tbuckley/cabot-search huggingface dataset:
Patent Foramen Ovale as a Risk Factor for Cryptogenic Stroke
Authors: Marco Di Tullio, Ralph L. Sacco, Aasha Gopal, J. P. Mohr, Shunichi Homma
Journal: Annals of Internal Medicine (1992)

To determine and compare the prevalence of patent foramen ovale in patients with stroke of undetermined origin (cryptogenic) and in patients with stroke of determined origin to assess the possible role of patent foramen ovale as a risk factor for cryptogenic stroke.Cross-sectional study with nested case-control analysis.A total of 146 patients (73 men, 73 women) with acute ischemic stroke referred to the echocardiography laboratory for evaluation.Neurovascular Unit and Echocardiography Laboratory, Columbia-Presbyterian Medical Center, New York, New York.Patients were considered to have strokes of determined origin or cryptogenic strokes according to National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank criteria. The presence of patent foramen ovale was assessed by contrast echocardiography, performed blinded for type of stroke. The association between patent foramen ovale and type of stroke was tested after correcting for patients' demographic variables and stroke risk factors.The overall prevalence of patent foramen ovale was 26 of 146 patients (18%; 95% Cl, 11.4% to 24.6%). Patients with cryptogenic stroke (31%) had a significantly higher prevalence of patent foramen ovale than did patients with an identifiable cause of stroke (69%) in both the younger (less than 55 years; 48% compared with 4%; P less than 0.001) and the older (greater than or equal to 55 years; 38% compared with 8%; P less than 0.001) age groups. Multiple logistic regression analysis was used to identify the presence of a patent foramen ovale as strongly associated with the diagnosis of cryptogenic stroke (odds ratio, 7.2; Cl, 2.4 to 21.7), irrespective of patient age and other stroke risk factors.Patients with cryptogenic stroke have a higher prevalence of patent foramen ovale than patients with stroke of determined cause in all age groups, even after correcting for the presence of recognized stroke risk factors. This identifies patent foramen ovale as a risk factor for cryptogenic stroke. Regardless of patient age, contrast echocardiography should be considered when the cause of stroke is unknown.
Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor
Authors: Audrey Clapéron, Martine Mergey, Lynda Aoudjehane, Thanh Huong Nguyen Ho-Bouldoires, Dominique Wendum, Aurélie Prignon, Fatiha Merabtene, Delphine Firrincieli, Christèle Desbois-Mouthon, Olivier Scatton, Filomena Conti, Chantal Housset, Laura Fouassier
Journal: Hepatology (2013)

Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant desmoplastic environment. Poor prognosis of CCA has been associated with the presence of alpha-smooth muscle actin (α-SMA)-positive myofibroblasts (MFs) in the stroma and with the sustained activation of the epidermal growth factor receptor (EGFR) in tumor cells. Among EGFR ligands, heparin-binding epidermal growth factor (HB-EGF) has emerged as a paracrine factor that contributes to intercellular communications between MFs and tumor cells in several cancers. This study was designed to test whether hepatic MFs contributed to CCA progression through EGFR signaling. The interplay between CCA cells and hepatic MFs was examined first in vivo, using subcutaneous xenografts into immunocompromised mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastatic dissemination of tumors. These effects were abolished by gefitinib, an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA tissues showed that stromal MFs expressed HB-EGF, whereas EGFR was detected in cancer cells. In vitro, HLMFs produced HB-EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells. These effects were abolished in the presence of gefitinib or HB-EGF-neutralizing antibody. We also showed that CCA cells produced transforming growth factor beta 1, which, in turn, induced HB-EGF expression in HLMFs.A reciprocal cross-talk between CCA cells and myofibroblasts through the HB-EGF/EGFR axis contributes to CCA progression.
Abstract 16789: Loss of Endothelial Barrier in Fibrillin-1-Deficient Marfan Mice (mgR/mgR) Results in Severe Inflammation After Adenoviral Gene Therapy
Authors: Philipp C Seppelt, Simon Schwill, Rawa Arif, Antje Weber, Marcin Zaradzki, Karsten Richter, Peter N. Robinson, Andreas Wagner, Stephan Ensminger, Karck Matthias, Klaus Kallenbach
Journal: Circulation (2014)

