tbuckley/cabot-search huggingface dataset:
Abstract 17348: Necrostatin 7 Limits Myocardial Infarct Size and Reduces Cardiac Remodeling After Permanent Coronary Occlusion in Rats
Authors: YuriDmitriev, SarkisMinasian, AnnaDracheva, AndreyKarpov, SvetlanaChefu, ElenaDemchenko, MichaelGalagudza
Journal: Circulation (2014)

Background: Reduction of irreversible myocardial ischemia-reperfusion injury (IRI) remains important. One of the promising strategies aimed at myocardial IRI alleviation is modulation of programmed cell death (PCD) pathways. PCD mode displaying morphological characteristics of necrosis, and amenable to pharmacological manipulation is referred to as necroptosis. Necroptosis inhibitor necrostatin-1 has been shown to exert cardio- and neuroprotective effects. In the present work, the effect of necrostatin-7 (Nec-7) on myocardial injury in the rat model of permanent coronary occlusion was studied. Methods: Male Wistar rats (n = 19) were anesthetized with pentobarbital. The animals were subjected to permanent coronary occlusion (PCO) and intraperitoneal (i.p.) Nec-7 administration 1 h prior to PCO at a dose of 14.5 mg/kg in dimethyl sulfoxide (DMSO) or DMSO alone at a dose of 3.1 g/kg. Control rats were treated with saline. Three weeks after PCO, serum levels of NT-proBNP were measured, and histological outcom...
Abstract 3763: IDO vaccine enhances antigen-specific anti-tumor effects by reducing IDO-expressing antigen presenting cells and MDSCs
Authors: Rahul Nandre, Vivek Verma, Pankaj Gaur, Pooja Vir, Hua Wang, Baolin Kang, Ayako Wakatsuki Pedersen, Mai-Britt Zocca, Mads Hald Andersen, Seema Gupta, Samir Khleif
Journal: Cancer Research (2018)

Abstract Tumors evade immune surveillance using several mechanisms such as induction of regulatory T-cells (Tregs) and upregulation of indolemine-2,3-dioxygenase (IDO) enzyme. IDO is an intracellular enzyme that mediates its immunosuppressive effects by depleting tryptophan leading to accumulation of kynurenine and in turn reducing the proliferation of effector cells while activating Tregs. IDO is expressed by several suppressive immune cells including Tregs, suppressive antigen presenting cells (APCs), as well as by tumor cells. These immunosuppressive effects of IDO make it an attractive target for cancer immunotherapy, including a target for vaccine therapy. To test the anti-tumor immune effect of IDO vaccine, we evaluated the anti-tumor effect of an IDO-derived MHC I restricted peptide (IDO-pep) vaccine in the low IDO-expressing (TC-1) and high IDO-expressing B16 (melanoma) mouse tumor models. For this, mice were treated with three doses of IDO-peptides in combination with the respective tumor-specific vaccines (E7 for TC-1 and gp100 for B16) at an interval of seven days, followed by assessment of tumor growth and mice survival. We observed a significant delay in the tumor growth and prolonged survival in both tumor models when IDO vaccine was combined with tumor-specific antigen vaccine. We found that tumor-infiltration of antigen-specific CD8+ T-cells was significantly enhanced following the addition of IDO vaccine. Furthermore, while CD4+ T-cells increased in the tumor microenvironment (TME), there was a significant reduction in the numbers of Treg cells. We also found a significant reduction in the numbers of IDO-expressing myeloid-derived suppressor cells (MDSCs), dendritic cells as well as macrophages out of the total CD45+CD11b+ myeloid cells in the TME after the administration of IDO-pep in combination with tumor antigen-specific vaccine. In conclusion, our findings suggest that IDO-pep vaccine enhances the specific anti-tumor immune response by increasing the tumor antigen-specific effector T-cell infiltration in the TME through inhibition of immune suppressive cells. These results also suggest that MHC I restricted IDO peptide treatment is a promising strategy to improve cancer immunotherapy. Citation Format: Rahul Nandre, Vivek Verma, Pankaj Gaur, Pooja Vir, Hua Wang, Baolin Kang, Ayako Wakatsuki Pedersen, Mai-Britt Zocca, Mads Hald Andersen, Seema Gupta, Samir Khleif. IDO vaccine enhances antigen-specific anti-tumor effects by reducing IDO-expressing antigen presenting cells and MDSCs [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 3763.
Improvement of Impaired Myocardial Vasodilatation Due to Diffuse Coronary Atherosclerosis in Hypercholesterolemics After Lipid-Lowering Therapy
Authors: IkuoYokoyama, Shin-ichiMomomura, TohruOhtake, KatsunoriYonekura, WeidongYang, NaoshiKobayakawa, TeruhikoAoyagi, SeiryoSugiura, NobuhiroYamada, KuniOhtomo, YasuhitoSasaki, MasaoOmata, YoshioYazaki
Journal: Circulation (1999)

