tbuckley/cabot-search huggingface dataset:
Abstract 5912: Tumor micoenvironment modulates RTK signaling
Authors: Dhruv Thakar, Shalini T. Low-Nam, Jay T. Groves, Valerie M. Weaver
Journal: Cancer Research (2017)

Abstract Receptor tyrosine kinases (RTKs) and their associated signaling molecules are mutated or dysregulated in many aggressive cancers such as non-small cell lung carcinoma (NSCLC), breast cancer, and colorectal cancer. Despite therapeutic interventions such as tyrosine kinase inhibitors (TKI) that target RTKs, majority of patients develop resistance even after initial tumor regression. Although clinical studies suggest sequential treatments with TKI, chemotherapy, and radiation can eliminate most cancer cells, resistance inevitably emerges (Sequist, et al., Sci Trans Med, 2011). We demonstrated that alterations in the extracellular matrix (ECM) correlate with cancer progression and that RTK signaling is subject to spatiotemporal regulation (Paszek, et al., Cancer Cell, 2005.; Salaita, et al., Science, 2010). Thus, geometric and mechanical properties of the ECM may directly modulate RTK signaling. Here, we use silicone gel substrates that exhibit tunable stiffness in the physiological range (100s Pa - 100s kPa) to measure RTK-adaptor protein interactions in mammary epithelial cells (MECs; MCF10A) (Ou, et al. Integ. Biol., 2016). These gels are compatible with total internal reflection fluorescence (TIRF) imaging and enable single molecule detection of activated RTK phosphotyrosine residues via recruitment of Grb2 tagged with the fluorescent protein mEos3.2. We demonstrate a spectrum of Grb2 behaviors that are determined by the stiffness of the substrate. This indicates that the same receptor is capable of different signaling activities that are dictated by material properties. These new insights create opportunities to target the tumor microenvironment to address RTK inhibitor resistance and metastasis in cancer patients and to develop effective therapeutic strategies for better prognosis and prolonged patient survival. Citation Format: Dhruv Thakar, Shalini T. Low-Nam, Jay T. Groves, Valerie M. Weaver. Tumor micoenvironment modulates RTK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5912. doi:10.1158/1538-7445.AM2017-5912
Abstract 2368: Differential role ofPik3caH1047RandPten-/-mutations in thyroid cancer development
Authors: Michela Ranieri, Antonio Di Cristofano
Journal: Cancer Research (2017)

Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from time of diagnosis. Molecular changes that characterize ATC involve most often p53 loss or inactivation (up to 80%), activation of the PI3K cascade through PTEN loss (12%) and PIK3CA activating mutations (20%) or gene amplification (30-60%), RAS family members activation (6-50%), and BRAF activation (25-50%). Studies performed in endometrial and breast cancer suggest that although PI3K activating mutations and PTEN loss of function both enhance PI3K signaling, these mutations are not equivalent. We have tested whether Pik3caH1047R and Pten-/- mutations have the same impact on thyroid cancer development and if these two mutations differ in their ability to cooperate with additional genetic alterations, such as p53 deletion and the KrasG12D activating mutation. We have generated a series of mouse models and cell lines carrying thyroid-restricted p53-/-, KrasG12D, Pten-/-, and Pik3caH1047R alleles. Analysis of single and compound mutants has revealed important and striking differences between Pten and PI3K abilities to control the PI3K signaling pathway. Tumor development analysis in Pten-/- and Pik3caH1047R mice has revealed that Pik3ca activation is less potent in inducing thyroid hyperplasia and subsequent transformation than Pten loss, even though the two mutations appear to have similar ability to induce AKT activation. This differential activity correlates with lower levels of PIP3 found in the thyroids of Pik3caH1047R mice, compared to that of Pten-/- mice. We also observed that while