tbuckley/cabot-search huggingface dataset:
177. Cross-Talk Between Human Relaxin Gene Therapy and Infarct-Related Coronary Artery
Authors: Young Sook Lee, Joung-Woo Choi, Jung-Eun Oh, Sung Wan Kim, Chae-Ok Yun
Journal: Molecular Therapy (2016)

Background & Aim: The occlusion of coronary artery causes myocardial infarction (MI), leading cause of morbidity and mortality in the world. In the coronary angiography (CAG), the revascularization by reperfusion of infarct-related coronary artery is the key therapeutic modality. The systolic function evaluated by ejection fraction is a well-known traditional prognostic parameter. The non-invasive transthoracic Doppler echocardiography has been feasible to evaluate coronary artery in clinic (J Am Soc Echocardiogr 17(2):178-185, 2004). The purpose of this study is to valuate the efficacy of human Relaxin gene therapy in an infarct-related coronary artery, correlate the assessment of human Relaxin gene therapy with a typical cardiac function-structure relationship, and expand the significance of human Relaxin gene therapy on infarct-related artery to be a promising candidate for cardioprotective therapeutics after MI. Method: MI was induced by 30 min surgical occlusion of proximal left anterior descending (pLAD) at 7-8 wks-old male Sprague-Dawley rats (ischemia-reperfusion (I/R) injury group). Compared with I/R group and intramyocardial injection of human Relaxin plasmid DNA alone, the effects of intramyocardial injection of human Relaxin gene delivered by a bioreducible polymer were evaluated by 2D speckle-tracking Doppler echocardiography. Results: The diameter and velocity of the pLAD, infarct-related coronary artery, was assessed both during diastole and systole on 1 and 4 wks after I/R injury of MI. The diameter of pLAD in human Relaxin gene delivery group was more preserved than I/R group, up to the level of thoracotomy sham group on 1 and 4 wks after MI. In addition, the time velocity integral (TVI), stroke volume, and output in pLAD of human Relaxin gene delivery group were significantly higher than I/R group on 1 and 4 wks after MI. This diagnostic approach of infarct-related coronary artery of human Relaxin gene delivery was well correlated to the systolic function (EF), hemodynamics, and structural parameters in rat hearts after MI. Conclusion: This study suggests that the human Relaxin gene delivery system exerts reverse remodeling after MI on infarct-related coronary artery as well as systolic function, hemodynamics, and cardiac chamber quantification.
Abstract SY10-04: Histone tail alterations in cellular senescence
Authors: Luis F. Duarte, Andrew R. J. Young, Zichen Wang, Hsan-Au Wu, Taniya Panda, Yan Kou, Avnish Kapoor, Dan Hasson, Nicholas R. Mills, Avi Ma'ayan, Masashi Narita, Emily Bernstein
Journal: Cancer Research (2015)

Abstract The process of cellular senescence generates a repressive chromatin environment, however, the role of histone tail modifications, histone variants and histone proteolytic cleavage in senescence remains unclear. Using well-characterized senescence models in human primary lung fibroblasts and melanocytes, we are investigating how chromatin alterations contribute to the senescence phenotype. Here we report novel histone H3 tail cleavage events in oncogene-induced and replicative senescence models mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and that H3.3 is the preferred cleaved form of H3 - an H3 histone variant that is deposited independent of DNA replication. Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first twenty-one amino acids of the H3 tail, is sufficient to induce senescence. Furthermore, we find that chromatin incorporation of H3.3cs1 is mediated by the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone complex. Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, our studies have identified histone H3.3 and its proteolytically processed forms as key regulators of cellular senescence. Citation Format: Luis F. Duarte, Andrew R. J. Young, Zichen Wang, Hsan-Au Wu, Taniya Panda, Yan Kou, Avnish Kapoor, Dan Hasson, Nicholas R. Mills, Avi Ma'ayan, Masashi Narita, Emily Bernstein. Histone tail alterations in cellular senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY10-04. doi:10.1158/1538-7445.AM2015-SY10-04
156. A Plasmid Manager, a Comprehensive Database for Archiving Plasmid DNA Sequence
Authors: Emily J. Heathward, Giun Sun, Ron U. Domingo, Calvin A. Johnson, Christopher T. Richie, Brandon K. Harvey
Journal: Molecular Therapy (2016)