Introduction: Nowadays surgery still remains option of choice for therapy of aneurysm in Marfan syndrome. Aortic tissue of Marfan patients shows elastolysis enhanced by proteolytic activity of Matrix Metalloproteinases (MMPs). In this study we performed adenoviral gene transfer of Tissue Inhibitor of MMP-1 (TIMP-1) in aortic grafts of Fibrillin-1-deficient Marfan mice (mgR/mgR) in order to reduce aortic elastolysis. Methods: We performed heterotopic infrarenal transplantation of thoracic aorta in female mice (n=35, n=7/group). MgR/mgR and wild-type (WT) aorta (C57BL/6) was either incubated ex vivo with adenoviral vector coding for human TIMP-1 or ß-Galactosidase (5x10^9pfu/ml) or as control with culture medium. 30 days after surgery overexpression of transgene was assessed by immunohistochemistry (IHC) and collagen in situ zymography (ISZ). Histologic staining was performed to outline elastin breaks, signs of inflammation and Neointimal Index (NI). Endothelial barrier was evaluated with the use of transmission electron microscope (TEM) and perfusion of fluorescent albumin. Results: IHC and ISZ revealed sufficient expression of transgene. Severe intimal hyperplasia and distinctive signs of cellular inflammation were solely observed in mgR/mgR aorta after adenoviral transduction (NI: ß-Gal 0.23; TIMP-1 0.43), but not in WT aorta (NI: Native 0.01; TIMP-1 0.00). Compared to native mgR/mgR and TIMP-1 treated WT aorta, NI in TIMP-1 treated mgR/mgR aorta was highly significantly larger (p=0.001; p=0.001). Native mgR/mgR grafts presented with severe elastolysis compared to WT (p=0.001). Regardless of the vector transduced elastolysis in mgR/mgR aorta after adenoviral gene therapy was more pronounced compared to WT aorta (ß-Gal p=0.001; TIMP-1 p=0.001). Albumin diffusion through the endothelial barrier was increased in native mgR/mgR aorta compared to native WT aorta (p=0.037). TEM analysis of mgR/mgR aorta displayed reconstruction of the basement membrane and basolateral space. Conclusions: Murine Marfan aortic grafts developed severe inflammation after adenoviral exposure. Fibrillin-1-deficiency is associated with dysfunction of endothelial barrier which could be a target for alternative therapies in Marfan syndrome.
T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV
Authors: Mario Clerici, Marina Saresella, Fulvia Colombo, Sabrina Fossati, Natascia Sala, Dorella Bricalli, Maria Luisa Villa, Pasquale Ferrante, Len Dally, Alessandra Vigano'
Journal: Blood (2000)
Ageing is a risk factor in imatinib mesylate cardiotoxicity
Authors: Wael Maharsy, Anne Aries, Omar Mansour, Hiba Komati, Mona Nemer
Journal: European Journal of Heart Failure (2014)