Pten loss synergizes with Trp53 loss to induce anaplastic thyroid cancer, activation of Pik3ca leads to the development of a smaller and well differentiated tumors. On the other hand, Pten loss and Pik3ca activation are equivalent in inducing poorly differentiated tumors in the presence of a Kras activating mutation. However, KrasG12D, Pik3caH1047R cell lines are more sensitive to PI3K, MEK and combined PI3K/MEK inhibition than KrasG12D, Pten-/- cell lines. Accordingly, tumors developing in mice carrying the KrasG12D, Pik3caH1047R alleles are more sensitive than KrasG12D, Pten-/- mice to a dual PI3K/mTor inhibitor as well as a MEK inhibitor. All together these results suggest that Pten loss has a stronger impact than Pik3ca activation to thyroid cancer development and resistance to small molecule inhibitors. Citation Format: Michela Ranieri, Antonio Di Cristofano. Differential role of Pik3caH1047R and Pten-/- mutations in thyroid cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2368. doi:10.1158/1538-7445.AM2017-2368
Impact of the SPRINT Trial on Hypertension Management
Authors: Lama Ghazi, Suzanne Oparil
Journal: Annual Review of Medicine (2018)

The Systolic Blood Pressure Intervention Trial is the first large prospective randomized controlled trial to demonstrate the benefit of an intensive systolic blood pressure (SBP) treatment target (&lt;120 mm Hg) compared to a standard target (&lt;140 mm Hg) in reducing cardiovascular morbidity and mortality and all-cause mortality in high-risk hypertensive patients. The impact of SPRINT on hypertension treatment has been large, but major questions remain about the feasibility of achieving the SPRINT intensive SBP target in routine practice, the generalizability of the SPRINT findings to hypertensive populations that were excluded from the trial, and the cost effectiveness of adopting the SPRINT intensive treatment goal. In this review, we discuss the generalizability of SPRINT data to the general population of adults with hypertension and with various comorbidities, the cost effectiveness of intensive SBP-lowering therapy, and the implications of SPRINT for future hypertension guideline development and clinical practice.
AB0934 Treatment of lateral epicondylitis with eswt: a sham-controlled double blinded randomised study
Authors: EA Gokmen, O Karatas, E Gilgil
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Lateral epicondylitis is a term describing the clinical condition that causes pain and sensitivity in musculotendinous adhesion sites of the wrist extensor muscles originating from the lateral epicondyle of the humerus, resulting in repetitive stresses due to overuse (1,2). <h3>Objectives</h3> The aim of this study was to investigate the efficiency of extracorporeal shockwave therapy (ESWT) in the treatment of lateral epicondylitis as randomized, prospective, controlled and double blind. <h3>Methods</h3> 47 patients (35 women, 12 men) with lateral epicondylitis were included in the study. The mean age of patients was 45.94±10.46 years. Patients were randomized into two groups: active ESWT (n=22) and <i>sham</i> ESWT (n=25). Patients were randomly allocated to receive 1 session per week for 3 weeks of either sham or active ESWT. Patients were evaluated before the treatment, and at the end of the first week, first month and third month after the last treatment session with Patient-rated Tennis Elbow Evaluation Questionnaire (PRTEE), Visual Analogue Scale (VAS) for pain assessment and physical examination of lateral epicondyle of the elbow with special clinical tests. <h3>Results</h3> Compared with pretreatment values in ESWT group, significant improvement was observed in all parameters after treatment. At the first week after the therapy significant improvement was observed in <i>sham</i> group but at the first and third month after the therapy no significant difference was found. In comparison of ESWT and <i>sham</i> over 3 months after the treatment, significant improvements were observed in ESWT