tbuckley/cabot-search huggingface dataset:
Disruption of SM22 Promotes Inflammation After Artery Injury via Nuclear Factor κB Activation
Authors: JianbinShen, MaozhouYang, DonghongJu, HongJiang, Jian-PuZheng, ZhonghuiXu, LiLi
Journal: Circulation Research (2010)

Rationale: SM22 (or transgelin), an actin-binding protein abundant in vascular smooth muscle cells (VSMCs), is downregulated in atherosclerosis, aneurysm and various cancers. Abolishing SM22 in apolipoprotein E knockout mice accelerates atherogenesis. However, it is unclear whether SM22 disruption independently promotes arterial inflammation. Objective: To investigate whether SM22 disruption directly promotes inflammation on arterial injury and to characterize the underlying mechanisms. Methods and Results: Using carotid denudation as an artery injury model, we showed that Sm22 knockout (Sm22−/−) mice developed enhanced inflammatory responses with higher induction of proinflammatory genes, including Vcam1, Icam1, Cx3cl1, Ccl2, and Ptgs2. Higher expression of these genes was confirmed in primary Sm22−/− VSMCs and in PAC1 cells after Sm22 knockdown, whereas SM22 recapitulation in primary Sm22−/− VSMCs decreased their expression. NFKB2 was prominently activated in both injured carotids of Sm22−/− mice and in...
Abstract 19821: 3D Tri-culture Model Promotes Enhanced Mechanical Forces and Sustained Long-Term Contractility of Human Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: KarinaNakayama, PaulBurridge, ScottMetzler, OscarAbilez, ChelseySimmons, MarcBruce, YukaMatsuura, PaulKim, JosephWu, ManishButte, PhillipYang, NganHuang
Journal: Circulation (2014)

BACKGROUND: Engineered myocardial tissue represents a promising methodology for cardiac repair and regeneration, but the survival and contractility of the cardiomyocytes (CMs) in the engineered tissue remains a limiting factor. Since native CMs interact with endothelial and stromal cells, we generated a three-dimensional (3D) engineered myocardial tissue to study the role of cell-cell interactions on CM survival and function. HYPOTHESIS: Using human pluripotent stem cells (hPSCs) as a therapeutic cell source, we hypothesize that 3D tri-culture of hPSC-derived CMs (hCMs), hPSC-derived endothelial cells (hECs), and human amniotic mesenchymal stem cells (hAMSCs) will enable sustained, long-term contractility of the hCM population. METHODS AND RESULTS: We engineered myocardial tissues by culturing combinations of the three cell populations, within a 3D hydrogel for up to 6 weeks as follows: 1) hCMs only (mono-culture), 2) hCMs + hECs (co-culture), 3) hCMs + hAMSCs (co-culture), and 4) hCMs + hECs + hAMSCs (tr...
Bronchoconstriction in the Presence of Pulmonary Embolism
Authors: Victorgurewich, Duncanthomas, Myronstein, Stanfordwessler
Journal: Circulation (1963)

In a group of seven patients with pulmonary embolism, evidence of bronchoconstriction was found. Heparin appeared to relieve partially the observed airway obstruction. A possible common mechanism for the initiation of intravascular coagulation and the production of bronchoconstriction was considered. When other causes can be eliminated, the detection of bronchoconstriction may serve as a useful index for the early recognition of pulmonary emboli.
Necl-5/Poliovirus Receptor Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis
Authors: MitsuoKinugasa, HisayukiAmano, SeimiSatomi-Kobayashi, KazuhikoNakayama, MuneakiMiyata, YoshikiKubo, YuichiNagamatsu, YusukeKurogane, FumieKureha, ShotaYamana, Ken-ichiHirata, JunMiyoshi, YoshimiTakai, YoshiyukiRikitake
Journal: Circulation Research (2012)

Rationale:Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin αVβ3. However, how the interaction between VEGFR2 and integrin αVβ3 is regulated is not clear. Objective:To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin αVβ3, regulates the interaction between VEGFR2 and integrin αVβ3, and to clarify the role of Necl-5 in the VEGF-induced angiogenesis. Methods and Results:Necl-5-knockout mice displayed no obvious defect in vascular development; however, recovery of blood flow after hindlimb ischemia and the VEGF-induced neovascularization in implanted Matrigel plugs were impaired in Necl-5-knockout mice. To clarify the mechanism of the regulation of angiogenesis by Necl-5, we investigated the roles of Necl-5 in the VEGF-induced angiogenic response...
Abstract 316: Cancer cell apoptosis is induced by soluble factors secreted from normal mammary fibroblasts
Authors: Matyas Abel Tsegaye, Mati Nemera, Zachary T. Schafer
Journal: Cancer Research (2018)

