associated with incident AF. Among 3908 patients with unilateral breast or lung tumors, radiotherapy was not associated with incident AF [HR: 1.23 (0.79-1.92)] and tumor laterality did not modify the effect (P for interaction: 0.201). Conclusions: In this large retrospective cohort study, radiotherapy for thoracic tumors was not associated with incident AF. Rather, previously described AF risk factors were the most important drivers of AF risk. Larger studies with extended follow-up may further elucidate whether thoracic radiotherapy is a risk factor for AF.
Abstract 1117: Norrin signaling is protumorigenic in glioblastoma progression
Authors: Ahmed A. Elsehemy, Hayden Selvadurai, Katherine Rowland, Peter Dirks, Valerie Wallace
Journal: Cancer Research (2018)

Abstract Norrin signaling is protumorigenic in GBM progression A-Introduction: Norrin, a secreted factor encoded by the Norrie Disease Protein gene (NDP), is an atypical WNT ligand that specifically binds the FZD4 receptor and activates the canonical WNT signaling pathway in endothelial cells to regulate vascular development and barrier function in the brain. Recently, our group identified a novel tumor inhibitory function of NDP/FZD4 signaling in the endothelium in mouse models of medulloblastoma. Here we investigated the function of the NDP/FZD4 signaling axis in glioblastoma (GBM) progression. B-Experimental approaches GBM patients' survival data was obtained from TCGA and analyzed using the cBioportal server. Low passage mitogen expanded GBM cancer stem cell lines were established from primary tumors using standard conditions. NDP expression in experimental cell lines was modulated using lentiviral delivery of short hairpins or full length cDNA. Cell number was assessed by trypan blue cell counting, and sphere forming cell frequency was tested using extreme limited dilution assay (ELDA). For in vivo assessment of tumorigenesis, experimental and control cell lines were xenografted intracranially in NOD/SCID/Gamma (NSG) mice and symptomatic animals were euthanized and brains collected for histological analysis. C-Results Analysis of GBM data from TCGA showed that survival and NDP expression are negatively GBM. Gene expression analysis indicated variable expression levels of NDP/FZD4 signaling pathway components in a panel of 10 primary GBM stem cell lines. In vitro gain and loss of function studies showed that NDP promotes proliferation and sphere formation in GBM. Moreover, the effects of are recapitulated in xenografts. NDP appears to control GBM differentiation, as it affects the proportion of cycling (Ki67+) cells and the level of stemness (Sox2 levels). Finally, NDP function is independent of FZD4 and canonical Wnt signaling, indicating that it functions through an alternative pathway. D-Conclusions Our in vitro and in vivo results indicate that Norrin might have an oncogeneic role in GBM. In addition, the effect of Norrin is FZD4- and WNT-independent. Our results indicate that targeting Norrin GBM might be a potential therapeutic approach. Citation Format: Ahmed A. Elsehemy, Hayden Selvadurai, Katherine Rowland, Peter Dirks, Valerie Wallace. Norrin signaling is protumorigenic in glioblastoma progression [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 1117.
Low Serum Insulin-Like Growth Factor I Is Associated With Increased Risk of Ischemic Heart Disease
Authors: AndersJuul, ThomasScheike, MichaelDavidsen, JesperGyllenborg, TorbenJørgensen
Journal: Circulation (2002)

Background— Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD). Methods and Results— We conducted a nested case-control study within a large prospective study on cardiovascular epidemiology (DAN-MONICA). We measured IGF-I and IGFBP-3 in serum from 231 individuals who had a diagnosis of IHD 7.63 years after blood sampling and among 374 control subjects matched for age, sex, and calendar time. At baseline when all individuals were free of disease, subjects in the low IGF-I quartile had significantly higher risk of IHD during the 15-year follow-up period, with a relative risk (RR) of 1.94 (95% CI, 1.03 to 3.66) of IHD compared with the high IGF-I quartile group, when IGFBP-3, body mass index, smoking, menopause, diabetes, and use of antihypertensives were controlled for. Conversely, individuals in the high IGFBP-3 quartile gr...
Abstract 3773: RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody
Authors: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif
Journal: Cancer Research (2018)

