tbuckley/cabot-search huggingface dataset:
Abstract 3806: The pattern of NKG2DL expressions determines immunogenicity and antitumor effect of protein-bound polysaccharide-K in tumor-bearing mouse models
Authors: Tomohiro Takehara, Kenzo Soejima, Tomoko Betsuyaku, Kiyoshi Yoshimura
Journal: Cancer Research (2018)

Abstract Background and Aim: Natural killer group 2, member D ligands (NKG2DLs) have paradoxical immunological characteristics, exerting both immune-stimulatory and immune-suppressive effects on T cell activation. First, we attempted to determine the relationship between the antitumor effect of protein-bound polysaccharide-K (PSK) in a tumor-bearing mouse model and the expression profile of NKG2DLs on a tumor. Next, we investigated whether NKG2DL expression on tumor cells affects T cell activation by examining the expression of NKG2D on and IFN-γ production in CD8+ T cells in mice bearing NKG2DL–expressing and NKG2DL–nonexpressing tumors.Materials and Methods: PSK was administered to evaluate its effectiveness against tumor growth. The expression of Rae-1 and H60 were analyzed in the cell lines. Results: PSK showed the highest antitumor effects in mice implanted with cells expressing neither Rae-1 nor H60. PSK had little antitumor effect in mice implanted with cells expressing both Rae-1 and H60. A correlation between the expression of NKG2DLs and the antitumor effect of PSK was observed. After PSK administration, INF-γ production in CD8+ T cells increased in mice with cells expressing neither Rae-1 nor H60, but did not change in mice implanted with cells expressing both Rae-1 and H60.Conclusion: we demonstrated that the expression pattern of NKG2DLs affects tumor immunity and the efficacy of immunotherapy in a tumor-bearing mouse model. In particular, the expression of H60 and Rae-1 family members may be an immunosuppressive factor. Further analysis is required to gain a better understanding of the mechanism of interaction between NKG2D expressed on immune effector cells and H60/Rae-1 expression on tumors. Although NKG2DL expression may represent a marker predicting response to immunotherapy, further studies in humans are required to validate this finding in the clinical setting. Citation Format: Tomohiro Takehara, Kenzo Soejima, Tomoko Betsuyaku, Kiyoshi Yoshimura. The pattern of NKG2DL expressions determines immunogenicity and antitumor effect of protein-bound polysaccharide-K in tumor-bearing mouse 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 3806.
Stage-Specific Role of Endogenous Smad2 Activation in Cardiomyogenesis of Embryonic Stem Cells
Authors: RyojiKitamura, TomosaburoTakahashi, NorioNakajima, KojiIsodono, SatoshiAsada, HikaruUeno, TomomiUeyama, ToshikazuYoshikawa, HiroakiMatsubara, HidemasaOh
Journal: Circulation Research (2007)

The role of Smads and their specific ligands during cardiomyogenesis in ES cells was examined. Smad2 was activated bimodally in the early and late phases of cardiac differentiation, whereas Smad1 was activated after the middle phase. Nodal and Cripto were expressed in the early stage and then downregulated, whereas transforming growth factor-β and activin were expressed only in the late phase. Suppression of early Smad2 activation by SB-431542 produced complete inhibition of endodermal and mesodermal induction but augmented neuroectodermal differentiation, followed by poor cardiomyogenesis, whereas inhibition during the late phase alone promoted cardiomyogenesis. Inhibitory effect of Smad2 on cardiomyogenesis in the late phase was mainly mediated by transforming growth factor-β, and inhibition of transforming growth factor-β–mediated Smad2 activation resulted in a greater replicative potential in differentiated cardiac myocytes and enhanced differentiation of nonmyocytes into cardiac myocytes. Thus, endog...
Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF
Authors: Jean-Daniel Malcor, Victoria Juskaite, Despoina Gavriilidou, Emma J. Hunter, Natalia Davidenko, Samir Hamaia, Sanjay Sinha, Ruth E. Cameron, Serena M. Best, Birgit Leitinger, Richard W. Farndale
Journal: Biomaterials (2018)

