tbuckley/cabot-search huggingface dataset:
Chelation Choices and Iron Burden Among Patients with Thalassemia in the 21st Century: a Report From the Thalassemia Clinical Research Network (TCRN) Longitudinal Cohort.
Authors: Janet L Kwiatkowski, Hae-Young Kim, Alexis A. Thompson, Charles T. Quinn, Brigitta U Mueller, Isaac Odame, Patricia J Giardina, Elliott P Vichinsky, Jeanne Boudreaux, John B Porter, Thomas Coates, Nancy F Olivieri, Ellis J Neufeld
Journal: Blood (2009)
B細胞非ホジキンリンパ腫の治療における新規免疫結合体であるイノツズマブオゾガマイシンの安全性,薬物動態,および予備的臨床活性:第1相試験の結果
Authors: Advani Anjali, Coiffier Bertrand, S Czuczman Myron, Dreyling Martin, Foran James, Gine Eva, Gisselbrecht Christian, Ketterer Nicolas, Nasta Sunita, Rohatiner Ama, G H Schmidt-Wolf Ingo, Schuler Martin, Sierra Jorge, R Smith Mitchell, Verhoef Gregor, N Winter Jane, Boni Joseph, Vandendries Erik, Shapiro Mark, Fayad Luis
Journal: Journal of Clinical Oncology (2010)
Abstract 17447: Experimental Sleep Curtailment Increases 24 - Hour Ambulatory Blood Pressure in Healthy Individuals
Authors: Naima Covassin, Jan Bukartyk, Andrew D Calvin, Filip Soucek, Lukas Ruzek, Erik K St Louis, Virend K Somers
Journal: Circulation (2016)

Introduction: Voluntary sleep curtailment is escalating in the general population. Mounting epidemiological research identifies chronic sleep deficiency as an independent determinant of cardiovascular diseases, with compelling evidence linking short sleep to incident hypertension. Nonetheless, experimental data supporting a causal relationship are scarce. Hypothesis: We tested the hypothesis that exposure to experimental prolonged sleep restriction would raise 24-hour ambulatory blood pressure (BP) and that this elevation would be driven by baroreflex impairment. Methods: Fourteen healthy subjects (6 male, age 24±1 years, body mass index 24±1 kg/m2) completed a randomized, controlled, crossover study comprising a 4-day acclimation period, followed by 9 days of experimental sleep restriction (4 hours of sleep/night) or normal sleep, and a 3-day recovery period. Twenty-four hour ambulatory blood pressure monitoring was performed repeatedly throughout the 16-day inpatient protocol. Spontaneous baroreflex sen...
Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia
Authors: NorifumiUrao, MitsuhikoOkigaki, HiroyukiYamada, YasushiAadachi, KuniharuMatsuno, AkihiroMatsui, ShinsakuMatsunaga, KentoTateishi, TetsuyaNomura, TomosaburoTakahashi, TetsuyaTatsumi, HiroakiMatsubara
Journal: Circulation Research (2006)

We investigated whether the mobilization of endothelial progenitor cells (EPCs) by exogenous erythropoietin (Epo) promotes the repair of injured endothelium. Recombinant human Epo was injected (1000 IU/kg for the initial 3 days) after wire injury of the femoral artery of mice. Neointimal formation was inhibited by Epo to 48% of the control (P<0.05) in an NO-dependent manner. Epo induced a 1.4-fold increase in reendothelialized area of day 14 denuded vessels, 55% of which was derived from bone marrow (BM) cells. Epo increased the circulating Sca-1+/Flk-1+ EPCs (2.0-fold, P<0.05) with endothelial properties NO dependently. BM replacement by GFP- or β-galactosidase-overexpressing cells showed that Epo stimulated both differentiation of BM-derived EPCs and proliferation of resident ECs. BM-derived ECs increased 2.2- to 2.7-fold (P<0.05) in the Epo-induced neoendothelium, where the expression of Epo receptor was upregulated. Epo induced Akt/eNOS phosphorylation and NO synthesis on EPCs and exerted an antiapopt...
Abstract 367: Methods to enhance the optical resolution for 3D-SIM for the study of Hodgkin's lymphoma nuclei
Authors: Aleksander T. Szczurek, Fabio Contu, Roberta Vanni, Hans Knecht, Nathalie Johnson, Tina Haliotis, Sabine Mai
Journal: Cancer Research (2018)