Aims Chemotherapy‐induced heart failure is increasingly recognized as a major clinical challenge. Cardiotoxicity of imatinib mesylate, a highly selective and effective anticancer drug belonging to the new class of tyrosine kinase inhibitors, is being reported in patients, some progressing to congestive heart failure. This represents an unanticipated challenge that could limit effective drug use. Understanding the mechanisms and risk factors of imatinib mesylate cardiotoxicity is crucial for prevention of cardiovascular complications in cancer patients. Methods and results We used genetically engineered mice and primary rat neonatal cardiomyocytes to analyse the action of imatinib on the heart. We found that treatment with imatinib (200 mg/kg/day for 5 weeks) leads to mitochondrial‐dependent myocyte loss and cardiac dysfunction, as confirmed by electron microscopy, RNA analysis, and echocardiography. Imatinib cardiotoxicity was more severe in older mice, in part due to an age‐dependent increase in oxidative stress. Mechanistically, depletion of the transcription factor GATA4 resulting in decreased levels of its prosurvival targets Bcl‐2 and Bcl‐ X L was an underlying cause of imatinib toxicity. Consistent with this, GATA4 haploinsufficient mice were more susceptible to imatinib, and myocyte‐specific up‐regulation of GATA4 or Bcl‐2 protected against drug‐induced cardiotoxicity. Conclusion The results indicate that imatinib action on the heart targets cardiomyocytes and involves mitochondrial impairment and cell death that can be further aggravated by oxidative stress. This in turn offers a possible explanation for the current conflicting data regarding imatinib cardiotoxicity in cancer patients and suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted.
Abstract 2694: Novel sesquiterpene lactones derived from Vernonia cinerea inhibit STAT3 activity and suppress human glioblastoma phenotype
Authors: Gabriella Miklossy, Ui Joung Youn, Peibin Yue, Leng Chee Chang, James Turkson
Journal: Cancer Research (2014)

Abstract Constitutively-active STAT3 is prevalent in glioblastoma multiforme, breast cancer and many other human tumors and is a valid target for the discovery of novel anticancer therapeutics. Screening of whole plant extracts from Vernonia cinerea identified sesquiterpene lactones of the hirsutinolide type that inhibit aberrant STAT3 activity and suppress human glioma phenotype in vitro and in vivo. Compounds 6, 10, 20 and 22 suppressed the viability of human glioma, U251MG cells that harbor aberrantly-active STAT3, with IC50 of 2.4-6 µM. Treatment of U251MG cells with any of the four natural product agents inhibited STAT3 phosphorylation in a time-dependent manner, with little or no effects on pErk1/2 and pAkt levels. By contrast, other hirsutinolides, including compounds 8, 9, 11, 18, 19 and 28 showed modest or undetectable effects on U251MG cell viability or on pSTAT3 in U251MG cells. Furthermore, treatment with compounds 6, 10 or 22 had moderate or no effects on phospho-JAK2 or phospho-Src or on the protein tyrosine phosphatase, PTP1B level, as measured by Western blot. Moreover, combined treatment with sodium orthovanadate had minimal effect on compound 6-induced decrease in pSTAT3 levels, altogether suggesting that protein tyrosine phosphatases are less likely to be the primary mechanism for down-regulation of pSTAT3 in treated U251MG cells. By contrast, co-treatment with compund 6 repressed the robust induction of pSTAT3 levels by sodium orthovanadate. Furthermore, treatment with compound 6, 10, 20 or 22 inhibited colony formation and the migration of U251MG cells in vitro, and repressed the expression of STAT3 regulated genes, including Mcl-1 in U251MG cells. In vivo anti-tumor efficacy studies of compound 6 revealed dose-dependent inhibition of the growth of human glioma tumor xenografts in mice. Our studies have identified natural product-based small molecules that potently inhibit STAT3 activity and preferentially induce antitumor cell effects in vitro and antitumor response in vivo against human glioma. Citation Format: Gabriella Miklossy, Ui Joung Youn, Peibin Yue, Leng Chee Chang, James Turkson. Novel sesquiterpene lactones derived from Vernonia cinerea inhibit STAT3 activity and suppress human glioblastoma phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2694. doi:10.1158/1538-7445.AM2014-2694
Cardiac Electrophysiology: From Cell to Bedside
Authors: Douglas P. Zipes, José Jalife
Journal: Annals of Internal Medicine (1991)