Collagen-based scaffolds may require chemical crosslinking to achieve mechanical properties suitable for tissue engineering. Carbodiimide treatment, often used for this purpose, consumes amino acid side chains required for receptor recognition, thus reducing cell–collagen interaction. Here, we restore recognition and function of both von Willebrand Factor (VWF) and Discoidin Domain Receptor 2 (DDR2) to crosslinked collagen films by derivatisation with a specific triple-helical peptide (THP), an approach previously applied to integrin-mediated cellular adhesion. The THP contained the collagen III-derived active sequence, GPRGQOGVNleGFO, conjugated to a photoreactive moiety, diazirine, allowing UV-dependent covalent coupling to collagen films. Crosslinking of collagen films attenuated the binding of recombinant VWF A3 domain and of DDR2 (as the GST and Fc fusions, respectively), and coupling of the specific THP restored their attachment. These derivatised films supported activation of DDR2 expressed in either COS-7 or HEK293 cells, reflected by phosphorylation of tyrosine 740, and VWF-mediated platelet deposition from flowing blood was restored. Further, such films were able to increase low-density lipoprotein uptake in vascular endothelial cells, a marker for endothelial phenotype. Thus, covalent linkage of specific THPs to crosslinked collagen films i) restores their cognate protein binding, ii) triggers the corresponding cellular responses, and iii) demonstrates the broad applicability of the approach to a range of receptors for applications in regenerative medicine.
Abstract 5396: Identification of meningioma patients in high risk of tumor recurrence using microRNA profiling
Authors: Josef Srovnal, Vladimir Balik, Hanus Slavik, Magdalena Houdova Megova, Miroslav Vaverka, Lumir Hrabalek, Jiri Ehrmann, Katerina Staffova, Marian Hajduch
Journal: Cancer Research (2018)

Abstract Introduction: Meningioma represents one of the most common intracranial tumors. They are generally thought to progress from low to high-grade lesions and relapse. However, the molecular mechanisms underlying their pathogenesis remains to be ellucidated. Identification of meningioma patients with higher risk of recurrence may have significant impact for future clinical management. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 45 meningioma patients (15 recurrent patients, 30 patients without recurrence) and 5 healthy controls (dura mater). Comprehensive clinical-pathological data were mined. There were 15 males and 30 females; median age was 54 years, range 28 - 99 years. Total RNA was purified from FFPE samples after pathological verification using miRNeasyMini kit (QIAGEN). Microarray analysis was performed using the MiRNA 4.0 Array and FlashTagTM Biotin HSR(Affymetrix). Affymetrix CEL files have been read with read.celfiles function from oligo package and preprocessed with rma function (Bioconductor). The expression dataset was analyzed with Wilcoxon exact two-sample test (exactRankTestsR package) in order to discover significantly altered miRNAs. Results: We revealed different miRNA profiles in primary meningioma tumors that will relapse in comparison with non-recurrent tumors. 54 differentially expressed miRNAs were identified in meningeoma patients at high risk of recurrence. High-risk patients had significantly higher expression of miR-572 and miR-320c, and lower expression of miR-140 and miR-16-5p. Sixteen candidate miRNAs (including miR-107, miR-16-5p, miR-320c, miR-371b-5p and miR-15a-5p) were chosen for further qPCR validation on independent dataset. Moreover, miRNA expression levels were also compared in paired samples (primary and recurrent tumors) of 15 meningioma patients. However, only small differences in miRNA expression were detected. Conclusion: We have found different miRNA profiles in meningioma patients identifying patients in high risk of recurrence. Sixteen candidate miRNAs (including miR-107, miR-16-5p, miR-320c, miR-371b-5p and miR-15a-5p) were further validated. Acknowledgment: This work was financially supported by Ministry of Health of the Czech Republic, grant nr. 15-29021A, IGA UP LF 2017_013, NPU LO1304 and NCMG LM2015091. Citation Format: Josef Srovnal, Vladimir Balik, Hanus Slavik, Magdalena Houdova Megova, Miroslav Vaverka, Lumir Hrabalek, Jiri Ehrmann, Katerina Staffova, Marian Hajduch. Identification of meningioma patients in high risk of tumor recurrence using microRNA profiling [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 5396.
Abstract 18019: Successful Surgical Management of Severely Symptomatic Hypertrophic Cardiomyopathy Patients With Minimal Septal Hypertrophy
Authors: Raabia N Ahmad, Barry J Maron, Ethan J Rowin, Tammy S Haas, Joseph A Dearani, Martin S Maron
Journal: Circulation (2014)