Abstract In spite of a great deal of knowledge already available, the precise higher order organization of chromatin is still a subject of an debate. Moreover, cancerous cells have an altered chromatin organization in comparison to their healthy counterparts. This is also the case for Hodgkin's lymphoma (HL) - a lymphoid malignancy of B cell origin. HL comprises two cell types, the Hodgkin cells and the diagnostic bi- or multinucleated Reed-Sternberg (RS) cells readily distinguishable from healthy lymphocytes. Patient stratitifcation has been proposed through the quantitative analysis of 3D nuclear telomere organization. With the advent of super resolution microscopy (SRM), further insights into the spatial organization of the cancer genome become feasible. This includes the study of chromatin arrangement with SRM. However, its application to HL remains limited due to technical difficulties: HL cells display thickness of &amp;gt;10µm resulting in light scattering and decreased signal-to-noise ratio. Structured Illumination Microscopy (SIM, a SRM type) in particular has advanced studies of the sub-cellular structures. It relies on projection of excitation pattern on to a fluorescently labeled sample. Sample's information is then shifted to a detectable band doubling the 3D resolution. Sample's refractive index homogeneity and counteracting photo-bleaching are both crucial for maintenance of the sharp illumination pattern and high-quality SIM, particularly in thick samples. Nevertheless, sample mounting media for SIM have not undergone a significant evolution since almost a decade. By identification and systematic comparison of non-hazardous components of mounting media we demonstrate increased sample's transparency and consequently improved SIM-quality. Using these novel sample clearing protocols we demonstrate high-resolution chromatin organization at ~120nm level in large RS cells of HL cell lines and in patient samples compared to lymphocytes. This work is of relevance of identification of new diagnostic structural biomarkers for HL. Citation Format: Aleksander T. Szczurek, Fabio Contu, Roberta Vanni, Hans Knecht, Nathalie Johnson, Tina Haliotis, Sabine Mai. Methods to enhance the optical resolution for 3D-SIM for the study of Hodgkin's lymphoma nuclei [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 367.
Circulating Matrix Metalloproteinases and Their Inhibitors in Patients with Kawasaki Disease
Authors: HideakiSenzaki, SatoshiMasutani, JunKobayashi, ToshikiKobayashi, HirofumiNakano, HironoriNagasaka, NozomuSasaki, HaruhikoAsano, ShuneiKyo, YujiYokote
Journal: Circulation (2001)

Background— Accelerated matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) and/or the quantitative imbalance between MMP and tissue inhibitor of MMP (TIMP) have been implicated in several pathological conditions. MMP and TIMP may also be involved in the destruction of the coronary arterial wall and the resultant coronary arterial lesions in Kawasaki disease. Methods and Results— Plasma levels of MMPs, neutrophil elastase, and TIMPs were measured by enzyme-linked immunoassay in 57 patients with Kawasaki disease and no coronary arterial lesions (group 1) and in 8 patients with Kawasaki disease and coronary arterial lesions (group 2). Blood samples were obtained before and after intravenous gamma globulin therapy and in the convalescent stage. Levels of MMPs, neutrophil elastase, and TIMPs were significantly higher in Kawasaki disease patients before gamma globulin therapy than in 18 age-matched afebrile control subjects and 17 age-matched febrile disease control subjects (...
Abstract 19319: Trends in Exercise Capacity at Baseline and Its Improvement After Cardiac Rehabilitation in Patients With Acute Myocardial Infarction Over 23 Years
Authors: Kyohei Marume, Michio Nakanishi, Reon Kumasaka, Shigefumi Fukui, Nakao Kazuhiro, Tetsuo Arakawa, Masanobu Yanase, Teruo Noguchi, Satoshi Yasuda, Yoichi Goto
Journal: Circulation (2016)

Background: The influences of recent trends of aging of patients and shortening of the bedrest period on exercise capacity at the entry of cardiac rehabilitation (CR) and its improvement after CR i...
Chronic Inhibition of Endothelium-Derived Nitric Oxide Synthesis Causes Coronary Microvascular Structural Changes and Hyperreactivity to Serotonin in Pigs
Authors: AkiraIto, KensukeEgashira, ToshiakiKadokami, YoshihiroFukumoto, TsuneoTakayanagi, RyuichiNakaike, TakeshiKuga, KatsuoSueishi, HiroakiShimokawa, AkiraTakeshita
Journal: Circulation (1995)

