tbuckley/cabot-search huggingface dataset:
Abstract 62: Sildenafil Inhibits Neointimal Hyperplasia After Angioplasty, and Reduces Platelet Aggregation
Authors: Han Mo Yang, Sooryeonhwa Jin, Hyo-Soo Kim, Sahmin Lee
Journal: Circulation Research (2017)

Background: Restenosis and stent thrombosis after stent implantation are one of the devating issues in interventional cardiology. Sildenafil has shown its effect in reducing cardiac hypertrophy as well as improving erectile dysfunction through protein kinase G (PKG) activation. Some studies have demonstrated that PKG occupies a central switching role in modulating vascular smooth muscle cell (VSMC) phenotype in response to vascular injury. In this study, we investigated the effects of PKG activation by sidenafil on platelet aggregation and neointimal hyperplasia. Methods and Results: In terms of restenosis after vascular injury, sildenafil significantly reduced neointimal hyperplasia in rat carotid arteries compared to control group. This effect of sildenafil was accompanied by the reduction of viability, cell cycle progression, and migration of VSMCs. This was also confirmed in the injured arteries in vivo. Further studies showed that the increased PKG activity by sildenafil inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-negative PKG reversed the effects of sildenafil, resulting in the increased viability of VSMCs and neointimal formation. In addition, the mice treated with sidenafil showed the facilitated re-endothelialization, compared to control group. Furthermore, we confirmed the effect of sidenafil through PKG activation using cGK-KO mice. Interestingly, sildenafil significantly inhibited platelet aggregation induced by ADP or thrombin. This effect was reversed by PKG inhibitor, suggesting that sildenafil inhibits platelet aggregation via PKG pathway. Furthermore, assays for VASP phosphorylation and P-selectin activation showed the same inhibitory effect of sildenafil on platelet activation. Conclusions: This study showed that sildenafil inhibits not only platelet aggregation, but also neointimal hyperplasia through the PKG pathway. These findings suggest that sildenafil could be a promising candidate drug of drug-eluting stents for the prevention of restenosis without other complications such as stent thrombosis.
Abstract 18363: ApoA-I Suppresses Neointimal Hyperplasia Following Stent Deployment and Modulates Neointimal Cellular Phenotype
Authors: LauraVanags, JoanneTan, StevenWise, ZiadAli, ChristinaBursill
Journal: Circulation (2014)

Background: Increases in smooth muscle cell (SMC) cholesterol content reduce the expression of SMC phenotypic markers and increase macrophage related markers. The balance of neointimal SMCs to macrophage-like cells may influence neointimal hyperplasia following stent deployment. Apolipoprotein (apo) A-I, the main protein component of high-density lipoproteins (HDL), mediates the efflux of cholesterol from cells via the cholesterol transporter ABCA1. In a murine model of balloon angioplasty and stenting, we aimed to investigate the effect of apoA-I on neointimal hyperplasia and neointimal cellular phenotype. Methods and Results: Thoracic aortic segments from apoE knockout mice underwent balloon angioplasty alone or balloon angioplasty with stenting then were carotid-interposition grafted into recipient mice. Mice received PBS or apoA-I (40mg/kg) injections on alternate days in the week prior to surgery and then until sacrifice (28 days). There were no changes in total cholesterol, LDL and HDL between group...
Abstract 1330: Role of epigenetic remodeling in sensitizing triple-negative breast cancer cells to treatment through enhanced chemotherapy-induced autophagy
Authors: Liliya Tyutyunyk, Joseph Landry, David Gewirtz, Nga Dao
Journal: Cancer Research (2018)