Abstract Combination immunotherapy strategies are being developed to improve the clinical outcome in cancer patients. T-cell costimulation through OX40 has been shown to promote expansion and proliferation of effector T-cells leading to enhanced effector functions, memory generation and immune inflammatory antitumor responses. However, treatment with anti-OX40 as a single agent has not led to major positive clinical outcomes. Therefore, anti-OX40 is an ideal candidate for combination immunotherapy. In preclinical models, we have recently shown that combining anti-PD-1 concurrently with anti-OX40 negates the effects of agonist anti-OX40, making identification of combination partners crucial for antitumor therapy. RORγt, a master transcription factor, is known to drive Type 17 T-cell differentiation. Synthetic, small-molecule RORγ agonists have been shown to enhance Type 17 T-cell effector functions and survival, decrease immune suppressive mechanisms and modulate expression of a number of costimulatory and coinhibitory molecules. We hypothesized that combining RORγ agonist could enhance the antitumor effects of anti-OX40. Using a murine model where vaccine is used to prime the immune system, we assessed the effects of anti-OX40 antibody combined with a RORγ agonist (LYC-54143) on growth of established tumors and survival. We found that the combined treatment resulted in a significantly delayed tumor growth and prolonged mice survival. Analysis of the tumor microenvironment revealed that combination therapy significantly increased the numbers of total CD4+ T-cells including RORγt+ and highly activated INFγ+ cells, decreasing Treg numbers. Moreover, we found that RORγ agonist resulted in an increase in the numbers of total, antigen-specific, granzyme B+, and IFNγ+ CD8+ T-cells in the TME. These results show that inducing Th17 cells within the TME produces better anti-OX40 effect, suggesting that agonist anti-OX40 and RORγ agonist treatment is a novel potent combination for cancer immunotherapy. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody [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 3773.
Abstract 1326: Nonprotective autophagy fails to confer resistance to radiation
Authors: Jingwen Xu, Emmanuel Kenneth Cudjoe, Tareq Saleh, Nipa Patel, Moureq Alotaibi, Yingliang Wu, Santiago Lima, David Gewirtz
Journal: Cancer Research (2018)

Abstract Radiation remains a predominant treatment option for advanced, inoperable lung cancer, however, resistance represents a major barrier against effective therapy. The exact mechanisms through which cancer cells exhibit resistance to radiotherapy still remains unresolved. Traditionally, radiation-induced autophagy is considered as a mechanism of resistance which attenuates the antitumor effects of radiotherapy i.e., autophagy plays a cytoprotective role on cell survival. To examine this concept further, we employed H460 non-small cell lung cancer (NSCLC) cells that were either p53 wild-type (p53 +/+) or p53 null (p53 -/-) to study the contribution of autophagy to radiation sensitivity. While autophagy was markedly higher in p53 +/+ cells (determined by p62 degradation, LC3B conversion, and acidic vesicle formation) the p53 +/+ cells were actually more radiosensitive than their counterpart H460 p53 -/- cells, which showed lower levels of radiation-induced autophagy. Despite modest radiosensitization by chloroquine, alternative pharmacological (3-methly adenine) and genetic (ATG5 silencing) inhibition of autophagy failed to radiosensitize either p53 +/+ or p53 -/- cells, indicating that radiation induced autophagy is not cytoprotective in function in these experimental models. Furthermore, secretome analysis (nLC-MS/MS) of p53 +/+ H460 cells showed no significant association with radioresistance-related proteins in comparison with p53 -/- H460 cells. The rate and extent of apoptosis was quite low and similar in the two cells lines, essentially ruling out apoptotic cell death as the basis for differential radiation sensitivity. Finally, Senescence was more pronounced in the p53 +/+ cells compared to the p53 -/- cells, which may contribute to the greater radiation sensitivity in the p53 +/+ cells. However, the most relevant finding in this work was that when autophagy is the nonprotective form, it does not confer inherent radiation resistance in tumor cells. Citation Format: Jingwen Xu, Emmanuel Kenneth Cudjoe, Tareq Saleh, Nipa Patel, Moureq Alotaibi, Yingliang Wu, Santiago Lima, David Gewirtz. Nonprotective autophagy fails to confer resistance to radiation [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 1326.