Background Endothelium-derived nitric oxide (NO) is believed to regulate myocardial perfusion and structural changes in the vascular wall. Our objective was to determine whether chronic inhibition of NO synthesis causes structural and functional changes in coronary arteries. Methods and Results Coronary vasomotor response was studied in pigs before and after chronic oral administration of the NO synthesis antagonist Nω-nitro-l-arginine methyl ester (L-NAME) 30 mg · kg−1 · d−1 for 2 weeks. Chronic L-NAME treatment increased (P<.01) arterial pressure but did not alter baseline coronary blood flow (CBF), epicardial coronary diameter, or heart rate. Chronic L-NAME treatment augmented (P<.01) the decrease in CBF in response to intracoronary serotonin (30 μg/kg) from 5±14% to 40±5% but did not alter the CBF response to prostaglandin F2α. The serotonin-induced decrease in CBF after acute L-NAME administration was still less before (1.3±0.4%) than after chronic L-NAME treatment (51±6%). Chronic L-NAME treatment a...
Hepatic Involvement of IgG4-Related Disease Presenting as Multiple Hypermetabolic Masses on FDG PET/CT
Authors: Qingqing Pan, Ying Wang, Yaping Luo, Yanru Ma, Fang Li
Journal: Clinical Nuclear Medicine (2018)

A 45-year-old man was found with multiple hepatic masses in CT/MR, suggesting liver metastases of unknown origin. F-FDG PET/CT showed several hypermetabolic masses in the liver; patchy increased uptake in the pancreas; and FDG-avid lymph nodes in the neck, axilla, and mediastinum. Histopathology with biopsy revealed enriched IgG4-positive lymphoplasmacytic cells infiltrating in the liver, pancreas, and lymph nodes, which confirmed the diagnosis of IgG4-related disease. The lesions were diminished on follow-up PET/CT 3 months after treatment with prednisone. This case illustrated that multifocal FDG-avid hepatic mass might be the involvement of IgG4-related disease, which should be differentiated from malignancies.
Abstract LB-376: Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma
Authors: Matthew R. Grimmer
Journal: Cancer Research (2018)

Abstract Hypermutated gliomas arising from treatment with alkylating agents, such as temozolomide (TMZ), are genetically distinct, recurrent tumors about which very little is known. Here, we have identified common and subtype-specific patterns in the tumor evolution of IDH-mutant, low-grade astrocytoma (1p/19q-intact) and oligodendroglioma (1p/19q-codeleted) from 57 glioma patients. Hypermutation involved unanimous defects in mismatch repair in both subtypes, with unique mismatch repair alterations differentiating hypermutation events in serial recurrences. Hypermutation was associated with malignant progression in astrocytoma, and can differentiate high-grade regions from low-grade regions within the same tumor. Hypermutated oligodendroglioma tumors associated with newly-arising p53 mutations and mirrored the early branching evolution of astrocytoma tumors. Results from this longitudinal clinical-genomic study suggest prominent roles for MMR and p53 in the establishment and maintenance of hypermutation. The evolution of TMZ-related tumor antigens across serial tumor recurrences will be presented. Citation Format: Matthew R. Grimmer. Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma [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 LB-376.
Abstract 15015: Spontaneous Beating of Cardiac Pacemaker Cell Requires Basal Epac1 Activation
Authors: Tatiana M Vinogradova, Daniel R Riordon, Kirill V Tarasov, Edward G Lakatta
Journal: Circulation (2016)

Spontaneous firing of sinoatrial node cells (SANC) is regulated by sarcoplasmic reticulum (SR) generated local subsarcolemmal Ca2+ releases (LCRs), which appear during diastolic depolarization (DD) and activate an inward Na+-Ca2+exchange current to increase DD rate and spontaneous SANC beating rate. Recent studies implicated activation of cAMP-binding protein Epac1 in the regulation of Ca2+ handling in ventricular myocytes (VM) via Epac1-PLC-CaMKII-dependent pathway. Compared to VM rabbit SANC have high basal level of cAMP, suggesting possible activation of Epac1 in the basal state. However, a role of Epac1 activation in modulation of SR Ca2+ cycling and spontaneous beating of SANC has not been evaluated. Here we studied impact of Epac1 inhibition or activation on spontaneous beating of rabbit SANC and possible mechanisms of Epac1-dependent regulation of cardiac pacemaker function. Although the expression of Epac1 (RNA-sequencing) in rabbit SANC was 2-fold less, than in VM, a selective Epac1 inhibitor CE3...
Abstract P286: Acetylation Affords Enhanced Proteolytic Function in Normal and Diseased Myocardium
Authors: Nobel Zong, Caiyun Fang, Ding Wang, Hongxiu Yu, Jun Zhang, Pengyuan Yang, Peipei Ping
Journal: Circulation Research (2011)