Abstract Dysregulation of the epigenome is implicated in initiation and progression of variety of cancers and their acquired resistance to chemotherapy. As such targeting epigenetic regulators has the potential to modulate cancer cell biology and their sensitivity to chemotherapy and/or radiation. Our studies demonstrates that silencing of the epigenetic regulator Nucleosome Remodeling Factor (NURF) sensitizes breast tumor cells to chemotherapy and enhances the anti-tumor immune response. A screen of a variety of chemotherapeutic agents shows that NURF KD cells are selectively sensitized to Topo II inhibitors, which includes doxorubicin. NURF KD increases DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in breast tumor cells exposed to doxorubicin (Dox) and enhances growth inhibition as well as suppressing the ability of the cells to recover proliferative capacity. Increased autophagy as well as breast tumor sensitization to doxorubicin were observed using a small molecule inhibitor of NURF, suggesting that NURF can also be targeted pharmacologically. Our studies suggest that enhanced autophagy may be a primary contributor to chemo sensitivity in NURF KD cells. Studies are currently underway to confirm the role of autophagy in chemosensitization in- vitro and enhanced immune response in-vivo using autophagy deficient cells (through ATG silencing). Doxorubicin produces profound DNA damage and promotes immunogenic cell death enhanced by NURF KD. Increased cell autonomous antitumor effects by doxorubicin in concert with increased cell non-autonomous antigenicity could help to achieve tumor regression, reduce metastasis, and possibly promote long term remission in breast cancer. Citation Format: Liliya Tyutyunyk, Joseph Landry, David Gewirtz, Nga Dao. Role of epigenetic remodeling in sensitizing triple-negative breast cancer cells to treatment through enhanced chemotherapy-induced autophagy [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 1330.
Comparison of Ascending Aorta Versus Femoral Artery Cannulation for Acute Aortic Dissection Type A
Authors: HiroyukiKamiya, KlausKallenbach, DominiqueHalmer, MerveÖzsöz, KathrinIlg, ArturLichtenberg, MatthiasKarck
Journal: Circulation (2009)

Background— The site of cannulation for repair of ascending aortic dissection remains controversial. We present our experience with ascending aortic cannulation for acute aortic dissection type A. Methods and Results— From January 1988 to September 2007, we operated on 242 patients for acute aortic dissection type A. Medical records of 235 patients who received ascending aortic cannulation or femoral cannulation were retrospectively reviewed. Long-term follow-up was complete in 97% of patients. Cannulation was accomplished in 82 patients through the ascending aorta and in 153 patients through the femoral artery. Preoperative patient characteristics were almost comparable between groups. Similarly, there were no differences in preoperative patient characteristics and intraoperative parameters including operation time, bypass time, cross-clamp time, hypothermic circulatory arrest time, and percentage of total arch replacement. The 30-day mortality rate was 14% in the aortic group and 23% in the femoral grou...
Suppression of Acute and Chronic Rejection by Hepatocyte Growth Factor in a Murine Model of Cardiac Transplantation
Authors: KazuhiroYamaura, Ken-ichiIto, KatsuakiTsukioka, YukoWada, AkikoMakiuchi, MasayukiSakaguchi, TomohiroAkashima, MinoruFujimori, YoshikiSawa, RyuichiMorishita, KunioMatsumoto, ToshikazuNakamura, Jun-ichiSuzuki, JunAmano, MitsuakiIsobe
Journal: Circulation (2004)

Background— Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation. Methods and Results— We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 μg · kg−1 · d−1 HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3±4.1 days, P<0.001) compared with the controls (11.1±0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF t...
Abstract 3044: Label-free detection and identification of cancer-associated vesicles in human breast cancer
Authors: Sixian You, Yi Sun, Haohua Tu, Ronit Barkalifa, Eric J. Chaney, Marina Marjanovic, Anna M. Higham, Natasha N. Luckey, Kimberly A. Cradock, Z. George Liu, Stephen A. Boppart
Journal: Cancer Research (2018)

Abstract Detection and identification of cancer-associated vesicles in their native tissue environment is essential to understand vesicle-mediated communication in cancer progression and potentially facilitate the treatment and management of cancer. Here we develop a label-free optical imaging method that can reliably detect cancer-associated vesicles in vitro, in vivo and in untreated human tissue ex vivo. Preliminary analysis conducted on fresh human breast tissue obtained from healthy and cancer subjects showed that a significant portion of vesicles from the cancer subjects have unique optical signatures in comparison with those from healthy subjects. Additionally, the spatial distribution of these vesicles with unique optical signatures in the tumor micro- and macro-environment appeared correlated with the staging of human breast cancer. These results suggest the potential capability of this methodology to identify and characterize the tumor associated vesicles in the authentic tumor microenvironment, which could open new windows in the explorations of their diagnostic values and physiological roles in cancer progression. Citation Format: Sixian You, Yi Sun, Haohua Tu, Ronit Barkalifa, Eric J. Chaney, Marina Marjanovic, Anna M. Higham, Natasha N. Luckey, Kimberly A. Cradock, Z. George Liu, Stephen A. Boppart. Label-free detection and identification of cancer-associated vesicles in human 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 3044.
Abstract 3437: Genomic alterations, mutation burden, and microsatellite instability status of Chinese intrahepatic cholangiocarcinoma
Authors: Jingyu Cao, Bo Jiang, Zimin Liu, Weibin Shu, Lei Li, Han Yang, Hua Li, Zhiyu Xiao, Maolin Yan, Jie Lin, Siqin Liu, Peng Zhang, Milind Javle, Ming Yao, Kai Wang, Haitao Zhao
Journal: Cancer Research (2018)

