tbuckley/cabot-search huggingface dataset:
RNAi-mediated abrogation of cathepsin B and MMP-9 gene expression in a malignant meningioma cell line leads to decreased tumor growth, invasion and angiogenesis
Authors: Padmaja Tummalapalli, Daniel Spomar, Christopher Gondi, William Olivero, Meena Gujrati, Dzung Dinh, Jasti Rao
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Malignant meningiomas are highly aggressive and frequently recur after surgical resection of the tumor. Earlier studies have reported that the cysteine protease cathepsin B and the matrix metalloproteinase MMP-9 play important roles in tumor progression. In the present study, we made an attempt to evaluate the roles of these proteases in the malignant meningioma tumor microenvironment and determined the effectiveness of using single or bicistronic siRNA constructs for cathepsin B and MMP-9, in both in vitro and in vivo models. Transfection of a plasmid vector expressing double-stranded RNA for cathepsin B and MMP-9 significantly inhibited mRNA and protein levels of cathepsin B and MMP-9. The migration and invasion of meningioma cells were decreased after treatment with single or bicistronic siRNA constructs for cathepsin B and MMP-9 compared to controls and vector controls. Inhibition of angiogenesis was observed when the cells were transfected with single or bicistronic constructs for cathepsin B and MMP-9, when compared to controls or empty vector controls. Our study revealed that abrogation of cathepsin B and MMP-9 expression decreased the activation of major proteins involved in MAP kinase and PI3 kinase pathways indicating that targeting these proteases may hinder intracellular signaling and thus decrease cell survival and proliferation in malignant meningiomas. In addition to the in vitro evidence, we observed a significant regression of pre-established orthotopic tumors after treatment with RNAi plasmid vectors targeting cathepsin B and MMP-9. Furthermore, these observations demonstrate that the simultaneous RNAi-mediated targeting of cathepsin B and MMP-9 has potential application for the treatment of human meningiomas.
Abstract 2762: Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations
Authors: Tadaaki Yamada, David Paul Carbone, Shinji Takeuchi, Naoya Fujita, Seiji Yano
Journal: Cancer Research (2014)

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show favorable effects in EGFR mutant lung cancer. However, responders eventually develop acquired resistance almost without exception, and secondary T790M mutations in EGFR account for approximately 50% of the acquired resistance. Recent studies indicated that EGFR mutant lung cancer cells are dependent on EGFR/Akt signaling for survival even after acquired T790M secondary mutation. Akt kinase-interacting protein1 (Aki1) is a scaffold protein that binds to wild-type EGFR after EGF ligand stimulation, maintains signaling specificity, and mediates activating signal to the PI3K/PDK1/Akt pathway. We hypothesized that Aki1 may play important roles in signal transduction in EGFR mutant lung cancer cells. Here, we showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M secondary mutation. Silencing of Aki1 inhibited phosphorylation of Akt and S6, and induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA markedly inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 inhibited H1975 cell growth in combination with new generation EGFR-TKIs in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a key mediator of survival signaling from mutant EGFR, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M secondary mutation. Citation Format: Tadaaki Yamada, David Paul Carbone, Shinji Takeuchi, Naoya Fujita, Seiji Yano. Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations. [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 2762. doi:10.1158/1538-7445.AM2014-2762
Basal cell carcinomas without histological confirmation and their treatment: an audit in four European regions
Authors: S.C. Flohil, C.M. Proby, A.D. Forrest, S. van Tiel, O. Saksela, S. Pitkänen, T. Ahti, R. Micallef, E. de Vries
Journal: British Journal of Dermatology (2012)

