tbuckley/cabot-search huggingface dataset:
Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci
Authors: Virgínea de Araujo Farias, Francisco O’Valle, Santiago Serrano-Saenz, Per Anderson, Eduardo Andrés, Jesús López-Peñalver, Isabel Tovar, Ana Nieto, Ana Santos, Francisco Martín, José Expósito, F. Javier Oliver, José Mariano Ruiz de Almodóvar
Journal: Molecular Cancer (2018)

We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT).We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment.The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment.Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.
No-Reflow Phenomenon and Lesion Morphology in Patients With Acute Myocardial Infarction
Authors: AtsushiTanaka, TakahikoKawarabayashi, YoshiharuNishibori, ToshihikoSano, YukioNishida, DaijuFukuda, KeneiShimada, JunichiYoshikawa
Journal: Circulation (2002)

Background— The no-reflow phenomenon is associated with poor functional and clinical outcomes for patients with acute myocardial infarction (AMI). In the era of primary intervention, accurately identifying lesions at high risk of no reflow is of crucial importance. At present, no study into the relationship between lesion morphology and no reflow has been performed. The aim of this study was to investigate the relationship between preintervention intravascular ultrasound (IVUS) lesion morphology and the no-reflow phenomenon. Methods and Results— This study comprised 100 consecutive patients with AMI who underwent preintervention IVUS and were successfully recanalized with primary balloon angioplasty or stenting. IVUS was again performed to identify and exclude any mechanical vessel obstruction in cases of thrombolysis in myocardial infarction flow grade 0, 1, or 2 after intervention in the absence of angiographic stenosis. Angiographic no reflow was seen in 13 patients (13%). Univariate analysis indicated...
Alteration in Left Ventricular Diastolic Filling and Accumulation of Myocardial Collagen at Insulin-Resistant Prediabetic Stage of a Type II Diabetic Rat Model
Authors: KatsufumiMizushige, LiYao, TakahisaNoma, HideyasuKiyomoto, YangYu, NaohisaHosomi, KojiOhmori, HirohideMatsuo
Journal: Circulation (2000)

Background—Considerable controversy exists regarding impairment of cardiac function in diabetes mellitus (DM). We investigated the serial changes in left ventricular (LV) histopathology and LV filling dynamics in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of type II DM. Methods and Results—In 54 OLETF and 54 non-DM rats, body weight, blood pressure, heart rate, and transmitral pulsed Doppler examinations were performed from 5 to 47 weeks of age. An oral glucose tolerance test was performed at 10, 20, and 30 weeks of age. The hearts were excised for histopathology, including immunohistochemistry and histomorphometry of collagen, and measurement of hydroxyproline at baseline and each stage of developing DM. In the prediabetic stage (15 weeks of age), in which fast blood glucose remained normal, OLETF rats manifested mild obesity, postprandial hyperglycemia, and hyperinsulinemia, and early diastolic transmitral inflow exhibited prolonged deceleration time (...
Pathogenetic Mechanisms of Prolapsing Aortic Valve and Aortic Regurgitation Associated With Ventricular Septal Defect
Authors: Katsuhikotatsuno, Soujikonno, Masahikoando, Shigerusakakibara
Journal: Circulation (1973)

The developmental mechanisms of prolapse and regurgitation of the aortic valve which complicate ventricular septal defect (VSD) were investigated from the anatomical, angiographic, and surgical viewpoints on the basis of autopsied heart specimens, preoperative thoracic aortography, and surgical records. Two major, conceptually distinct but functionally interdependent factors contribute to the aortic valve's prolapse into the VSD. The major feature of the first category is the lack of anatomical support for the valve. In subpulmonary VSD, a regional defect of the conal septal musculature which supports a section of the right coronary sinus and the annulus was observed. In infracristal VSD, a deficiency of the sinus of Valsalva was noted. The hemodynamic effects, which actually produce prolapse of the anatomically unsupported valve into the VSD, is the second contributing factor. The left-to-right shunt of blood through the VSD during the early systolic phase pulls the sagging aortic valve into the defect. ...
Abstract 4037: Interactions between STAT3 and TGFβ in the regulation of hyaluronic acid synthesis and signaling in immortalized human mammary epithelial cells
Authors: Brenda G. Trevizo-Barresi, JoEllen Welsh
Journal: Cancer Research (2018)