Cardiac Electrophysiology: From Cell to Bedside defines the entire state of current scientific and clinical knowledge in this subspecialty. In response to the many major recent developments in the field, Drs. Zipes and Jalife have completely updated this modern classic, making the 5th Edition the most significant revision yet. From our latest understanding of ion channels, molecular genetics, and cardiac electrical activity through newly recognized syndromes, unique needs of special patient populations, and new diagnostic and therapeutic options, you'll find all the state-of-the-art guidance you need to make informed, effective clinical decisions. What's more, a significantly restructured organization, a new full-color layout, and full-text online access make reference easier than ever.
The use of <scp>ATG</scp> abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors
Authors: Alessandro Busca, Roberto Passera, Massimo Pini, Francesco Zallio, Chiara Dellacasa, Ernesta Audisio, Luisa Giaccone, Enrico Maffini, Cristina Costa, Rossana Cavallo, Benedetto Bruno
Journal: American Journal of Hematology (2015)

Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft‐versus‐host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5‐year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5‐year cumulative incidence of relapse was the disease status at HSCT ( P &lt; 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02‐5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32‐8.54; P = 0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15‐0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07‐15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T‐cell depleted HSCT using ATG do not benefit from CMV reactivation. Am. J. Hematol. 90:E117–E121, 2015. © 2015 Wiley Periodicals, Inc.
Abstract 2746: An evaluation of poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer
Authors: Jana Heitmann, Paul Geeleher, Michaela Keck, Zhixiang Zuo, Arun Khattri, Susanne Tepper, Michael Beckett, Ralph R. Weichselbaum, Sebastian Fetscher, Everett E. Vokes, Tanguy Seiwert
Journal: Cancer Research (2014)

Abstract Background: Synthetic lethality induced by poly (ADP-ribose) polymerase (PARP) inhibitors can occur in tumors without BRCA mutations. This “BRCAness” phenomenon has been observed in ovarian and triple negative breast cancers, but its role in other malignancies is not known. This study aims to evaluate the potency of PARP inhibitors in head and neck cancer, where BRCA mutations are rare. Methods: First, we compared three PARP inhibitors (veliparib, olaparib and rucaparib). We subsequently established dose response curves for rucaparib for ten head and neck cancer cell lines and compared with two BRCA deficient breast cancer cell lines. Furthermore, we used immunofluorescent staining for γH2AX and RAD51 to study the capability for the DNA repair mechanism homologous recombination. Results: We identified rucaparib as the most potent of the three PARP inhibitors tested and found a subset of tumors that show high rucaparib sensitivity (IC50 values: 7.0µM, 10.3µM and 11.7µM) comparable to a BRCA deficient breast cancer cell line (IC50 value: 8.9µM). Foci formation of the homologous recombination marker RAD51 did not serve as a reliable post-treatment biomarker. Conclusion: In conclusion, we demonstrate that PARP inhibitors are effective in a subset of head and neck cancer cell lines, suggesting that these compounds could play a role in the treatment of a subset of head and neck tumors that exhibit the “BRCAness” phenotype. Further studies regarding the underlying mechanism of this phenotype are warranted. Citation Format: Jana Heitmann, Paul Geeleher, Michaela Keck, Zhixiang Zuo, Arun Khattri, Susanne Tepper, Michael Beckett, Ralph R. Weichselbaum, Sebastian Fetscher, Everett E. Vokes, Tanguy Seiwert. An evaluation of poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2746. doi:10.1158/1538-7445.AM2014-2746
Abstract 15481: Abrogation of Senescence-associated Microrna-195 in Aged Skeletal Myoblasts Facilitates Reprogramming to Produce Induced Pluripotent Stem Cells
Authors: Hideyuki Kondo, Ha Won Kim, Ronald W Millard, Yi-Gang Wang
Journal: Circulation (2014)