Journal Article Basal cell carcinomas without histological confirmation and their treatment: an audit in four European regions Get access S.C. Flohil, S.C. Flohil Department of Dermatology, Erasmus MC University Center, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar C.M. Proby, C.M. Proby Department of Dermatology, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K Search for other works by this author on: Oxford Academic Google Scholar A.D. Forrest, A.D. Forrest Department of Dermatology, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K Search for other works by this author on: Oxford Academic Google Scholar S. van Tiel, S. van Tiel Department of Dermatology, Erasmus MC University Center, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar O. Saksela, O. Saksela Department of Dermatology and Allergology, Helsinki University Central Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar S. Pitkänen, S. Pitkänen Department of Dermatology and Allergology, Helsinki University Central Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar T. Ahti, T. Ahti Department of Dermatology and Allergology, Helsinki University Central Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar R. Micallef, R. Micallef Malta National Cancer Registry, Department of Health Information and Research, Guardamangia, Malta Search for other works by this author on: Oxford Academic Google Scholar E. de Vries, E. de Vries Department of Dermatology, Erasmus MC University Center, Rotterdam, The NetherlandsDepartment of Public Health, Erasmus MC University Center, Rotterdam, The NetherlandsComprehensive Cancer Center South, Eindhoven, The Netherlands Esther de Vries. E‐mail: e.devries@erasmusmc.nl Search for other works by this author on: Oxford Academic Google Scholar on behalf of the EPIDERM Group on behalf of the EPIDERM Group Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 167, Issue s2, 1 August 2012, Pages 22–28, https://doi.org/10.1111/j.1365-2133.2012.11083.x Published: 01 August 2012 Article history Accepted: 05 April 2012 Published: 01 August 2012
CTCF/cohesin-binding sites are frequently mutated in cancer
Authors: Riku Katainen, Kashyap Dave, Esa Pitkänen, Kimmo Palin, Teemu Kivioja, Niko Välimäki, Alexandra E Gylfe, Heikki Ristolainen, Ulrika A Hänninen, Tatiana Cajuso, Johanna Kondelin, Tomas Tanskanen, Jukka-Pekka Mecklin, Heikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Eevi Kaasinen, Outi Kilpivaara, Sari Tuupanen, Martin Enge, Jussi Taipale, Lauri A Aaltonen
Journal: Nature Genetics (2015)
594. Gene-Directed Enzyme Therapy with Carboxylesterase/CPT-11, but Not Thymidine Kinase/GCV, Enhances the Efficacy of the Conditionally Replicating Adenovirus AdΔ24
Authors: Dinja Oosterhoff, Herbert M. Pinedo, M. Adhiambo Witlox, Jan E. Carette, Winald R. Gerritsen, Victor W. van Beusechem
Journal: Molecular Therapy (2004)

Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill cancer cells. While the efficacy of CRAds as monotherapeutic agents in clinical trials was limited, treatment modalities in which virotherapy was combined with conventional chemotherapy were significantly more effective. This warrants studies into combinations of CRAds with the more selective Gene-Directed Enzyme Prodrug Therapy (GDEPT). Arming CRAds with prodrug converting enzymes should result in anti-tumor effects by two different mechanisms, i.e., by viral replication of the CRAd and by expression of the prodrug converting enzyme in infected cells. After administration of the prodrug, conversion to the drug at the site of the tumor causes selective toxicity on infected as well as uninfected tumor cells via the bystander effect. Here, we investigated combination treatment in human colon cancer cell lines using the CRAd AdΔ24 that selectively replicates in cells with a mutated pRb pathway, and the prodrug converting enzymes thymidine kinase (TK) and carboxylesterase (CE) that activate the prodrugs ganciclovir (GCV) and CPT-11, respectively.
Abstract 18067: Maladaptive Aortic Properties after the Norwood Procedure: an Angiographic Analysis of the Pediatric Heart Network Single Ventricle Reconstruction Trial
Authors: Sarah T Plummer, Christoph P Hornik, Hamilton Baker, Gregory A Fleming, Susan Foerster, Eric Ferguson, Andrew Glatz, Russel Hirsch, Jeffrey P Jacobs, Kyong-Jin Lee, Alan Lewis, Jennifer S Li, Mary H Martin, Diego Porras, Wolfgang A Radtke, John F Rhodes, Julie A Vincent, Jeffrey D Zampi, Kevin D Hill
Journal: Circulation (2014)