group in all parameters. <h3>Conclusions</h3> there was a significant decrease in pain and a significant improvement in function following ESWT. Although there was a reduction in pain and improvement in function with sham treatment as well, this difference was not as significant as in active group. <h3>References</h3> Murrey PM, Ön Kol ve Dirsek. In: Weinstein SL, Buckwalter JA, Alpaslan M (Ç. Ed). Turek Ortopedi İlkeler ve Uygulamaları. Ankara, Güneş 2009; 401–15. Cordasco FA, Parkes JC II. Overuse Injuries of the Elbow. In: Nicholas JA, Hershman EB. The Upper Extremity In Sports Medicine. Missouri, Mosby-Year Book 1995; 317–30. <h3>Disclosure of Interest</h3> None declared
Baseline Factors Affecting Changes in Diabetic Retinopathy Severity Scale Score After Intravitreal Aflibercept or Laser for Diabetic Macular Edema
Authors: Dilsher S. Dhoot, Keith Baker, Namrata Saroj, Robert Vitti, Alyson J. Berliner, Carola Metzig, Desmond Thompson, Rishi P. Singh
Journal: Ophthalmology (2017)
Abstract 5746: TRAF1 is required for solar UV-induced skin carcinogenesis
Authors: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Naomi Oi, Ruihua Bai, Tatyana A. Zykova, Dong Hoon Yu, Margarita Malakhova, Kenji Moriyama, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2017)

Abstract Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a member of the TRAF protein family, which regulates the canonical and non-canonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors is reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for skin carcinogenesis induced by chronic solar UV radiation. In vivo studies with solar UV exposure indicate that the deletion of TRAF1 results in the inhibition of AP-1 activity by down-regulating the induction of c-Fos and c-Jun by regulating ERK5 activity. Furthermore, we show that TRAF1 is required for solar UV-induced ERK5 activation. Mechanistic studies revealed that TRAF1 expression enhances the ubiquitination of ERK5 on K184, which is necessary for AP-1 activation. Altogether, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating skin cancer. Citation Format: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Naomi Oi, Ruihua Bai, Tatyana A. Zykova, Dong Hoon Yu, Margarita Malakhova, Kenji Moriyama, Ann M. Bode, Zigang Dong. TRAF1 is required for solar UV-induced skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5746. doi:10.1158/1538-7445.AM2017-5746
Abstract 3056: Genetic deletion of insulin-like growth factor binding protein-7 (IGFBP7) promotes hepatocellular carcinoma (HCC): a novel role of IGFBP7 in regulating antitumor immune surveillance
Authors: Maaged A. Akiel, Chunqing Guo, Xia Li, Devaraja Rajasekaran, Rachel G. Mendoza, Nidhi H. Jariwala, Chadia L. Robertson, Mark A. Subler, Jolene J. Windle, Paul B. Fisher, Devanand Sarkar
Journal: Cancer Research (2017)

Abstract In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/-) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross-presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response. Citation Format: Maaged A. Akiel, Chunqing Guo, Xia Li, Devaraja Rajasekaran, Rachel G. Mendoza, Nidhi H. Jariwala, Chadia L. Robertson, Mark A. Subler, Jolene J. Windle, Paul B. Fisher, Devanand Sarkar. Genetic deletion of insulin-like growth factor binding protein-7 (IGFBP7) promotes hepatocellular carcinoma (HCC): a novel role of IGFBP7 in regulating antitumor immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3056. doi:10.1158/1538-7445.AM2017-3056
Abstract 910: Phloridzin docosahexaenoate (PZ-DHA) inhibits breast cancer cell invasion and angiogenesis
Authors: Wasundara Fernando, Emma MacLean, Krysta Coyle, Paola Marcato, David W. Hoskin, H. P. Vasantha Rupasinghe
Journal: Cancer Research (2017)