Abstract The tumor microenvironment (TME), comprised of a heterogeneous population of transformed and non-transformed cells, plays a crucial role in cancer growth. Studies have shown that there is continuous bidirectional communication between cancer cells and the different cell populations within the TME. This communication can either work to promote tumor growth, as seen with carcinoma associated fibroblasts (CAFs), or inhibit tumor growth, as observed with tumor infiltrating lymphoid cells. To date, the majority of research focusing on understanding the role of fibroblasts in the TME has been on CAFs and their ability to enhance tumorigenesis. Although the majority of studies have focused on CAFs, some studies have shown that certain fibroblast populations can antagonize tumor growth. Despite this evidence for an inhibitory role of normal fibroblasts, the precise molecular mechanism by which these cells modulate cancer cell growth has yet to be elucidated. Here, we show that normal mammary fibroblasts (fibroblasts isolated from normal breast tissue) secrete soluble factors that induce caspase mediated cell death in a variety of cancer cell lines. This phenotype was observed in MDA-MB-231s as well as T47D, and BT474 cell lines. Further verification of this phenotype was performed in MDA-MB-231s using Annexin V staining and flow cytometry. When examining the mechanism of apoptotic induction, we observed a substantive increase in the cleavage of caspase 8, evidence that the extrinsic apoptotic pathway is activated. We are currently working to further elucidate the signaling pathways activated in the aforementioned cancer cell lines resulting in the induction of apoptosis by normal mammary fibroblasts. Our research reveals a novel and potentially tumor suppressive function of normal mammary fibroblasts in the tumor microenvironment through secretion of soluble factors that induce apoptosis in cancer cells. Citation Format: Matyas Abel Tsegaye, Mati Nemera, Zachary T. Schafer. Cancer cell apoptosis is induced by soluble factors secreted from normal mammary fibroblasts [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 316.
Enhancing Osteosarcoma Killing and CT Imaging Using Ultrahigh Drug Loading and NIR‐Responsive Bismuth Sulfide@Mesoporous Silica Nanoparticles
Authors: Yao Lu, Lihua Li, Zefeng Lin, Mei Li, Xiaoming Hu, Yu Zhang, Mingying Peng, Hong Xia, Gang Han
Journal: Advanced Healthcare Materials (2018)

Abstract Despite its 5‐year event‐free survival rate increasing to 60–65% due to surgery and chemotherapy, osteosarcoma (OS) remains one of the most threatening malignant human tumors, especially in young patients. Therefore, a new approach that combines early diagnosis with efficient tumor eradication and bioimaging is urgently needed. Here, a new type of mesoporous silica–coated bismuth sulfide nanoparticles (Bi 2 S 3 @MSN NPs) is developed. The well distributed mesoporous pores and large surface areas hold great promise for drug protection and encapsulation (doxorubicin (DOX), 99.85%). Moreover, the high photothermal efficiency of Bi 2 S 3 @MSNs (36.62%) offers great possibility for cancer synergistic treatment and highly near‐infrared‐triggered drug release (even at an ultralow power density of 0.3 W cm −2 ). After covalently conjugated to arginine‐glycine‐aspartic acid (RGD) peptide [c(RGDyC)], the NPs exhibit a high specificity for osteosarcoma and finally accumulate in the tumor cells (tenfold more than peritumoral tissues) for computed tomography (CT) imaging and tumor ablation. Importantly, the synergistic photothermal therapy–chemotherapy of the RGD–Bi 2 S 3 @MSN/DOX significantly ablates the highly malignant OS. It is further proved that the superior combined killing effect is achieved by activating the mitochondrial apoptosis pathway. Hence, the smart RGD–Bi 2 S 3 @MSN/DOX theranostic platform is a promising candidate for future applications in CT monitoring and synergistic treatment of malignant tumors.
Directional Difference of Conduction Velocity in the Cardiac Ventricular Syncytium Studied by Microelectrodes
Authors: Toyomisano, Noriyukitakayama, Takioshimamoto
Journal: Circulation Research (1959)