Objectives: Aortic arch reconstruction in patients with single ventricle lesions may predispose to circulatory inefficiency and maladaptive physiology leading to increased myocardial workload. We sought to describe potentially maladaptive aortic anatomy and physiology, risk factors, and impact on right ventricle (RV) function in patients with single RV lesions after Norwood. Methods: Pre-stage II angiograms for subjects from the Single Ventricle Reconstruction (SVR) Trial were compared to 50 single left ventricle controls with no prior arch reconstruction. Arch geometry was defined as normal, crenel (elongated), or gothic (angular). Aortic index (ascending /descending aorta diameter) and distensibility index (systolic aortic area - diastolic area) / (diastolic area x pulse pressure) were calculated. Univariable tests were used for comparisons, and Spearman’s rho was used for correlation. Results: Interpretable angiograms were available for 326/389 (84%) SVR subjects. Table 1 summarizes findings. Age at catheterization was similar for SVR subjects and controls. SVR subjects more often demonstrated abnormally elongated (crenel) arch geometry with dilated ascending and transverse aortae tapering to a small isthmus. Distensibility was reduced in both the ascending and descending aorta. Risk factors for ascending aortic dilation (aortic index ≥ 2.5) included native aortic stenosis (OR = 2.2 [95% CI: 1.2, 3.8] vs. aortic atresia) and receipt of a RV-pulmonary artery shunt (OR = 2.6 [1.47, 4.5] vs. Blalock-Taussig shunt). There was no association between reduced distensibility and any demographic, anatomic, or reported surgical factors. Aortic dilation and reduced distensibility did not correlate with RV function at 14-month echocardiogram (p=0.5). Conclusions: After Norwood single RV surgery, the reconstructed aorta demonstrates abnormal anatomy and physiology. Further study is needed to evaluate the longer-term impact of these findings.
Corticosteroid Treatment and Intensive Insulin Therapy for Septic Shock in Adults
Authors: Djillali Annane, Alain Cariou, Virginie Maxime, Elie Azoulay, Gilles D'honneur, Jean François Timsit, Yves Cohen, Michel Wolf, Muriel Fartoukh, Christophe Adrie, Charles Santré, Pierre Edouard Bollaert, Armelle Mathonet, Roland Amathieu, Alexis Tabah, Christophe Clec'h, Julien Mayaux, Julie Lejeune, Sylvie Chevret
Journal: JAMA (2010)

Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear.To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone.A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France.Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days.In-hospital mortality.Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50).Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality.clinicaltrials.gov Identifier: NCT00320099.
417. Simultanous Transfer of the p16INK4a and p21Waf1 Tumor Suppressor Genes Plus GFP Mediated by a Novel Polycistronic Retroviral Vector
Authors: Lia K. Muschellack, Bryan E. Strauss, Eugenia Costanzi-Strauss
Journal: Molecular Therapy (2004)

The disregulated growth of cancer cells is associated with the hyperphosphorylation of the retinoblastoma gene product, Rb. In the majority of tumors, loss of Rb function is associated with the alteration of expression of CDK inhibitors, such as p16INKa and p21Waf1, but not the loss of Rb itself. Therefore, we have focused our efforts on regaining control of Rb function by the introduction of p16INK4a and p21Waf1 in tumor cells, maintaing Rb in the active, growth-inhibiting form.
Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 <scp>G</scp>aucher disease
Authors: Deborah Elstein, Atul Mehta, Derralynn A. Hughes, Pilar Giraldo, Joel Charrow, Laurie Smith, Suma P. Shankar, Thomas N. Hangartner, Yune Kunes, Nan Wang, Eric Crombez, Ari Zimran
Journal: American Journal of Hematology (2015)

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10-50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10(9) /L at baseline, were given at least one 15 U/kg-dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti-imiglucerase antibodies at baseline. This patient tested positive for anti-velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes.
Abstract 2007: Hypoxia induced TGF-β regulates Semaphorin7A to promote a pro-tumorigenic mesenchymal phenotype in mammary cells
Authors: Ramon A. Garcia-Areas, Stephania Libreros, Samantha Amat, Camila Castro-Silva, Kathy Schilling, Vijaya Iragavarapu-Charyulu
Journal: Cancer Research (2014)