Abstract In our previous studies, we showed the selective cytotoxicity, in vitro anti-proliferative and anti-metastatic activities of phloridzin docosahexaenoate (PZ-DHA). PZ-DHA combines phloridzin (PZ), a dihydrochalcone found in apple peels, and docosahexaenoic acid (DHA), an ω-3 fatty acid found in fish oil, through an acylation reaction. Significant suppression of tumor growth resulted from the intratumoral administration of PZ-DHA to non-obese diabetic severe combined immunodeficient (NOD-SCID) female mice xenografted with MDA-MB-231 breast cancer cells. Examination of haematoxylin and eosin-stained tumor sections confirmed that PZ-DHA caused tumor cell death. PZ-DHA also suppressed the invasion of MDA-MB-231 cells through membranes coated with extra cellular matrix proteins, fibronectin and gelatin, in a Boyden chamber assay. The effect of PZ-DHA on the mRNA transcription of the gelatinase, matrix metalloproteinase-2 (MMP-2,) was measured in RT-qPCR analysis, which showed that MMP-2 mRNA expression was inhibited at 12 h and 24 h following PZ-DHA treatments. Furthermore, suppression of MMP-2 protein expression was shown by western blot analysis of cell lysates of PZ-DHA-treated MDA-MB-231 cells. Intraperitoneal administration of PZ-DHA suppressed the growth of primary tumors and metastasis of 4T1 and green fluorescence protein (GFP)-tagged-MDA-MB-231 cells to lungs of BALB/c and NOD-SCID female mice, respectively. Anti-angiogenic activity of PZ-DHA was investigated using human umbilical vein endothelial cells (HUVECs). PZ-DHA suppressed the metabolic activity of HUVECs in MTS assays and the cell death was confirmed using flow cytometric analysis of 7-AAD and Annexin-V-FLUOS/propidium iodide-stained HUVECs. Anti-proliferative activity of PZ-DHA was shown using Oregon Green 488 stained-HUVECs by flow cytometry. PZ-DHA treatment arrested the HUVEC cell cycle at S-phase. PZ-DHA also suppressed the migration of HUVECs in a gap closure assay and inhibited HUVEC tubule formation on a matrigel matrix. For comparison purposes, PZ and DHA were included in all experiments, but in all cases were less effective than PZ-DHA. Taken together, these findings reveal the potential of PZ-DHA to inhibit triple-negative breast cancer progression. We are currently working on identifying potential phase I and II metabolites of PZ-DHA and understanding its pharmacokinetic parameters. Citation Format: Wasundara Fernando, Emma MacLean, Krysta Coyle, Paola Marcato, David W. Hoskin, H. P. Vasantha Rupasinghe. Phloridzin docosahexaenoate (PZ-DHA) inhibits breast cancer cell invasion and angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2017-910
Abstract 29: Addition of Galunisertib to DC101 increased angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC)
Authors: Annemilai Tijeras-Raballand, Christian Hobeika, Elise Payen, Matthieu Martinet, Philippe Bonnin, Karim A. Benhadji, Clarisse Eveno, Marc Pocard, Sandrine Faivre, Eric Raymond, Armand de Gramont
Journal: Cancer Research (2017)

Abstract Introduction: Galunisertib is a selective ATP-mimetic TGF-β receptor (TGFβR)-I inhibitor and DC101 is a rat antagonist antibody to mouse VEGFR-2 and is used to model VEGFR-2 blockade in murine tumor models. Ramucirumab and galunisertib being independently under clinical investigation in HCC patients, our study aimed at exploring the anti-tumoral potency of a combination of galunisertib and DC101 in an in vivo transgenic model of HCC. Methods: Transgenic mice developing stage-defined HCC were treated for 8 weeks (W) from W8 to W16 with either vehicle, DC101 (40mg/kg, twice weekly, IP), galunisertib (100mg/kg, daily, oral gavage) or DC101 plus galunisertib. Tumor growth was evaluated by ultrasound (liver size) and by the number of macronodules at sacrifice. Angiogenesis was evaluated by doppler (blood flow in the coeliac trunk) and by CD31 staining. Results: Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to placebo control at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of galunisertib and DC101 showing increased tumor control at W16 (4,43±0,55 mean liver volume (in mm3) in the combination arm vs 5,22±0,86, 5,68±0,78, 7,09±1,54 in the DC101, galunisertib and placebo arms respectively). Angiogenesis assessed by measuring the mean blood flow