Proteasome complexes have essential implications on protein homeostasis and myocardial viability under stress. In the heart, the dynamics of proteasome complexes is regulated by post-translational modifications. In particular, acetylation contributes to the adjustment of cardiac functional proteome. However, the regulation of proteasome complexes by acetylation remains largely unknown. We characterized the acetylome (N-terminal and lysine acetylation) of cardiac 20S proteasomes using proteomic technology. With targeted enrichment, eight sites of lysine acetylation and nine sites of N-terminal acetylation were captured, which constituted the first comprehensive acetylome map of cardiac 20S proteasomes. Among them, six sites of lysine acetylation were inducible with pharmacological inhibitors of histone de-acetylases (HDACs). Both in vitro and in vivo assays demonstrated that HDACs inhibition led to elevated proteasome function. With purified 20S proteasomes, this impact directly related to acetylation modifications. Significantly, this endogenous regulatory mechanism manifests in both clinical and murine model of diseased myocardia. Proteasome biology is modulated by acetylation modifications in the heart. The potency of this regulatory mechanism was demonstrated in both mouse and human species. Moreover, this inherent rheostat effects in both acutely pathological murine model of ischemia-reperfusion and chronically pathological model of end-stage heart failure. With the novel observation made in this investigation, restoration of proteasomal function via pharmacological application after stress turns feasible.
Comparison of chemosensitivity testing of CETCs and spheroids in cancer patients with solid tumors.
Authors: Katharina Pachmann, Dorothea Zimon, Monika Pizon, Ulrich A. Pachmann
Journal: Journal of Clinical Oncology (2014)

2598 Background: In vitro chemosensitivity testing of circulating epithelial tumor cells (CETCs) provides real-time information about the sensitivity of the tumor cells present in the patient and correlates with treatment success. Nevertheless, a fraction of CETCs can survive after conventional chemotherapy and grow into distant metastasis. A subpopulation of CETCs with proliferation activity has the ability to form spheroids in suspension culture. Spheroids exhibit stem cell-like properties and may be responsible for chemo therapeutic resistance. Therefore, the aim of our study was the comparison of the efficacy of chemo therapeutics on CETCs and on spheroids originated from the same individuals. Methods: The enumeration of CETCs collected from patients with solid tumors in clinical stage 1-4 were performed using the maintrac method. Subsequently, viable CETCs were cultured in suspension culture system allowing for spheroid formation. To evaluate the cytotoxic effect CETCs and spheroids were exposed to anticancer drugs in short time culture in different concentrations and for different periods of time. Results: Theresponse to chemotherapeutics was different between CETCs and spheroids. In contrast to CETCs, spheroids from the same patients were significantly more chemoresistant. Whereas active drugs led to membrane permeability in single CETCs with subsequent staining of the nuclei with propidium iodide, the same drugs led to disintegration of tumorspheres with destruction of part of the cells but often part of the cells in the spheres were able to survive. Epirubicin and, interestingly, and especially salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, showed the best effects. Docetaxel, cyclophosphamide and 5-Fluoruracil showed almost no cytotoxic effects onto the cells in the spheres. Conclusions: Our results show, for the first time that stem cells circulating in peripheral blood, capable of forming spheroids are way more resistant to anticancer drugs than the remnant circulating tumor cells. We, furthermore, demonstrate that salinomycin efficiently destroys spheroids cultured from CETCs, strengthening its role as promising anti-cancer therapeutic.
Abstract 4098: New strategy of drug response assessment using PDX organoid platform for non-resectable pancreatic cancer
Authors: A-Ra Jeon, Sun Il Choi, Sang-Jae Park, Sung-Sik Han, Sun-Young Kong, Min Kyeong Kim, Yu-sun Lee, Jieun Im, Min Kyeong Lee, Sang Hyun Park, Joon-Ki Kim, Kyong-Ah Yoon, Young-Hwan Koh, Ju Hee Lee, Woo Jin Lee, Sang Myung Woo, Yun-Hee Kim
Journal: Cancer Research (2018)