Abstract The study of breast cancer relies heavily upon the identification of tumor-associated proteins that are involved with tumor growth and development. Our lab has discovered that mammary tumor cells express high levels of a novel protein known as Semaphorin7A (SEMA7A). After analyzing breast tissue samples collected at Boca Raton Regional Hospital, we have found that normal human mammary epithelial cells express negligible mRNA levels of SEMA7A, while the malignant mammary tumor cells express elevated levels of SEMA7A. Additionally, our laboratory has established a murine model of mammary cell lines that parallels our human findings. Currently, we have correlated high levels of SEMA7A with increasing tumor malignancy and metastasis. However, it is still unknown what factors could induce the production of SEMA7A in mammary tumors. Recent studies have proven that the expression and induction of SEMA7A in normal endothelial cells is regulated under a hypoxic-response element in the promoter of its gene. Although hypoxia is an established tumorigenic factor, it is unknown if the increased hypoxic conditions in breast tumors could induce SEMA7A. In this study we have investigated if exposing mammary cells to hypoxia induces the expression of pro-tumorgenic SEMA7A. Our results show that SEMA7A is up-regulated in 4T07 and 4T1 mammary tumor cells after hypoxic exposure via TGF-β activation of the PI3/AKT pathway. Furthermore, we have found that shRNA silencing of the SEMA7A in 4T1 mammary cells attenuates the activation of pro-angiogenic and mesenchymal genes even after hypoxic stimuli. In vivo, these cells show a reduced proliferation and metastatic potential. We therefore postulate an exciting new role for SEMA7A as a TGF-β effector that promotes tumorigenesis during breast cancer progression. Citation Format: Ramon A. Garcia-Areas, Stephania Libreros, Samantha Amat, Camila Castro-Silva, Kathy Schilling, Vijaya Iragavarapu-Charyulu. Hypoxia induced TGF-β regulates Semaphorin7A to promote a pro-tumorigenic mesenchymal phenotype in mammary cells. [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 2007. doi:10.1158/1538-7445.AM2014-2007
Abstract 9634: As Compared With Cardiac Magnetic Resonance Imaging, Transthoracic Echocardiography Has an Excellent Accuracy in Diagnosing a Left Ventricular Thrombus After an Anterior Myocardial Infarction Complicated With Left Ventricular Dysfunction: Results of a Prospective Multicentric Study
Authors: Philippe Meurin, Virginie Brandao Carreira, Raphaelle D Dumaine, Alain Shqueir, Olivier Milleron, Benjamin Safar, Sergio Perna, Charles Smadja, Marc Genest, Jerome Garot, Bernard Carette, Laurent Payot, Jean Yves Tabet
Journal: Circulation (2014)

Introduction: The generalization of reperfusion techniques to treat acute myocardial infarction (MI) has allowed for markedly reduced incidence in left ventricular (LV) thrombi because of the reduced myocardial damage. LV thrombi are estimated to complicate 5% to 10% of unselected anterior-wall MI (Ant-MI). However, the incidence and evolution of LV thrombi in high-risk patients with Ant-MI complicated by LV systolic dysfunction is not well known. Cardiac magnetic resonance imaging with contrast delayed enhancement (CMR-DE) is the gold standard in assessing LV thrombus, but comparisons of transthoracic echocardiography (TTE) and CMR-DE are scarce. Hypothesis: We assessed whether LV thrombi are still frequent after major Ant-MI, despite systematic dual antiplatelet therapy, and whether focused TTE has a good accuracy for detection as compared with CMR-DE. Methods: From 2011 to 2013, from 7 centers, we prospectively included patients with LV ejection fraction (LVEF) &lt; 45% at a first TTE performed &lt; 7 days after Ant-MI. A second evaluation including TTE and CMR-DE (analyzed by blinded examiners) was performed at 30 days. A third TTE and assessment of clinical status and adverse events were performed between months 6 and 12. Results: We included 100 consecutive patients (71% males; mean age 59.1 ± 12.1 years; LVEF 33.5 ± 6.0%) at a mean of 4.8 ± 1.9 days after Ant-MI; 88% had undergone primary coronary angioplasty. In total, 26 patients had LV thrombi detected at a mean of 23.2 ± 34.8 days after MI (6 during the first week after the MI, 16 from days 8 to 30, 4 after day 30). As compared with CMR-DE, TTE sensitivity and specificity were 94.7% and 98.5%, respectively. For 24 patients (92.3%), the LV thrombi disappeared with triple antithrombotic therapy including dual antiplatelet therapy and a vitamin K antagonist. One patient died from a recurrent subdural haematoma and another had a peripheral embolism. Conclusions: In this prospective multicenter study, LV thrombus occurred in 26% of patients after Ant-MI complicated by LV dysfunction. Focused TTE has a high accuracy for detection. CMR-DE should be performed only when the apex is not clearly seen.