in the coeliac trunk (TCm), decreased in all treatment arms compared to placebo. At W16, galunisetib potentiated the effect of DC101 with a TCm decrease of 66% compared to 59% and 10% in the DC101 and galunisertib, respectively. These results will be confirmed by the assessment of micronodules number on HPS section for tumor growth and CD31 staining for angiogenesis analysis (number of vessels and the vessel lumen area). The effects of the combination versus monotherapies will be evaluated on the immune landscape. Conclusion: The combination of galunisertib and DC101 showed promising anti-tumor activities that were associated with decreased angiogenesis. Citation Format: Annemilai Tijeras-Raballand, Christian Hobeika, Elise Payen, Matthieu Martinet, Philippe Bonnin, Karim A. Benhadji, Clarisse Eveno, Marc Pocard, Sandrine Faivre, Eric Raymond, Armand de Gramont. Addition of Galunisertib to DC101 increased angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 29. doi:10.1158/1538-7445.AM2017-29
Abstract 5441: Circulating exosomal microRNA-203 and microRNA-373 as non-invasive biomarkers for predicting prognosis and metastasis in human hepatocellular carcinoma
Authors: Gyeonghwa Kim, Eunhye Lee, Se Young Jang, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur
Journal: Cancer Research (2017)

Abstract Background and Aim Hepatocellular carcinoma (HCC) is the fifth most common cancer and the most leading cause of cancer-related death worldwide. Although considerable progress has been made in treatment of HCC, early detection is still highly considered the key to improved survival. Thus, for the earlier diagnosis and accurate prediction of HCC, identification of non-invasive molecular biomarkers for HCC patients is an imperative need. Recently, cancer cell-derived extracellular vesicles (EVs) have been known to contain various intracellular biomolecules including microRNAs (miRNAs). The aim of this study was to evaluate whether exosomal miRNAs can serve as a serum-based biomarker in HCC. Materials and Methods We isolated exosome from serum samples from HCC patients as well as normal healthy controls using ultracentrifugation, and it was confirmed by expression of exosome markers (CD9, CD63, ALIX, and TSG101) based on immunoblotting. Next, the expression of 6 miRNAs (miRNA-24, -130a, -182, -203, -373, and -423) was analyzed in the exosome samples. We also investigated expression status of the 6 miRNAs in matched HCC tissues and corresponding normal liver tissues. MiRNAs expression was determined by quantitative real-time PCR (qRT-PCR), and miRNAs expression was normalized relative to cel-miR-39 and RNU6B expression for serum and tissue samples, respectively. Results We successfully purified exosome from serum clinical samples and detected miRNAs in the exosome. We observed that a subset of miRNAs from serum exosome, including miRNA-24, -130a, -182, -203, and -373 were enhanced in HCC patients than normal healthy controls. In further comparison between early stage and advanced stage of HCC patients, serum exosomal miRNA-203 (P&amp;lt;0.05) and miRNA-373 (P&amp;lt;0.05) were significantly up-regulated in advanced HCC patients. While no significant changes in the expression of other serum exosomal miRNAs (miRNA-24, -130a, -182, and -423) according to HCC progression. More interestingly, high serum exosomal miRNA-203 and miRNA-373 was associated with HCC progression (P&amp;lt;0.01) as well as prognosis (P&amp;lt;0.05) of HCC patients. Conclusions We provided the novel evidence for usefulness of serum circulating exosomal miR-203 and miR-373 expressions as strong potential biomarkers for predicting prognosis and metastasis of HCC patients. Citation Format: Gyeonghwa Kim, Eunhye Lee, Se Young Jang, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur. Circulating exosomal microRNA-203 and microRNA-373 as non-invasive biomarkers for predicting prognosis and metastasis in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5441. doi:10.1158/1538-7445.AM2017-5441