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. Targeted and immune-therapy have yielded promising therapeutic effects in various solid tumor patients (pts). Thus the understanding of ICC genomic profiling, especially which of Chinese pts, seems to be necessary for the treatment strategy for ICC. Methods: Comprehensive genomic profiling of molecular alterations and predictive biomarkers to personalized treatment genes were performed on Formalin Fixed Paraffin Embedded (FFPE) samples and matched blood samples of 69 Chinese ICC pts. Genomic alterations (GAs) including substitutions, short and long insertion/deletions (indels), copy number variations and gene rearrangements were assessed. Tumor mutation burden (TMB) of total somatic substitutions and indels per megabase after filtering known driver mutations was calculated. Microsatellite instability (MSI) status was determined by identifying and scoring multiple mono-nucleotide repeats loci. Results: Median age of the 69 ICC pts was 58 years (range: 38-88), and male vs female was approximately 3:1. Average of 3.7 GAs /sample and 0.9 actionable GAs/sample were detected. The most widespread genomic alterations among the pts were revealed as TP53 (44.9%), ARIDIA (23.2%), KRAS (18.8%), BAP1 (14.5%), IDH1/2 (14.5%), PIK3CA (11.6%), FGFR2/3 (10.1%), MLC1 (8.7%), CDKN2A/B (8.7%), BRAF (7.2%), TERT (7.2%), PBRM1 (7.2%). The actionable mutations of the PI3K/mTOR pathway were found in 18.8% of the pts. In total, pts with one or more actionable GAs were 62.3%. Pts presented MSI-high were 7.2% of the total. Proportion was 10.1% for the pts with TMB value higher than 20 mut/Mb, and 32.8% for those higher than 10 mut/Mb. The TMB range of the 69 pts was 1.1 to 58.4 mut/Mb, and median was 7.4 mut/Mb. Conclusions: In our study, 62.3% of Chinese ICC pts were detected to have actionable GAs which could potentially guide and influence their personalized treatments. The identification of more frequent high TMB level than the published western populations indicated that Chinese ICC pts may more likely derive therapeutic benefits from immune checkpoint inhibitors. Citation Format: Jingyu Cao, Bo Jiang, Zimin Liu, Weibin Shu, Lei Li, Han Yang, Hua Li, Zhiyu Xiao, Maolin Yan, Jie Lin, Siqin Liu, Peng Zhang, Milind Javle, Ming Yao, Kai Wang, Haitao Zhao. Genomic alterations, mutation burden, and microsatellite instability status of Chinese intrahepatic cholangiocarcinoma [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 3437.
Reconstituted High-Density Lipoprotein Inhibits Thrombin-Induced Endothelial Tissue Factor Expression Through Inhibition of RhoA and Stimulation of Phosphatidylinositol 3-Kinase but not Akt/Endothelial Nitric Oxide Synthase
Authors: HemaViswambharan, Xiu-FenMing, ShengsiZhu, AlphonseHubsch, PeterLerch, GuyVergères, SandroRusconi, ZhihongYang
Journal: Circulation Research (2004)