Abstract To develop an efficient drug screening platform which overcomes the difference of drug response between initial screening and clinical trial stage is a pivotal issue for drug discovery. The patient-derived Xenograft (PDX) model has been reported as a screening system to reflect the microenvironment and heterogeneity of tumor. However, in pancreatic cancer that 80 % of patients is non-resectable, PDX is not be suitable for an initial screening model in terms of economic- and time cost of mouse-based amplification system as well as the lack of obtaining pancreatic tumor tissue from fine needle biopsy or percutaneous gun. To overcome this limitation, here we newly suggested organoids system, miniature organ culture on a dish, that are generated from tumor tissues of orthotopic PDX model, which has the advantages of reflection of each patient's characteristics as well as amplification of limited tumor tissue. Besides, it is possible to screen of drug responsibility with a little number of cells. 12 organoids derived from PDX using needle or gun biopsy tumor tissues showed EpCAM overexpression and each unique morphological phenotype. Moreover, from drug responsibility test, H #43 and H #44, an organoids derived from a gemcitabine-sensitive patients, were highly responsible to gemcitabine, whereas the organoids from gemcitabine-resistant patients, G #20 and H #19 showed a strong resistance to gemcitabine as measuring the IC50 value. In addition, combined treatment with gemcitabine and abraxane to the G #13 model which has no clinical information of drug response due to early death, it inhibited organoid formation significantly, showing a combination index below 1, which was proved through in vivo (PDX) validation. Taken together, the PDX-Organoid system might be able to reflect primary tumor characteristics as well as to overcome the quantitative limitations of the specimen and time cost, and thereby it is possible to predict drug response early in vitro, making it very efficient as an anti-cancer drug development platform for pancreatic cancer. Citation Format: A-Ra Jeon, Sun Il Choi, Sang-Jae Park, Sung-Sik Han, Sun-Young Kong, Min Kyeong Kim, Yu-sun Lee, Jieun Im, Min Kyeong Lee, Sang Hyun Park, Joon-Ki Kim, Kyong-Ah Yoon, Young-Hwan Koh, Ju Hee Lee, Woo Jin Lee, Sang Myung Woo, Yun-Hee Kim. New strategy of drug response assessment using PDX organoid platform for non-resectable pancreatic 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 4098.
Abstract 1851: Combined inhibition of PARP and the unfolded protein response synergistically reduces viability in BRCA1-mutant breast cancer cells
Authors: Jennifer E. Endress, Isaac S. Harris, Jacob Stewart-Ornstein, Galit Lahav, Joan S. Brugge
Journal: Cancer Research (2018)

Abstract As single agents, small molecule inhibitors of poly-ADP-ribose polymerase (PARP) have shown remarkable efficacy in BRCA1/2-mutant tumors due to their synthetic lethality in DNA damage response-deficient cells. While PARP inhibitors, such as olaparib, have gained FDA-approval for gynecological malignancies, recurrent disease remains a challenge. To identify drug combinations with the potential to improve the initial response to PARP inhibition, we carried out a high-throughput drug screen in which we examined the ability of olaparib to synergize with more than 500 small molecules in BRCA1-mutant breast cancer cells. The compounds investigated included not only conventional “anti-cancer” agents but also lesser-studied metabolic and stress-inducing drugs. All compounds were tested across 10-point dose curves using an image-based readout to avoid false positives/negatives associated with more traditional metabolic readouts of cell viability (i.e. Cell Titer Glo). This screening approach revealed that inhibition of the unfolded protein response (UPR) sensitizes breast cancer cells to PARP inhibition. We have further characterized interaction of one class of inhibitors that target IRE1 (inositol-requiring enzyme 1), which initiates adaptive responses to ER stress through unconventional mRNA splicing of the transcription factor X-box binding protein 1 (XBP1). Combining olaparib with an inhibitor of IRE1-mediated XBP1 splicing (STF-0831010) synergistically reduced cancer cell viability in BRCA1-mutant SUM149 breast cancer cells. This combination led to increased DNA damage, indicated by increased γ-H2AX staining. This study provides evidence that UPR inhibition sensitizes cells to PARP inhibition, suggesting a previously un-recognized connection between PARP inhibition and protein homeostasis. Furthermore, it identifies a potential new drug combination to increase the efficacy of PARP inhibitors in the clinic. Citation Format: Jennifer E. Endress, Isaac S. Harris, Jacob Stewart-Ornstein, Galit Lahav, Joan S. Brugge. Combined inhibition of PARP and the unfolded protein response synergistically reduces viability in BRCA1-mutant breast 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 1851.