Background: Marked septal hypertrophy is considered a requirement for effective myectomy in obstructive hypertrophic cardiomyopathy (HCM), with mitral valve replacement recommended as the alternative strategy in patients with minimal hypertrophy. However, it remains uncertain whether relief of obstruction can be effectively abolished without mitral valve replacement in patients with minimal septal wall thickening. Methods: Of 500 patients who underwent surgical myectomy from 2004 to January 2014, 21 (4.2%) were identified with a maximum LV wall thickness ≤ 15mm and constitute the study cohort. Results: All 21 patients (56 ± 10 years old; 62% male) were followed for advanced heart failure symptoms refractory to drug therapy with a maximal septal wall thickness of 13.6 ± 1.7 mm (range: 10-15 mm; ≤ 12 mm in 5 patients). Outflow obstruction ≥ 30 mmHg due to mitral valve-septal contact was present after exercise in 17 of 21 patients (range: 50-150 mmHg), and under resting conditions in 4 patients (range: 30-65 mmHg). In all patients, surgical relief of obstruction consisted of muscular resection of the basal septum with revision of abnormal and apically displaced papillary muscles, which were judged intraoperatively to be contributing to obstruction. In addition, in 10 patients (47%) myectomy alone was not sufficient to relieve obstruction due to the limited opportunity for septal reduction and adjunctive mitral valve repair was performed to shorten an elongated anterior leaflet. No patient required mitral valve replacement or incurred a ventricular septal defect. Post-operatively, 4 patients developed complete heart block requiring permanent pacemaker (1 patient with pre-operative right bundle branch block) and 1 had a cerebrovascular event. At most recent follow up 18 ± 19 months post-myectomy, septal thickness was reduced to 10 ± 2 mm, no patient had an outflow gradient at rest or with provocation, and all patients were alive with the majority asymptomatic (class I: n=13; 62% and class II n=8; 38%). Conclusion: In patients with minimal septal hypertrophy, outflow obstruction can be effectively abolished with surgical myectomy and adjunctive mitral valve repair with a small increased risk of heart block, but without the need for mitral valve replacement.
Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets
Authors: Wai HoTang, JeremiahStitham, YuJin, RenjingLiu, Seung HeeLee, JingDu, GourgAtteya, ScottGleim, GeralynSpollett, KathleenMartin, JohnHwa
Journal: Circulation (2014)

Background—Platelet abnormalities are well-recognized complications of diabetes mellitus. Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in diabetes mellitus. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in platelets in diabetes mellitus is unknown. Methods and Results—Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase activation and subsequent reactive oxygen species production lead to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage, and rupture by sequestration of the antiapoptotic protein Bcl-xL. In a glucose dose–dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation, and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, aldose reductase activation, reactive oxygen species produ...
Long-Term Right Ventricular Volume Overload Increases Myocardial Fluorodeoxyglucose Uptake in the Interventricular Septum in Patients With Atrial Septal Defect
Authors: HirokiOtani, YutakaKagaya, YurikoYamane, MasanobuChida, KentaIto, ShigetoNamiuchi, NobuyukiShiba, YoshitoKoseki, MototsuguNinomiya, JunIkeda, HaruoSaito, ShinMaruoka, TakehikoFujiwara, TatsuoIdo, NobumasaIshide, KunioShirato
Journal: Circulation (2000)