Background—Diminished myocardial vasodilatation (MVD) in hypercholesterolemics without overt coronary stenosis has been reported. However, whether the diminished MVD of angiographically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy is not known. Methods and Results—A total of 27 hypercholesterolemics and 16 age-matched controls were studied. All patients had >1 normal coronary artery, and those segments that were perfused by anatomically normal coronary arteries were studied. Myocardial blood flow (MBF) was measured during dipyridamole loading and at baseline using positron emission tomography and 13N-ammonia, after which MVD was calculated before and after lipid-lowering therapy. Total cholesterol was significantly higher in hypercholesterolemics (263±33.8) than in controls (195±16.6), and it normalized after lipid-lowering therapy (197±19.9). Baseline MBF (ml · min−1 · 100 g−1) was comparable among hypercholesterolemics (both before and after therapy) and...
Abstract 2510: Clinicopathologic significance of fibroblast growth factor 2 type IIIb and type IIIc in gastric cancer
Authors: Kenji Kuroda, Masakazu Yashiro, Go Masuda, Yuichiro Miki, Tomohisa Okuno, Shingo Togano, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2018)

Abstract [Background]Fibroblast Growth Factor Receptor 2(FGFR2) amplification occuers flequently in undifferentiated gastric cancer(GC), and accounts for 3-10% of primay GC. FGFR2 shows two isoforms, IIIb-type expressed in epithelial cells, and IIIc-type expressed in mesenchymal cells. The aim of this study is evaluating clinicopathological significance of FGFR2-IIIb and IIIc expression on GC cells. [Method]562 patients who had undergone GC surgery were retrospectively examined. Immunohistochemistry of resected specimen was used to investigate the expression of FGFR2-IIIb and IIIc. [Result]FGFR2-IIIb and FGFR2-IIIc were positive in 28 cases (4.9%) and 4 cases (0.7%) of 562 gastric cancers. All of FGFR2-IIIc positive tumors were also positive for FGFR2-IIIb in a same tumor, but both were not positive in same cells. 5-year overall survival rate of FGFR2 positive group is significantly poorer (p=0.0011, log-lank) than that of FGFR2 negative. Moreover, the prognosis of FGFR2-IIIc positive group was significantly poorer (p=0.003, log-lank) than that of FGFR2-IIIb positive group. In univariate analysis, the overall survival was significantly correlated to FGFR2-IIIb positive, FGFR2-IIIc positive, invasion depth, macroscopic type, histological type, lymph node metastasis, peritoneal dissemination, lymphatic invasion, and cytology. In multivariate analysis, FGFR2IIIc was significantly correlated to overall survival (p=0.045) [Conclusion] The expression of FGFR2IIIc and/or FGFR2IIIb was observed in 5% of gastric cancer. FGFR2 amplification is associated with poor overall survival. As a result, treatment targeting FGFR2 amplification has the potential to provide clinical benefit for FGFR2 positive GC. Citation Format: Kenji Kuroda, Masakazu Yashiro, Go Masuda, Yuichiro Miki, Tomohisa Okuno, Shingo Togano, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Clinicopathologic significance of fibroblast growth factor 2 type IIIb and type IIIc in gastric 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 2510.
Immunoglobulin Adsorption in Patients With Idiopathic Dilated Cardiomyopathy
Authors: JohannesMüller, GerdWallukat, MichaelDandel, HeidrunBieda, KerstenBrandes, SusanneSpiegelsberger, EberhardNissen, RudolfKunze, RolandHetzer
Journal: Circulation (2000)