Abstract Evidence suggests that growth of cancer stem cells (CSCs) drives intratumor heterogeneity, a major clinical problem that results in drug resistance, recurrence of tumors, and metastatic progression of breast cancer. Therapeutic strategies to eliminate CSCs require identification of signaling pathways that facilitate the emergence and/or expansion of CSCs. These signaling pathways are implicated in altering cell behavior, as well as promoting the expression of genes involved in epithelial-mesenchymal transition (EMT), cell migration and invasion. Previous work demonstrated that a cooperative STAT3/SMAD3 gene transcription program increased the expression of Hyaluronan Synthase 2 (HAS2), an enzyme that produces Hyaluronic Acid (HA) which serves as a CD44 ligand and facilitates EMT. We hypothesize that STAT3 is a critical regulator of HA synthesis and signaling which enhances EMT and stemness of human mammary epithelial cells, driving tumor progression. We tested this hypothesis in a TGFβ triggered model of EMT. Immortalized human mammary epithelial cells (HMLE) expressing either a control vector (pWZL-GFP) or a vector containing TGFβ1 (pWZL-TGFβ1-GFP) were characterized with respect to STAT3 signaling, HA synthesis, and mammosphere formation. Our data revealed that HMLE-pWZL-TGFβ1-GFP cells have significantly higher expression of active STAT3 (Y705) compared to control cells, but total STAT3 gene and protein expression were similar in the two cell lines. HMLE-pWZL-TGFβ1-GFP cells exhibited a significant increase in expression of HAS2 and HAS2-AS1, a long non-coding RNA that enhances the transcription of HAS2. Preliminary results show that overexpression of TGFβ1 increased HA secretion in media compared to control cells. HMLE-pWZL-TGFβ1-GFP cells demonstrated significantly higher mammosphere forming ability compared to control cells, suggesting that TGFβ increases the percentage of stem cells in the population. Initial results demonstrated changes in mammosphere size and morphology of HMLE-pWZL-TGFβ1-GFP cells treated with the HA synthesis inhibitor 4-Methylumbelliferone (4MU). Together, these results suggest STAT3 and TGFβ1 co-regulate HAS2 expression and HA production in a model of EMT supporting the use of the HMLE-pWZL cell series as a promising model to study STAT3 regulation of the HA-CD44 signaling pathway. Citation Format: Brenda G. Trevizo-Barresi, JoEllen Welsh. Interactions between STAT3 and TGFβ in the regulation of hyaluronic acid synthesis and signaling in immortalized human mammary epithelial cells [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 4037.
Prospective Intraindividual Comparison of Magnetic Resonance Imaging With Gadoxetic Acid and Extracellular Contrast for Diagnosis of Hepatocellular Carcinomas Using the Liver Imaging Reporting and Data System
Authors: Ji Hye Min, Jong Man Kim, Young Kon Kim, Tae Wook Kang, Soon Jin Lee, Gyu Seong Choi, Seo‐Youn Choi, Soohyun Ahn
Journal: Hepatology (2018)