Background—Several studies have shown that long-term right ventricular (RV) overload in animal models alters myocardial energy substrate metabolism. However, whether long-term RV volume overload alters this metabolism in the human is unclear. Methods and Results—We performed positron emission tomography with [18F]fluorodeoxyglucose (FDG) and single-photon emission tomography (SPECT) with [201Tl]TlCl (Tl) and [123I]15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in 11 patients with atrial septal defect (ASD) and 11 control subjects. In the FDG study, we calculated myocardial metabolic rate of glucose (MMR) in interventricular septum (IVS) and left ventricular (LV) free wall. MMR was significantly increased in IVS compared with LV free wall in the ASD patients (420±35 versus 333±32 mol · kg−1 · min−1; P<0.05) but not in the control group (347±27 versus 357±25 mol · kg−1 · min−1). In both ASD and control groups, SPECT count was not significantly different between IVS and LV free wall in Tl (ASD, 160...
Regression of Left Ventricular Hypertrophy Prevents Ischemia-Induced Lethal Arrhythmias
Authors: TetsuroKohya, HisashiYokoshiki, NoritsuguTohse, MorioKanno, HaruakiNakaya, HideyaSaito, AkiraKitabatake
Journal: Circulation Research (1995)

Abstract To evaluate the preventive effect of regression of left ventricular hypertrophy (LVH) on sudden cardiac death (SCD), the incidence of ventricular tachycardia or ventricular fibrillation (VT/Vf) after left coronary artery occlusion in Langendorff preparations was studied in the following five groups: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR treated with captopril (SHR-C), (3) SHR treated with the angiotensin II receptor antagonist TCV-116 (SHR-A), (4) SHR treated with hydralazine (SHR-H), and (5) Wistar-Kyoto (WKY) rats. Although blood pressure was equally lowered in all treated groups, SHR-C and SHR-A but not SHR-H showed regression of LVH. The incidence of VT/Vf was 5% in WKY rats, 63% in SHR-N (P<.005 versus WKY rats), 0% in SHR-C, 10% in SHR-A, and 45% in SHR-H (P<.05 versus WKY rats). Further evaluation of the effect of TCV-116 revealed that SHR treated with a low dose of TCV-116 (1 mg/kg per day) showed a decrease in left ventricular mass with only a littl...
MicroRNAs in Vascular and Metabolic Disease
Authors: AnnaZampetaki, ManuelMayr
Journal: Circulation Research (2012)

Recent findings demonstrated the importance of microRNAs (miRNAs) in the vasculature and the orchestration of lipid metabolism and glucose homeostasis. MiRNA networks represent an additional layer of regulation for gene expression that absorbs perturbations and ensures the robustness of biological systems. This function is very elegantly demonstrated in cholesterol metabolism where miRNAs reducing cellular cholesterol export are embedded in the very same genes that increase cholesterol synthesis. Often their alteration does not affect normal development but changes under stress conditions and in disease. A detailed understanding of the molecular and cellular mechanisms of miRNA-mediated effects on metabolism and vascular pathophysiology could pave the way for the development of novel diagnostic markers and therapeutic approaches. In the first part of this review, we summarize the role of miRNAs in vascular and metabolic diseases and explore potential confounding effects by platelet miRNAs in preclinical m...
Abstract 14446: Prostaglandin E2 Receptor EP4 Signaling in Vascular Smooth Muscle Decreased Elasticity of the Aorta
Authors: Yasuhiro Ichikawa, Utako Yokoyama, Mari Iwamoto, Shumpei Yokota, Susumu Minamisawa, Yoshihiro Ishikawa
Journal: Circulation (2013)