Background—Idiopathic dilated cardiomyopathy (IDC) frequently is a progressive disease without causative therapy options. Following the hypothesis that in certain patients autoantibodies against cardiac structures may induce, maintain, or promote the progression of the disease, we investigated whether the elimination of these autoantibodies through immunoadsorption would improve cardiac function. Methods and Results—This prospective case-control study included 34 patients with IDC. Each patient presented with moderate to severe heart failure and evidence of autoantibodies directed against β1-adrenoceptors (β1-AABs). Seventeen patients received standard medical therapy (control group), whereas 17 were also treated with immunoadsorption (treatment group) to eliminate β1-AABs. A 1-year follow-up included echocardiographic assessment of left ventricular ejection fraction and internal diameters, β1-AAB levels, and clinical status every 3 months. Within 1 year, the mean±SD left ventricular ejection fraction ros...
Abstract 11920: Electrocardiographic Predictors of Heart Failure With Reduced versus Preserved Ejection Fraction: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Matylda Mazur, Wesley T O’Neal, Alain G Bertoni, David A Bluemke, Mouaz H Al-Mallah, Joao A Lima, Dalane W Kitzman, Elsayed Z Soliman
Journal: Circulation (2016)

Background: A number of studies have shown usefulness of the electrocardiogram (ECG) in predicting heart failure (HF). However, whether these ECG predictors can distinguish between the risk of heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction is unknown. Methods: We analyzed data of 6,638 participants (53% female; mean age 62±10 years) from the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease at the time of enrollment. Digital ECGs were collected and centrally read at baseline (2000-2002) while HF was classified by an adjudication committee during a median follow-up of 11.2 years. A Cox competing risks analysis was used to compare the association of several ECG predictors with HFpEF and HFrEF. Results: A total of 226 HF events occurred during follow up, of which 116 events were HFrEF. Most of the ECG predictors of HF showed stronger associations with HFrEF than HFpEF. However, only a few showed a difference that reached statistical significance including prolonged QT, ST/T abnormalities and delayed QRS intrinsicoid deflection time ( Table ). Conclusion: Repolarization abnormalities and delayed ventricular activation may have the potential to distinguish between participants at future risk of HFrEF and HFpEF.
Abstract 4967: HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition
Authors: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor
Journal: Cancer Research (2018)

Abstract In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC's in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells. Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells. Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [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 4967.
Abstract 764: GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) growth
Authors: Rahul Raj Singh, Katie M. Reindl
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortalities in the Western world and continues to be a major unresolvable health problem at the start of the 21st century. Resistance to the currently available treatment options has led to development of new approaches, such as personalized medicine and immunotherapy. However, new therapeutic strategies based on the unique molecular biology and physiology of pancreatic cancer hold the greatest promise. Glutathione S-transferase pi 1 (GSTP1) is a key detoxification enzyme which metabolizes xenobiotic compounds and byproducts of cellular metabolism. GSTP1 is overexpressed in many tumors, particularly ovarian, non-small cell lung, breast, colon, and pancreas. Moreover, GSTP1 is overexpressed in drug-resistant cancer cell lines. The reasons for increased expression ratios compared to normal tissues or wild-type cell lines are not well understood. To investigate the role of GSTP1 in PDAC pathogenicity, we generated two knockdown lines of GSTP1 in metabolically diverse PDAC cells. We showed that GSTP1 knockdown impairs the growth and proliferation of PDAC cells. Additionally, GSTP1 knockdown cells exhibit elevated reactive oxygen species (ROS) levels and a prolonged G0/G1 phase of the cell cycle. Intrigued by these results, we next examined whether pharmacological inhibition with a selective GSTP1 inhibitor, Ezatiostat (TLK199), also impaired PDAC pathogenicity. Ezatiostat is a small molecule drug and is novel glutathione analog, which selectively binds and inhibits GSTP1. Ezatiostat treatment in PDAC cells recapitulated the proliferation impairments observed with genetic inactivation of GSTP1 and elevated ROS levels. Orthotopic implantation of GSTP1 knockdown cells in athymic nude mice resulted in reduced tumor weight and volume compared to the control. The growth trajectory of the tumors was monitored via Vevo-3100 ultrasound imaging system. Our preliminary data indicate enhanced sensitivity of glycolytic cancer cells towards an ROS-inducing agent and a GSTP1 inhibitor, piperlongumine (PL). Interestingly, we have found PL is less cytotoxic to cells with reduced GSTP1 levels, indicating that PL primarily works by inhibiting GSTP1 activity. Together, these data suggest that GSTP1 knockdown and inhibition impairs the growth and survival of phenotypically diverse PDAC cells in vitro and in vivo. Moreover, GSTP1 knockdown results in elevated ROS levels and an extended G0/G1 phase of the cell cycle. With these data, we propose that GSTP1 is a novel therapeutic target for PDAC. Citation Format: Rahul Raj Singh, Katie M. Reindl. GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) 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 764.
Flow Volume and Shunt Quantification in Pediatric Congenital Heart Disease by Real-Time Magnetic Resonance Velocity Mapping
Authors: HermannKörperich, JürgenGieseke, PeterBarth, RomhildHoogeveen, HermannEsdorn, AndreasPeterschröder, HansMeyer, PhilippBeerbaum
Journal: Circulation (2004)