A freely available plasmid database that is interoperable with popular freeware (such as a Plasmid Editor, or ApE [1]) has been developed by the Center of Information Technology (CIT) for the NIDA Optogenetics and Transgenic Technology Core (OTTC). As a core facility at the National Institute on Drug Abuse, the NIDA OTTC group has accrued a wealth of plasmid DNA data that can no longer be efficiently analyzed without a comprehensive cataloging system. The OTTC Plasmid Manager provides an intuitive plasmid database with analytical and search capabilities, offering a versatile platform for the storage and organization of plasmid sequences and their associated metadata. The database has been designed with informatics and visualization support to enhance the efficiency and analytic capabilities of the user, with a user-friendly interface. Annotations performed in ApE can be imported directly into the database, and unlike most commercially available and free DNA editing software, A Plasmid Manager (APM) also includes a mechanism to standardize the annotations of uploaded sequences, facilitating the direct comparison of multiple plasmids at the feature level. The visualization component generates a graphic representation of the plasmid map together with its features and annotations, allowing the visual comparison of multiple plasmids side-by-side. The contents of the database can be browsed and searched using a variety of criteria, including plasmid name, database accession number and associated features. This innovative plasmid database presents a new platform for molecular biologists to catalog plasmids relevant to their laboratory, saving time and enhancing the analytical capabilities of researchers.
Prognostic analysis of the patients with operable gastric cancer and the importance of tolerability of therapy: Study of Anatolian Society of Medical Oncology.
Authors: Mehmet Kucukoner, Erkan Arpaci, Abdurrahman Isikdogan, Mehmet Bilici, Dogan Uncu, Bulent Cetin, Faysal Dane, Kerim Cayir, Mevlude Inanc, Ahmet Siyar Ekinci, Ali Inal, Tarkan Yetisyigit, Nuriye Ozdemir, Muhammed Ali Kaplan, Sercan Aksoy, Necati Alkis, Salim Basol Tekin, Celalettin Eroglu, Serdar Turhal, Suleyman Buyukberber
Journal: Journal of Clinical Oncology (2012)

e14526 Background: The aims of this study were to evaluate the tolerability and toxicity with adjuvant chemoradiotherapy (CRT) and prognostic analysis of patients with operable gastric cancer. Methods: The retrospective analysis included 723 patients with operable gastric cancer, stage IB-IV (M0), received adjuvant CRT from 8 Medical Centers in Turkey between 2003 and 2010. Patients’ age, sex, tumor localization, Lauren classification, grade, stage, type of dissection, toxicity and tolerability status were analyzed. Results: 73.9% of the patients were with stage III- IVM0. 61.0% of the patients were in the intestinal type, 51.1% of the patients were with the distal type of gastric cancer and 61.4% of the patients had undergone D2 dissection. 545 (75.4%) of patients completed the entire of adjuvant CRT. The median follow-up period was 20.8 months. Overall Survival (OS) rates were 80% and 52% while relapse free survival (RFS) rates were 75% and 48%, at 1, 3 years, respectively. In univariate analysis of groups, according to the group under the age of 65 and above (p=0.16 / p=0.003), Lauren classification (p=0.004 / p&lt;0.001), localization of tumor (p=0.02 / p=0.04), tumor grade (p=0.06 / p=0.003), stage (p&lt;0.001 / p&lt;0.001), type of dissection (p=0.445 / p=0.043), toxicity (p=0.062 / p=0.077), tolerability of therapy (p=0.002 / p=0.001) were significantly different in both RFS and OS. In multivariate analysis, three independent prognostic factors were identified on RFS / OS; stage (ods ratio (OR)=3.0, 95% confidence interval (CI):1.8-5.0, / OR=3.2, CI=1.8-5.4), for Lauren classification (OR=1.5, CI=0.9-2.2 / OR=1.5, CI= 1.1-2.2), for tolerability of therapy (OR=2.0, CI=1.0-3.8 / OR=1.9, CI=1.0-3.6). Conclusions: We found a new independent prognostic factor whether or not tolerate adjuvant CRT because of toxicity, except for the known prognostic factors like tumor stage and Lauren classification. We suggest that the treatment of the patients with intolerable to adjuvant CRT, is to change with less toxic adjuvant therapies.
Abstract 3780: Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells
Authors: Zuzanna Baranski, Tijmen T.H. Booij, Yvonne de Jong, Jolieke van Oosterwijk, Anne-Marie Cleton, Leo Price, Bob van de Water, Judith V.M.G. Bovée, Pancras C.W. Hogendoorn, Erik Danen
Journal: Cancer Research (2015)