We intraindividually compared the efficacy of magnetic resonance imaging (MRI) with extracellular contrast agents (ECA‐MRI) and MRI with hepatobiliary agents (HBA‐MRI) for the diagnosis of hepatocellular carcinoma (HCC) using the Liver Imaging Reporting and Data System (LI‐RADS). Between November 2016 and November 2017, we enrolled 91 patients with chronic liver disease who underwent both ECA‐MRI and HBA‐MRI within a 1‐month interval for a first detected hepatic nodule on ultrasound. In total, 117 observations (95 HCCs, 19 benign lesions, and 3 other malignancies; median size, 18 mm) were identified with surgical resection. Two observers assessed two MRIs based on LI‐RADS v2017, with consensus by a third observer. We then compared the diagnostic performance of LR‐5 according to LI‐RADS and modified LI‐RADS. ECA‐MRI had higher sensitivity (77.9% versus 66.3%) and accuracy (82.1% versus 72.6%) than HBA‐MRI in the LR‐5 category ( P &lt; 0.001). When applying either modified washout on the portal venous phase (PVP)/transitional phase (TP) of HBA‐MRI or isointensity with a capsule during the PVP/delayed phase of ECA‐MRI (illusional washout), 13 HCCs on HBA‐MRI and 11 HCCs on ECA‐MRI were correctly classified as HCC, while achieving 100% specificity. One cholangiocarcinoma was accurately classified only with HBA‐MRI due to its targetoid appearance in the TP and hepatobiliary phase. Conclusion : ECA‐MRI showed better sensitivity and accuracy than HBA‐MRI for the diagnosis of HCC with LI‐RADS. We achieved better diagnostic performance when applying a modified washout on PVP/TP HBA‐MRI and an illusional washout on ECA‐MRI than we did with conventional criteria.
Rapid Ventricular Induction of Brain Natriuretic Peptide Gene Expression in Experimental Acute Myocardial Infarction
Authors: NorioHama, HiroshiItoh, GotaroShirakami, OsamuNakagawa, Shin-ichiSuga, YoshihiroOgawa, IzuruMasuda, KuniakiNakanishi, TakaakiYoshimasa, YukiyaHashimoto, MasayukiYamaguchi, RyouheiHori, HirofumiYasue, KazuwaNakao
Journal: Circulation (1995)

Background We have demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone predominantly synthesized in and secreted from the ventricle. We have also reported that, compared with atrial natriuretic peptide (ANP), the plasma concentration of BNP is increased to a greater degree in patients with congestive heart failure and more rapidly in patients with acute myocardial infarction (AMI). Methods and Results To investigate ventricular gene expression of BNP in AMI, we analyzed plasma and ventricular BNP concentrations along with ventricular BNP mRNA in rats with AMI produced by coronary artery ligation. The BNP concentration in the left ventricle increased about 2-fold as early as 12 hours postinfarction and 5-fold 1 day postinfarction compared with sham-operated rats, whereas left ventricular ANP concentration remained unchanged within 1 day. The tissue concentration of BNP increased in the noninfarcted region as well as in the infarcted region. The surviving myocytes in and around the necrot...
Abstract 3839: A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo
Authors: Seung Ho Shin, Do Young Lim, Kanamata Reddy, Margarita Malakhova, Fangfang Liu, Ting Wang, Mengqiu Song, Hanyong Chen, Ki Beom Bae, Joohyun Ryu, Kangdong Liu, Mee-Hyun Lee, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2018)

Abstract Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biologic consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer. Citation Format: Seung Ho Shin, Do Young Lim, Kanamata Reddy, Margarita Malakhova, Fangfang Liu, Ting Wang, Mengqiu Song, Hanyong Chen, Ki Beom Bae, Joohyun Ryu, Kangdong Liu, Mee-Hyun Lee, Ann M. Bode, Zigang Dong. A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo [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 3839.
Abstract 5132: Lactic acidosis-mediated transcriptomic and metabolomic rewiring in pancreatic cancer cells
Authors: Divya Murthy, Jaime Abrego, Ryan James King, Pankaj Kumar Singh
Journal: Cancer Research (2018)