Introduction: Elasticity largely contributes to mechanical properties of the arteries and loss of elastic properties exacerbates aortic diseases, such as atherosclerosis or aortic aneurysms (AA). It is well known that prostaglandin E2 (PGE2) synthesis is enhanced in aortic diseases. We have demonstrated that the PGE2 receptor EP4 was abundantly expressed in smooth muscle cells (SMCs) from human AA tissues. Hypothesis: We examined whether PGE2-EP4 signaling in SMCs decreases elasticity in the aorta. Methods: We generated mice with vascular smooth muscle-specific overexpression of human EP4 using the Cre-loxP system (EP4loxP/-/SM22-Cre mice: EP4TG and EP4-/-/SM22-Cre mice: EP4NTG). Transcription profiles of the aorta were examined by quantitative RT-PCR and DNA microarray analyses. EP4 protein expression was examined by immunohistochemistry. Isometric tension of the aorta was measured using a wire myograph. Elasticity was evaluated by simultaneous measurement of dimension and pressure of the aorta under bas...
Abstract 3777: RORγ agonist enhances antitumor effects of immune checkpoint anti-PD1
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 Anti-PD1/PDL1 therapies have demonstrated great clinical benefit in some cancers, albeit in a limited percentage of patients. RORγt is a master transcription factor, which promotes Type 17 T cell differentiation and is known to enhance the stemness and plasticity of effector cells and to modulate PD1 expression. Since one of the potential failure mechanism of anti-PD1 is the lack of sustained CD8 infiltration within the TME, we assessed whether combining a synthetic, small-molecule RORγ agonist could enhance the antitumor effects of anti-PD1 treatment. To assess this combination treatment, we tested the effects of anti-PD1 antibody (1 mg/kg twice weekly) combined with a RORγ-agonist (LYC-54143; 100 mg/kg PO, BID given continuously till the end of study) in tumor-bearing murine mode lthat utilizes a vaccine for proper priming. We found that RORγ agonist combined with PD1 antibody significantly enhanced the anti-PD1 antitumor effect. This result was manifested by further delaying the tumor growth and prolonging mice survival. At day 35 after tumor implantation, 66% of mice survived in the group treated with anti-PD1 and RORγ agonist and vaccine when compared to 0% survival following anti-PD1 + vaccine or vaccine- alone treatments. This enhanced antitumor activity was observed/confirmed in several tumor models with the combination of RORγ agonist + anti-PD1 treatment. These results show that RORγ agonists may enhance the effectiveness of anti-PD1 therapy and therefore this combination is a promising therapeutic strategy for cancer. 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 immune checkpoint anti-PD1 [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 3777.
Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance
Authors: Kwon-Ho Song, Jae-Hoon Kim, Young-Ho Lee, Hyun Cheol Bae, Hyo-Jung Lee, Seon Rang Woo, Se Jin Oh, Kyung-Mi Lee, Cassian Yee, Bo Wook Kim, Hanbyoul Cho, Eun Joo Chung, Joon-Yong Chung, Stephen M. Hewitt, Tae-Wook Chung, Ki-Tae Ha, Young-Ki Bae, Chih-Ping Mao, Andrew Yang, T.C. Wu, Tae Woo Kim
Journal: Journal of Clinical Investigation (2018)

The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1α stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.
Bone Marrow-Derived Cells Do Not Incorporate Into the Adult Growing Vasculature
Authors: TiborZiegelhoeffer, BorjaFernandez, SawaKostin, MatthiasHeil, RobertVoswinckel, ArminHelisch, WolfgangSchaper
Journal: Circulation Research (2004)

Bone marrow-Derived cells have been proposed to form new vessels or at least incorporate into growing vessels in adult organisms under certain physiological and pathological conditions. We investigated whether bone marrow-Derived cells incorporate into vessels using mouse models of hindlimb ischemia (arteriogenesis and angiogenesis) and tumor growth. C57BL/6 wild-type mice were lethally irradiated and transplanted with bone marrow cells from littermates expressing enhanced green fluorescent protein (GFP). At least 6 weeks after bone marrow transplantation, the animals underwent unilateral femoral artery occlusions with or without pretreatment with vascular endothelial growth factor or were subcutaneously implanted with methylcholanthrene-induced fibrosarcoma (BFS-1) cells. Seven and 21 days after surgery, proximal hindlimb muscles with growing collateral arteries and ischemic gastrocnemius muscles as well as grown tumors and various organs were excised for histological analysis. We failed to colocalize GF...