In the theory of electrocardiography the direction of myocardial fibers has been almost ignored. In order to evaluate whether this is proper or not, directional difference of conduction velocity in the ventricular syncytium was examined by capillary microelectrodes. Conduction velocity in the direction of myocardial fibers was found to be usually several times larger than that vertical to them. This difference is significantly large and cannot be ignored even though rapidity of conduction through Purkinje fibers is considered. This statement became more applicable in various abnormal conditions. Thus it is concluded that the direction of myocardial fibers should be given more attention in discussion of propagation of excitation waves in the cardiac ventricle.
Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy
Authors: Wenquan Ou, Liyuan Jiang, Raj Kumar Thapa, Zar Chi Soe, Kishwor Poudel, Jae-Hoon Chang, Sae Kwang Ku, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
Journal: Theranostics (2018)

The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and recurrence has gained increasing research attention. Regulatory T cells in the tumor microenvironment constitute a major obstacle in achieving robust CD8+ T cell antitumor immunotherapy. In the present study, we designed a photoimmunotherapy-based strategy involving a combination of photothermal and photodynamic therapies, followed by Treg cell suppression, for eliciting an immune response with IR-780- and imatinib-loaded layer-by-layer hybrid nanoparticles. Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Their photothermal effect, photodynamic effect as well as their effect on inhibiting Treg cells' suppressive function were investigated in vitro and in vivo. Their antitumor effect was evaluated using B16/BL6 and MC-38 tumor-bearing mice. Results: The layer-by-layer hybrid nanoparticles, which were pH-sensitive, enabled the release of IR-780 dye for NIR-induced photothermal and photodynamic effects, and the release of imatinib-loaded glucocorticoid-induced TNF receptor family-related protein/poly(lactic-co-glycolic acid) (GITR-PLGA) nanoparticles to initiate antitumor immunotherapy. The photothermal and photodynamic effects caused by IR-780 under NIR exposure resulted in direct tumor apoptosis/necrosis and the production of tumor-associated antigen, promoted dendritic cell maturation, and enhanced the presentation of tumor-associated antigen to T cells, while the imatinib-loaded GITR-PLGA cores reduced the suppressive function of Treg cells, and consequently activated effective CD8+ T cells towards tumors. Conclusion: With the significant photothermal, photodynamic and immunotherapies, the system successfully eradicated tumor growth, diminished tumor recurrence, and improved survival in vivo. The proposed nanoparticles provide a novel and versatile approach to boost antitumor photoimmunotherapy.
Physiological Analysis of Middle-Aged and Old Former Athletes
Authors: Bengtsaltin, Gunnargrimby
Journal: Circulation (1968)

Blood lipids, red cell volume, heart volume, dynamic spirometry, electrocardiograms made at rest and during exercise, and maximal oxygen uptake were determined in 29 former athletes 45 to 70 years old. The subjects had been very successful competitors in endurance events before the age of 30, but for at least 10 years preceding this study had been sedentary. Maximal oxygen uptake averaged 40 ml/kg/min which is 20% higher than that of sedentary middle-aged men but 25% lower than that of still active athletes of the same ages. Vital capacity, forced expiratory volume, and maximal voluntary ventilation showed normal values. Heart volume was large in relation to maximal oxygen uptake and was of the same magnitude as in still active athletes. Red cell volume was also large in relation to maximal oxygen uptake, but normal in relation to the body weight. Cholesterol in serum averaged 260 mg/100 ml. Values for neutral fat averaged 1.6 mM, which was higher than that for still active athletes. In the athletes still...
Abstract 713: Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients
Authors: Hye Ryun Kim, Hyo Jin Park, Jimin Son, Hyo Sup Shim, Byoung Chul Cho, Sun Young Rha, Sang-Jun Ha
Journal: Cancer Research (2018)