Abstract Tumor microenvironment plays a critical role in regulating tumor cell metabolism and progression. The tumor cells are constantly exposed to hypoxia, nutrient starvation, and extracellular acidification that contribute to tumor malignancy. These malignant cells exhibit Warburg effect by maintaining glycolytic phenotype even in the presence of oxygen and excrete lactate and protons via monocarboxylate transporters, and sodium-hydrogen antiporter 1 (NHE1) causing constant acidification of the tumor microenvironment. The tumor cells must thus adapt to acidosis to thrive in such hostile microenvironment. The purpose of the study is to identify the functional response of pancreatic cancer cells to the acidic tumor microenvironment. We performed integrated transcriptomic and metabolomic analyses to identify the existence of low pH-responsive transcriptional and metabolic regulators. Culturing the cells under low pH resulted in a reduction in cell growth and an increase in oxidative stress within the cells. RNA-seq-based transcriptomic analyses revealed that acidosis drives distinct gene expression patterns in PDAC cells with the expression of 499 and 496 genes up- and downregulated, respectively in PDAC cells. GSEA analyses of significantly modulated genes identified pathways including cell cycle, DNA repair, metabolic pathways, ABC transporters, glutathione metabolism, and genes involved in signaling cascades such as the inositide signaling pathway. As the transcriptomic analyses showed an enrichment of metabolic genes, intracellular metabolomic analyses revealed that chronic acidosis leads to a shift in cellular metabolism towards oxidative metabolism. Our studies demonstrate that while chronic acidosis in the tumor microenvironment leads to reduced proliferation and glycolysis in tumor cells, it also results in increased expression of genes involved in cellular migration, signaling pathways and switching to anaplerotic glutamine metabolism in response to an acidic tumor microenvironment. Overall, our studies demonstrate metabolic reprogramming in PDAC cells in response to low pH microenvironments creating a metabolic vulnerability that could be exploited for therapeutic targeting of pancreatic cancer. Citation Format: Divya Murthy, Jaime Abrego, Ryan James King, Pankaj Kumar Singh. Lactic acidosis-mediated transcriptomic and metabolomic rewiring in pancreatic cancer cells [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 5132.
Abstract 3927: Clinicopathologic features and immune microenvironment of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors
Authors: Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C. Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
Journal: Cancer Research (2018)

Abstract Background: Approximately 20-30% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations are not responsive to EGFR-tyrosine kinase inhibitors (TKIs). Although, primary resistance to EGFR-TKI is attributed to various genetic alterations, little is known about the clinical and immunopathological features of patients with primary resistance. The tumor immune microenvironment including tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) has been reported to play an important role in tumor progression in NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKI. Materials and Methods: Characteristics of 124 NSCLC patients with EGFR mutations who received EGFR-TKI were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8, and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. Results: Primary resistance was observed in 13.7% (17/124) of patients. Smoking Tobacco correlated significantly with primary resistance compared to non-primary resistance. Lower density of total TILs and negative PD-L1 expression as per immunohistochemical analysis correlated significantly with primary resistance. Moreover, immune ignorant phenotype of tumor microenvironment, negative PD-L1 expression with low TIL density, was significantly observed in primary resistance. Conclusions: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs. Citation Format: Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C. Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura. Clinicopathologic features and immune microenvironment of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors [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 3927.
Distal Protection Improved Reperfusion and Reduced Left Ventricular Dysfunction in Patients With Acute Myocardial Infarction Who Had Angioscopically Defined Ruptured Plaque
Authors: IsamuMizote, YasunoriUeda, TomohitoOhtani, MasahikoShimizu, YasuharuTakeda, TakafumiOka, MasahikoTsujimoto, AtsushiHirayama, MasatsuguHori, KazuhisaKodama
Journal: Circulation (2005)

Background— Distal protection, in the Saphenous Vein Graft Angioplasty Free of Emboli (SAFER) trial, is demonstrated to prevent distal embolism in the percutaneous coronary intervention of saphenous vein graft. However, in the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) trial, it was not effective in the percutaneous coronary intervention of native coronary arteries in patients with acute myocardial infarction (AMI). We hypothesized that its effectiveness would be determined by lesion characteristics. Therefore, we classified the type of culprit lesion by angioscopy and examined its influence on the effectiveness of distal protection, comparing patients with AMI treated with and without distal protection. Methods and Results— Consecutive patients with AMI treated without distal protection (n=110) from July 2000 to July 2002 and those treated with distal protection (n=81) from July 2002 to July 2004 were included. Patients in each group were subdivided according to...