Background:  Older age is the major risk factors for heart failure, and reprogramming a patient’s own cells to produce induced pluripotent stem cells (iPSCs) is a promising strategy for autologous cell transplantation therapy. However, low reprogramming efficiency of senescent cells remains as a major pitfall. Recently, we have shown that inhibition of senescence-associated miR-195 rejuvenated aged stem cells by reactivating telomerase reverse transcriptase (Tert). This study investigated the effects of abrogation of miR-195 expression on the reprogramming efficiency of old skeletal myoblasts (OSkMs).   Methods and Results:  MiR-195 expression was significantly higher in OSkMs isolated from aged mice (24 months) as compared to SkMs from young mice (2 months), as examined by RT-PCR. In addition, OSkMs showed impaired expression of anti-aging factors (Tert and Sirt1) and higher expression of pro-aging markers (p53, p21, p16). Intriguingly, blockage of miR-195 expression in OSkMs by transfection with anti-miR-195 significantly induced expression of Tert and Sirt1 as well as telomere re-lengthening as examined by RT-PCR and quantitative fluorescent in situ hybridization (Q-FISH). It is important to note that lower reprogramming efficiency of OSkMs was improved by miR-195 abrogation. Notably, inhibition of miR-195 did not alter karyotype or expression of pluripotency markers, and iPSCs lacking miR-195 successfully differentiated into all three germ layers, indicating that deletion of miR-195 does not affect pluripotency. Furthermore, contraction rates were markedly higher in beating cells transfected with anti-miR-195 as compared to that with scramble (68.5±5.6 vs 47.3±2.8/min).   Conclusions:  Abrogation of age-induced miR-195 is a novel promising approach for efficient iPSCs generation from senescent cells, which will contribute to successful autologous transplantation therapy in elderly patients.
Abstract 1914: Functional characterization of oncogenic-induced dedifferentiation in neurons and astrocytes using DP-seq
Authors: Dinorah Friedmann-Morvinski, Vipul Bhargava, Shakti Gupta, Inder M. Verma, Shankar Subramaniam
Journal: Cancer Research (2014)

Abstract Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. Using a Cre-inducible lentiviral GBM mouse model we recently showed that gliomas can originate from dedifferentiation of mature neurons and astrocytes. Expression analysis of the known markers (of the differentiated cell-types) showed diminished expression while the expression of the undifferentiated state markers were significantly up-regulated in the dedifferentiated transformed neurons and astrocytes. In this study, we performed whole transcriptome analysis of these cells along with mouse pluripotent embryonic stem cells (mESC), neural stem cells (NSC), neurons and astrocytes to characterize the undifferentiated state of these cells. Our analysis revealed that dedifferentiated cell-types shared traits with neurons and NSCs at the global transcriptome level suggesting that they have retained memory of their cell-of-origin and share markers of undifferentiated cells with NSCs. Functional analysis of the transcriptomics data revealed involvement of the Wnt signaling, cell cycle and the focal adhesion pathways in defining the state of the dedifferentiated cell-types. Our analysis further revealed conservation of a gene interaction network in both dedifferentiated cell-types. This network exhibited a modular architecture, connecting components of the cell cycle pathway to Wnt signaling and the focal adhesion pathways. One of these components, Osteopontin (OPN), also known as Spp1, is highly expressed and secreted by the tumors and dedifferentiated transformed neurons and astrocytes. Attempts to inhibit the action of OPN, either by using a neutralizing antibody or silencing the OPN gene (shRNA), blocked the formation of tumorspheres and diminished their proliferating capacity. We are currently assessing the effects of the inhibition of OPN function in vivo. Further genetic perturbation of additional interacting partners and/or the abolishment of the interactions can help elucidate the regulatory mechanism of this network in maintaining the dedifferentiated state of the transformed neurons and astrocytes. Citation Format: Dinorah Friedmann-Morvinski, Vipul Bhargava, Shakti Gupta, Inder M. Verma, Shankar Subramaniam. Functional characterization of oncogenic-induced dedifferentiation in neurons and astrocytes using DP-seq. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1914. doi:10.1158/1538-7445.AM2014-1914