Abstract Osteosarcoma is the most common primary bone malignancy with relatively high incidence in young people. Here, we found that expression of Aven was inversely correlated with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary osteosarcoma biopsies. Also in chondrosarcoma, the second most common bone sarcoma, expression correlated with increased histological grade. Aven is an adaptor protein that has been implicated in anti-apoptotic signaling and serves as an oncoprotein in acute lymphoblastic leukemia. In human osteosarcoma cells, silencing Aven triggered a G2 cell cycle arrest. Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signaling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells while ATM, Chk2, and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures Chk1 inhibition effectively sensitized human osteosarcoma cells to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signaling and point towards Chk1 inhibition as a strategy to sensitize osteosarcomas to chemotherapy. Citation Format: Zuzanna Baranski, Tijmen T.H. Booij, Yvonne de Jong, Jolieke van Oosterwijk, Anne-Marie Cleton, Leo Price, Bob van de Water, Judith V.M.G. Bovée, Pancras C.W. Hogendoorn, Erik Danen. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2015-3780
Whole Genome and Transcriptome Analysis of Genetic Alterations in Context of Busulfan in Vitro Resistance in Pediatric Acute Leukemias
Authors: Joanna Szczepanek, Krzysztof Domagalski, Joanna Laskowska, Monika Pogorzala, Andrzej Tretyn, Jan Styczynski
Journal: Blood (2015)
The significance of HPV status in patients with anal cancer: A comparative technical analysis.
Authors: C. M. Doll, G. B. Roldán, A. Klimowicz, K. Gustafson, S. K. Petrillo, A. K. Chan, S. P. Lees-Miller, A. M. Magliocco
Journal: Journal of Clinical Oncology (2011)

425 Background: HPV status is an important prognostic factor for outcome in head and neck cancers, with improved survival noted in HPV-positive vs -negative tumors. However, this effect has not been studied in anal cancer. Challenges exist in defining reliable and methods of detecting the presence of high-risk HPV virus or the expression of HPV-related proteins. Purpose: To determine p16 expression and HPV16 status, in association with HPV subtyping, in pre-treatment anal cancers, and to correlate marker status with clinical outcome. Methods: This retrospective study evaluated anal cancer patients treated between 1992-2005 with definitive RT or CRT at a single institution (Tom Baker Cancer Centre, Calgary, Canada). HPV subtyping, p16 protein expression via conventional immunohistochemistry (IHC) and automated quantitative IHC (AQUA), and HPV16 in-situ hybridization (CISH) was performed in a subset of patient tumors with sufficient pretreatment tumor specimen. The correlation between results using these different techniques and association of HPV markers with clinical outcome was evaluated. Results: 89 patients were identified; M:F 1:2; median age 57 years. Median tumor size was 3.5 cm. All patients were treated with radical external beam RT with curative intent; 81% received concurrent chemotherapy. Clinical CR was observed in 73% of patients at 3 months post-treatment. Median OS was 82 months. Of tumor specimens analyzed for HPV subtype, 78% (28/36) were HPV16. Using conventional IHC (DAB), 80% (28/35) of tumors over-expressed p16 (score 3). HPV16 CISH was positive in 81% (34/42). P16 AQUA™ score correlated with HPV16 subtyping, CISH for HPV16, and p16 DAB. With HPV16 subtyping as the gold standard for HPV16 infection, false positive and false negative rates were 8% and 4% with DAB, and 10% and 13% with CISH. In univariate analysis only p16 AQUA score &gt; 244 (upper 15%) was associated with PFS (p= 0.006-95% CI 8.4 [1.8-38.6]) and OS (p= 0.013-95% CI 4.5 [1.4-15]). Conclusions: p16 expression via quantitative IHC correlates with other methods, including HPV16 subtyping, and appears more reliable for defining HPV16 status than CISH. Only quantitative IHC identified a subset of patients with worse outcome. No significant financial relationships to disclose.
345. Transient Removal of CD46 Sensitizes Breast Tumor Cells to Complement Attack Combination with Curcumin
Authors: Pei-Rong Wang
Journal: Molecular Therapy (2016)