Background— Flow quantification in real time by phase-contrast MRI (PC-MRI) may provide unique hemodynamic information in congenital heart disease, but available techniques have important limitations. We sought to validate a novel real-time magnetic resonance flow sequence in children. Methods and Results— In 14 pediatric patients (mean age 5.2±2.0 years) with cardiac left-to-right shunt, pulmonary (Qp) and aortic (Qs) flow rates were determined by nontriggered free-breathing real-time PC-MRI with single-shot echo-planar imaging combined with sensitivity encoding, which yielded 25 phase images per second at 2.7×2.7-mm in-plane resolution (field of view 30×34 cm2). Over a 9.5-second period that included 2 to 5 respiratory cycles, 16.6±2.6 subsequent stroke volumes (range 13 to 22) were acquired in each vessel. Results were compared with conventional retrospectively ECG-gated PC-MRI. Mean Qp/Qs by conventional PC-MRI was 1.91±0.64, and it was 1.94±0.68 (mean±SD) by real-time PC-MRI. For blood flow rate thro...
CD44-Targeting PLGA Nanoparticles Incorporating Paclitaxel and FAK siRNA Overcome Chemoresistance in Epithelial Ovarian Cancer
Authors: Yeongseon Byeon, Jeong-Won Lee, Whan Soo Choi, Ji Eun Won, Ga Hee Kim, Min Gi Kim, Tae In Wi, Jae Myeong Lee, Tae Heung Kang, In Duk Jung, Young-Jae Cho, Hyung Jun Ahn, Byung Cheol Shin, Young Joo Lee, Anil K. Sood, Hee Dong Han, Yeong-Min Park
Journal: Cancer Research (2018)

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma.Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. Cancer Res; 78(21); 6247-56. ©2018 AACR.
Human Vascular Adhesion Protein-1 (VAP-1) Plays a Critical Role in Lymphocyte–Endothelial Cell Adhesion Cascade Under Shear
Authors: MarkoSalmi, SamiTohka, SirpaJalkanen
Journal: Circulation Research (2000)

Abstract—Lymphocyte binding to vascular endothelium is a prerequisite for the movement of immune cells from the blood into lymphoid tissues and into sites of inflammation. Human vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein involved in this interaction. It also displays an enzymatic (monoamine oxidase) activity. Here we examined how recombinant human VAP-1 mediates lymphocyte binding using rotatory and flow chamber binding assays. VAP-1 cDNA transfected into an endothelial cell line, which does not bind lymphocytes, renders the cell line capable of binding lymphocytes in a shear-dependent manner. VAP-1 transfectants bound lymphocytes 5 times better than monocytes with a preference for T killer cells, and no specific granulocyte adherence was detectable. The binding is partially inhibited by anti–VAP-1 monoclonal antibodies or by blocking lymphocyte L-selectin and CD18 integrins, but not by inhibition of several other homing-associated molecules. In contrast, CD44 ligation on lymphocyt...
Bradykinin-Induced Vasodilation Is Impaired at the Atherosclerotic Site but Is Preserved at the Spastic Site of Human Coronary Arteries In Vivo
Authors: TakeshiKuga, KensukeEgashira, MasahiroMohri, HiroyukiTsutsui, YasuhikoHarasawa, YoshitoshiUrabe, ShinichiAndo, HiroakiShimokawa, AkiraTakeshita
Journal: Circulation (1995)

Background Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. Methods and Results The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor re...