Abstract Purpose: Regulatory T (Treg) cells perform the immune suppressive function in cancer, but their suppressive mechanism in tumor microenvironment (TME) has not been clearly elucidated. We aim to identify the phenotype and functional mechanism of Treg cells in TME from cancer patients. Experimental Design: We collected 72 malignant effusion (ME) and peripheral blood (PB) specimens from stage IV cancer patients and 10 tumor tissue (TM) and PB from lung cancer patients who underwent surgery. Lymphocytes from ME, TM, and PB were analyzed for subtype of Tconv and Treg cells, and their expressions of immune checkpoint (IC) molecules including programmed death (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and T cell immunoglobulin containing molecule-3 (TIM-3) using by flow cytometry. To examine the functional role of PD-1 expressed Treg cells, TC-1 lung cancer mouse model was used. Result: Upregulation of PD-1 on Treg cells in TM and ME compared to PB was even more distinguishable than that on CD4+ and CD8+ Tconv cells. To clarify the characteristics of tumor infiltrating Treg cells, we comprehensively examined the characteristics of Treg cells from tumor, peri-tumor, and PB in lung cancer patients by analyzing the expression of IC molecules including PD-1, TIM-3, CTLA-4, and TIGIT, of which PD-1 is the highest expressed on tumor infiltrating Treg cells. To investigate the mechanism by which Treg cells mediate immune suppression, we compared the suppressive activity of Treg cells expressing high and low levels of PD-1 by co-culturing each population with naïve CD8+ T cells with or without αCD3/CD28 stimulation. This was more potently inhibited in co-cultures with PD-1high tumor infiltrating Treg cells than in those with PD-1low Treg cells. PD-1 blocked tumor infiltrating Treg cells demonstrated a significantly decreased suppressive function in the proliferation of CD8+ cells and their IFN-γ production. These results implicate that PD-1 expressed tumor infiltrating Treg confers the suppressive function of proliferation in CD8+ T cells through PD-1: PD-L1 interaction. Conclusion: Our study evidently demonstrated that upregulated PD-1 on tumor infiltrating Treg cells and their PD-1: PD-L1 interaction could be potential cause of T cell suppression, which might be helpful to completely understand their suppressive mechanism in cancer patients. Citation Format: Hye Ryun Kim, Hyo Jin Park, Jimin Son, Hyo Sup Shim, Byoung Chul Cho, Sun Young Rha, Sang-Jun Ha. Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients [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 713.
Renal Myogenic Response
Authors: RodgerLoutzenhiser, AnilBidani, LisaChilton
Journal: Circulation Research (2002)

The kinetic attributes of the afferent arteriole myogenic response were investigated using the in vitro perfused hydronephrotic rat kidney. Equations describing the time course for pressure-dependent vasoconstriction and vasodilation, and steady-state changes in diameter were combined to develop a mathematical model of autoregulation. Transfer functions were constructed by passing sinusoidal pressure waves through the model. These findings were compared with results derived using data from instrumented conscious rats. In each case, a reduction in gain and increase in phase were observed at frequencies of 0.2 to 0.3 Hz. We then examined the impact of oscillating pressure signals. The model predicted that pressure signals oscillating at frequencies above the myogenic operating range would elicit a sustained vasoconstriction the magnitude of which was dependent on peak pressure. These predictions were directly confirmed in the hydronephrotic kidney. Pressure oscillations presented at frequencies of 1 to 6 Hz...
Abstract 3360: Origins of mutations in colorectal cancer
Authors: Barry Gold
Journal: Cancer Research (2018)

Abstract The origins of most human cancers remain unclear. In selected cases, exposure to potent environmental mutagens or familial germ line mutations, which affect tumor suppressor genes or oncogenes, have been identified with specific cancers. Wnt signaling due to mutations in APC is compromised as an early event in 75% of human colorectal cancer (CRC), with truncating nonsense mutations (65%) dominating the mutation spectrum. Because 43% of the nonsense mutations occur at Arg CGA codons, the C→T mutation is attributed to hydrolytic deamination of 5-methylC. The enhanced incidence of colorectal cancer (CRC) associated with the Western diet has been epidemiologically linked to heterocyclic aromatic amines (HAA) produced by high temperature cooking of meat. Analysis of the mutation spectra in CRC indicated that the G→T transversions, which are produced by this class of mutagens were not enriched but were actually lower than what would be statistically anticipated based on random mutations. Moreover, the APC mutation patterns in the U.S.A. vs. China are indistinguishable despite differences in diet. However, dissection of the APC mutation pattern in tumors that arise in the different anatomical regions of the large intestine shows that the nonsense mutation pattern in APC differ in the different regions: there is a statistically significant increase in G→T transversions in the rectum vs. the other regions, albeit, the percent of G→T mutations still remains lower than predicted based on random mutagenesis. Therefore, it appears that HAA's may contribute to the incidence of rectal cancer. Citation Format: Barry Gold. Origins of mutations in colorectal 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 3360.
Abstract B64: The novel ZIP4 regulation and its role in cancer stem cell-related activities in ovarian cancer
Authors: Yan Xu, Qipeng Fan, Qingchun Cai, Kenneth P. Nephew
Journal: Clinical Cancer Research (2018)