Wang et al has developed a technology, which is based on a small recombinant protein, Ad35K++, that induces the internalization and subsequent degradation of complement regulatory protein (CRP) CD46. Curcumin, a polyphenol compound derived from the rhizome of the plant Curcuma longa L. has been verified as an anticancer compound against several types of cancer. In preliminary studies, we have demonstrated the utility of Ad35K++ in transient removal of CD46 from the cell surface. Then we found that treatment of Ad35K++ increased the sensitivity of the breast cancer cells induced by curcumin to CDC. Apoptosis triggered by curcumin and Ad35K++ was visualized using Annexin V-FITC/7-AAD staining. Further studies demonstrated that the down-regulation of Bcl-2 and up-regulation of Bax that led to the cleavage of caspase-3 and increased cleaved PARP resulted in the apoptosis of breast cancer cells treated with curcumin and Ad35K++. Enzyme-linked immunosorbent assay (ELISA) showed that curcumin and Ad35K++ treatment resulted in the increased expression of C3b, which is mediated by downregulated CD46. These results show that the combination of Ad35K++ and curcumin can augment the anti-tumor effect of CDC on human breast cancer cells and suggest their promising applicability as a new candidate for the therapy against human breast cancer in the future.
Diagnostic and therapeutic pathways in Head &amp; Neck sarcomas (H&amp;NS): an effective example of good clinical practice in Piedmontese Oncologic Network
Authors: A. Comandone, A. Boglione, P. Pochettino, O. Dal Canton, C. Oliva, F. Garetto, P. Bergnolo, D. Ottaviani, S. Chiadò Cutin
Journal: Annals of Oncology (2015)
490. Electroporation-Mediated Gene Transfer of Caveolin-1 Protects from Bleomycin-Induced Pulmonary Fibrosis Through Regulating Activation of Inflammasome
Authors: Xin Lin, Michael Barravecchia, David A Dean
Journal: Molecular Therapy (2016)

Pulmonary fibrosis (PF) is a progressive chronic interstitial lung disease associated with high morbidity and mortality. It is characterized by increased deposition of extracellular matrix proteins and the accumulation of scar tissue in the lung interstitium, resulting from alveolar epithelial injury and the accumulation of inflammatory cells. Currently, there is no effective therapy. Gene therapy is a promising approach to treat a variety of lung diseases, including pulmonary fibrosis. Caveolin-1 (Cav-1) is a major component of caveolae, and has been found greatly reduced expression in the lungs of PF patients. Moreover, Cav-1-deficient mice develop spontaneous pulmonary fibrosis. To investigate if Cav-1 can protect from bleomycin-induced pulmonary fibrosis, we delivered plasmids expressing Cav-1 driven by the ubiquitin promoter using electroporation. PF was induced 2 days after gene transfer by intratracheal administration of bleomycin (2 unit/kg). We found that electroporation-mediated gene transfer of Cav-1 to the lung significantly protected from subsequent bleomycin-mediated fibrogenesis by histological analysis and the expression of alpha-smooth muscle actin (alpha-SMA) and collagen measurement. We also found attenuated recruitment of neutrophils and monocytes and/or macrophages in bronchoalveolar lavage (BAL) fluid after gene transfer of Cav-1 compared with vector control. The underlying mechanism was associated with reduced activation of the inflammasome by determining the expression of cleaved caspase-1 and IL-1 beta in both mouse models and cultured cells after overexpression of Cav-1. These results demonstrate that Cav-1 might be a potential target for treatment of pulmonary fibrosis.
A Comparative Study of the Outcome of High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with High-Risk or Standard-Risk Myeloma Treated Concurrently,
Authors: Syed Kazmi, Gary Lu, Nina Shah, Qaiser Bashir, Simrit Parmar, Robert Z. Orlowski, Jatin J Shah, Chitra M Hosing, Uday Popat, Yvonne T Dinh, Sofia Qureshi, Gabriela Rondon, Sergio Giralt, Richard Champlin, Muzaffar H. Qazilbash
Journal: Blood (2011)
Characterization of NPM1-Mutated/FLT3 ITD-Negative Acute Myeloid Leukemia with Normal Karyotype by Gene Expression Profiling.
Authors: Lars Bullinger, Konstanze Dohner, Raphael Kranz, Frank G. Rucker, Stefan Frohling, Richard F. Schlenk, Jonathan R. Pollack, Hartmut Dohner
Journal: Blood (2006)
322. Genome Editing for Nucleotide Repeat Disorders: Towards a New Therapeutic Approach for Myotonic Dystrophy Type 1
Authors: Mirella Lo Scrudato, Samia Martin, Geneviève Gourdon, Denis Furling, Ana Buj-Bello
Journal: Molecular Therapy (2016)