Endothelial cells express negligible amounts of tissue factor (TF) that can be induced by thrombin, which is important for acute coronary syndromes. Recent research suggests that endothelial TF expression is positively regulated by RhoA and p38mapk, but negatively by Akt/endothelial nitric oxide synthase (eNOS) pathway. High-density lipoprotein (HDL) is atheroprotective and exerts antiatherothrombotic effect. This study investigated the effect of a reconstituted HDL (rHDL) on endothelial TF expression induced by thrombin and the underlying mechanisms. In cultured human umbilical vein and aortic endothelial cells, thrombin (4 U/mL, 4 hours) increased TF protein level, which was reduced by rHDL (0.1 mg/mL, 43% inhibition, n=3 to 7, P<0.01). Activation of RhoA but not p38mapk by thrombin was prevented by rHDL. rHDL stimulated Akt/eNOS pathway. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 abolished the activation of Akt/eNOS and reversed the inhibitory effect of rHDL on TF expres...
Abstract 5242: NFĸB pathway activation is a key determinant of tamoxifen tolerance and recurrence in breast cancer
Authors: Irida Kastrati, Svitlana D. Brovkovych, Joshua D. Stender, Elaine T. Alarid, Jonna Frasor
Journal: Cancer Research (2018)

Abstract Nearly 75% of breast tumors express estrogen receptor (ER) and will be treated with endocrine therapies, such as tamoxifen or aromatase inhibitors. Despite their proven success, it is estimated that up to 50% of tumors fail on endocrine therapy and recur as aggressive therapy-resistant tumors. Therefore, preventing recurrence remains a major clinical problem. One hypothesis is that recurrences are driven by cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease that consists of drug-tolerant cells capable of surviving by entering a state of negligible growth. In trying to model tamoxifen tolerance and minimal residual disease in vitro, we have utilized the clonogenic assay where ER+ breast cancer cells' clonal growth and survival in the presence of tamoxifen is examined. Tamoxifen-tolerant cells show activation of the pro-inflammatory NFĸB pathway measured by an NFĸB-reporter, elevated expression of bona-fide target genes, and enhanced nuclear localization of p65 and p50, two major transcription factors of the NFĸB pathway. Tamoxifen does not directly activate the NFĸB pathway, but rather cells with high NFĸB activity proliferate independently of tamoxifen despite retaining ER expression. Mechanistically, NFĸB-dependent ER phosphorylation at S305 residue may contribute to failure to respond to tamoxifen. More importantly blocking NFĸB with multiple NFĸB inhibitors is sufficient to eradicate this population of tamoxifen-tolerant cells, suggesting NFĸB is required and can be exploited for therapy. We find that dimethyl fumarate, an FDA-approved anti-inflammatory and immune-modulatory drug, which we have established as an effective NFĸB inhibitor in breast cancer cells, prevents recurrence modeled both in vitro and in vivo. Altogether this work shows a novel role for the NFĸB pathway in promoting a population of cells that are tamoxifen tolerant and capable of seeding recurrent breast cancer disease. Furthermore, therapeutic targeting by an NFĸB inhibitor such as dimethyl fumarate can be used to eradicate residual disease and prevent breast cancer recurrence. Citation Format: Irida Kastrati, Svitlana D. Brovkovych, Joshua D. Stender, Elaine T. Alarid, Jonna Frasor. NFĸB pathway activation is a key determinant of tamoxifen tolerance and recurrence in 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 5242.
Abstract 3534: Protein acylation mediates encapsulation of Src kinase into exosomes
Authors: Ru Wen, Qianjin Li, Sungjin Kim, Yongjie Ma, Jin Xie, Houjian Cai
Journal: Cancer Research (2018)