Abstract The role and regulation of ZIP4, a zinc (Zn) transporter, have been studied in the context of extracellular Zn transporting. Factors other than Zn with ZIP4 regulatory effects are essentially unknown. In addition, its role in cancer stem cell (CSC) has not been reported in any type of cancer. RNA-seq analyses were conducted to compare genes differentially expressed in less and more aggressive epithelial ovarian cancer (EOC) cells. ZIP4 expression and its regulation was assessed by immunoblotting, quantitative PCR, or immunofluorescence staining in human ovarian tissues. CSC-related activities were examined to evaluate the role of ZIP4 in human high-grade serous ovarian cancer (HGSOC) cells. RNAi and CRISPR techniques were used to knock down or knock out ZIP4 and related genes. EOC tumors overexpressed ZIP4 when compared with normal and benign tissues. ZIP4 knockout significantly reduced several CSC-related activities in EOC cells, including proliferation, anoikis resistance, colony formation, spheroid formation, drug resistance, and side-population (SP). Only ZIP4-expressing SP highly expressed known CSC markers ALDH1 and OCT4. ZIP4 knockout dramatically reduced tumorigenesis and ZIP4 overexpression increased tumorigenesis in vivo. In addition, the ZIP4-expressing SP population had the tumor initiating activity. Moreover, the oncolipid lysophosphatic acid (LPA) effectively upregulated ZIP4 expression via the nuclear receptor peroxisome proliferator-activated receptor gamma, and LPA’s promoting effects in CSC-related activities in HGSOC cells was at least partially mediated by ZIP4 in an extracellular Zn-independent manner. Our critical data imply that ZIP4 is a new and important cancer stem cell regulator in EOC. Our data also provide an innovative interpretation for the apparent disconnection between low levels of zinc and upregulation of ZIP4 in EOC tissues. Citation Format: Yan Xu, Qipeng Fan, Qingchun Cai, Kenneth P. Nephew. The novel ZIP4 regulation and its role in cancer stem cell-related activities in ovarian cancer. [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 B64.
Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial
Authors: Robert J S Coelen, Eva Roos, Jimme K Wiggers, Marc G Besselink, Carlijn I Buis, Olivier R C Busch, Cornelis H C Dejong, Otto M van Delden, Casper H J van Eijck, Paul Fockens, Dirk J Gouma, Bas Groot Koerkamp, Michiel W de Haan, Jeanin E van Hooft, Jan N M IJzermans, G Matthijs Kater, Jan J Koornstra, Krijn P van Lienden, Adriaan Moelker, Steven W M Olde Damink, Jan-Werner Poley, Robert J Porte, Rogier J de Ridder, Joanne Verheij, Victor van Woerden, Erik A J Rauws, Marcel G W Dijkgraaf, Thomas M van Gulik
Journal: The Lancet. Gastroenterology & hepatology (2018)
Reducing anaemia in low income countries: control of infection is essential
Authors: Sant-Rayn Pasricha, Andrew E Armitage, Andrew M Prentice, Hal Drakesmith
Journal: BMJ (2018)

In settings with high infection burdens, iron interventions for anaemia may be neither safe nor effective. Strategies to tackle the global burden of anaemia must take this into account, argue <b>Sant-Rayn Pasricha and colleagues</b>
Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women
Authors: Lesley Hoyles, José-Manuel Fernández-Real, Massimo Federici, Matteo Serino, James Abbott, Julie Charpentier, Christophe Heymes, Jèssica Latorre Luque, Elodie Anthony, Richard H. Barton, Julien Chilloux, Antonis Myridakis, Laura Martinez-Gili, José Maria Moreno-Navarrete, Fadila Benhamed, Vincent Azalbert, Vincent Blasco-Baque, Josep Puig, Gemma Xifra, Wifredo Ricart, Christopher Tomlinson, Mark Woodbridge, Marina Cardellini, Francesca Davato, Iris Cardolini, Ottavia Porzio, Paolo Gentileschi, Frédéric Lopez, Fabienne Foufelle, Sarah A. Butcher, Elaine Holmes, Jeremy K. Nicholson, Catherine Postic, Rémy Burcelin, Marc-Emmanuel Dumas
Journal: Nature Medicine (2018)