Myotonic dystrophy type 1 (DM1) belongs to the group of nucleotide repeat disorders. More specifically this autosomal form of muscular dystrophy is caused by the expansion of the CTG trinucleotide repeat located at the 3' untranslated region (3'-UTR) of the DMPK gene. Elongated CUG repeats of the mutated DMPK mRNAs become sequestration sites for splicing factors, and induce the formation of stable ribonucleoprotein complexes visualized as foci. As a consequence, the alternative splicing of numerous transcripts is dysregulated, which leads to the DM1 pathological alterations affecting various tissues. We have developed a strategy to delete the CTG repeat expansion in the human DMPK locus by using the CRISPR/Cas9 system. For that purpose, we constructed different expression platforms for small size Cas9 nucleases under either a ubiquitous or a muscle-specific promoter and guide RNAs (sgRNAs) targeting the 3'-UTR of the DMPK gene. Co-transfection of these constructs in DM1 primary myoblasts resulted in the deletion of the CTG repeat. We are currently optimizing the delivery of these Cas9 and sgRNAs constructs in cells by their vectorization in lentiviral and adeno-associated vectors and will present data on in vitro (DM1 patient-derived cell lines) and in vivo (wild-type mice) assays.
Abstract 3339: Silibinin improves radiotherapeutic efficacy in prostate cancer by reducing IR-induced toxicity and EMT
Authors: Dhanya K. Nambiar, Paulraj Rajamani, Anil Jain, Gagan Deep, Rajesh Agarwal, Rana P. Singh
Journal: Cancer Research (2015)

Abstract Radiotherapy of prostate carcinoma is well established and frequently utilized in a significant proportion of cancer patients. However, two major concerns with radiotherapy is the effect on normal tissues and development of more invasive-radioresistant population. We have previously shown that the use of a plant flavonoid, silibinin can radiosensitize prostate cancer cells preferentially in vitro, by inhibiting DNA damage repair. We extended this study further, to validate the effects of silibinin in improving the radiotherapeutic efficacy in vivo. Our results showed that, in vivo, silibinin strongly radiosensitized DU145 tumor xenograft inhibition (84%, P&amp;lt;0.01) with higher apoptotic response (10-fold, P&amp;lt;0.01) and reduced repair of DNA damage as evidenced by reduced Chk2 activation and enhanced pH2A.X foci in tumor tissues. Interestingly, we also observed that silibinin could rescue the mice from IR-caused hematopoietic injury and normal tissue toxicity. Studies have shown that ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of radiation induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. In the current study, we demonstrate that silibinin can also radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it significantly reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. We have found that most of the pro-angiogenic, migratory and EMT promoting proteins were up regulated in response to IR in PCa cells. All of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3 by silibinin. Therefore, the study not only underlines the preferential radiosensitizing ability of silibinin in PCa, but also shows its efficacy in modulating IR-induced toxicity in normal cells and EMT in PCa cells. Citation Format: Dhanya K. Nambiar, Paulraj Rajamani, Anil Jain, Gagan Deep, Rajesh Agarwal, Rana P. Singh. Silibinin improves radiotherapeutic efficacy in prostate cancer by reducing IR-induced toxicity and EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3339. doi:10.1158/1538-7445.AM2015-3339