Abstract Exosomes are nanosized vesicles (30-150 nm) secreted from almost all cell types (1). Exosomes play important roles in cell-cell communication through the transfer of exosomal proteins, mRNA, and microRNAs, mediating immune escape and promoting tumor progression (2,3). However, it remains unclear how oncogenic proteins are selectively disseminated through exosomes. Myristoylation is lipid modification of protein involved in the attachment of N-terminal glycine of proteins with a myristoyl group. It is critical for various biologic functions including cell signaling, protein localization, and cell-cell communication (4). In this study, we evaluated the role of protein acylation for the encapsulation of Src family kinases in exosomes. Myristoylation promotes the enrichment of Src kinase in exosomes whereas palmitoylation inhibits the encapsulation process. Additionally, phosphorylated Src protein was more favored to be capsulated in exosomes. Mechanistically, knockdown of TSG101 decreased expression levels of Src kinase in exosomes, indicating that Src encapsulation into exosomes is associated with endosomal sorting complexes required for transport (ESCRT). Finally, Src kinase can be translocated to normal cells via exosomes cargo to induce pathologic signaling. These results provide new insights of Src kinase encapsulation mechanism into exosomes, and therapeutic approaches for inhibiting the transfer of oncogenic proteins through targeting protein myristoylation process. References: 1. Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009;21(4):575-81. 2. Skog J et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biol 2008;10(12):1470-6. 3. Abusamra AJ et al. Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 2005;35(2):169-73. 4. Casey PJ. Protein lipidation in cell signaling. Science 1995;268(5208):221. Citation Format: Ru Wen, Qianjin Li, Sungjin Kim, Yongjie Ma, Jin Xie, Houjian Cai. Protein acylation mediates encapsulation of Src kinase into exosomes [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 3534.
Abstract A02: Investigating the contribution of RAD51 paralog mutations to cancer development
Authors: Robert A. Baldock, Catherine A. Pressimone, Kara A. Bernstein
Journal: Clinical Cancer Research (2018)

Abstract Homologous recombination (HR) is a high-fidelity DNA repair mechanism that utilizes a homologous template to repair double-strand breaks (DSBs). The defining step of HR is the formation of a RAD51 nucleoprotein filament, which performs the homology search and strand invasion steps. RAD51 filament formation is aided by the RAD51 paralogs, which structurally resemble RAD51. The RAD51 paralogs form sub-complexes including CX3 (RAD51C and XRCC3) and BCDX2 (RAD51B, RAD51C, RAD51D, and XRCC2). Here we use a use a Yeast 3-hybrid assay to determine which patient-identified mutations in RAD51D impair the interaction with RAD51C and XRCC2. We further validate this interaction data in mammalian cells. Lastly, we are going to complement RAD51D and XRCC2-depleted cells with mutant versions of the proteins to determine their impact on HR as well as sensitivity to specific chemotherapeutic agents. Citation Format: Robert A. Baldock, Catherine A. Pressimone, Kara A. Bernstein. Investigating the contribution of RAD51 paralog mutations to cancer development. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A02.
Abstract 725: Targeting the skin microenvironment for effective cancer vaccines
Authors: Jack R. You, Rong Hao, Louis D. Falo, Guo Chen, Xingxing Hao, Cara Carey, Zhaoyang You, Louis D. Falo
Journal: Cancer Research (2018)

Abstract Skin, the most accessible organ, harbors keratinocytes and immunocytes that contribute to both innate and adaptive immunity, rendering it an ideal anatomic target for immunization. Keratinocytes can drive skin inflammation by producing pro-inflammatory mediators that promote cutaneous immune responses. Thus, targeting accessible keratinocytes to express transgenic antigens and increase production of pro-inflammatory mediators is a salient and attractive approach to vaccination, but remains a critical challenge to achieve. Toward this goal, we evaluated the effects of transient overexpression of the stress response factor x-box binding protein 1 (XBP1) in keratinocytes on the skin microenvironment. In vitro, keratinocytes genetically engineered to overexpress XBP1 increased production of both co-transduced exogenous antigen and pro-inflammatory mediators. In vivo, overexpression of XBP1 and transgenic antigen in keratinocytes induced both protective and therapeutic antitumor immunity that was associated with enhanced cutaneous expression of pro-inflammatory mediators and co-delivered antigen, increased skin-infiltrating immunocytes including dendritic cells (DCs), and the induction of durable antigen-specific CD8+ T cells and skin-resident memory CD8+ T cells. Importantly, in human skin, correlative effects were observed: transient overexpression of XBP1 in skin triggered the expression of genes linked to a pro-immunogenic microenvironment, increased the expression of the co-delivered antigen, and promoted the activation and IFN-γ-producing T cell-stimulating function of skin DCs. These findings provide novel insights into the rational design of cancer vaccines with improved immunogenicity through strategic modulation of the skin microenvironment. Citation Format: Jack R. You, Rong Hao, Louis D. Falo, Guo Chen, Xingxing Hao, Cara Carey, Zhaoyang You, Louis D. Falo. Targeting the skin microenvironment for effective cancer vaccines [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 725.