tbuckley/cabot-search huggingface dataset:
Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma
Authors: Müge Çeliktaş, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F. Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B. Dennison, Edwin J. Ostrin, Hong Wang, Carmen Behrens, Kim-Anh Do, Adi F. Gazdar, Samir M. Hanash, Ayumu Taguchi
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95% confidence interval = 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.
Abstract 3144: Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes
Authors: Daniela Achkova, James Spicer, John Maher
Journal: Cancer Research (2015)

Abstract Anaplastic large cell lymphoma (ALCL), a type of T/null-cell lymphoma, represents about 20-30% of paediatric lymphomas and has an aggressive clinical course with frequent relapse. Recently, high-level expression of CSF1R on malignant cells in ALCL has been linked to shorter progression free survival, providing a rationale to test adoptive C28ζ-mediated T-cell therapy. This approach encompasses the genetic modification of T-cells to express a chimeric antigen receptor (CAR) named C28ζ, a fusion receptor coupling the recognition of CSF1R on the tumour cell surface to the delivery of tailored T-cell activation signal provided by a fused CD28+CD3ζ endodomain. To optimize this approach for human translation, the C28ζ CAR was co-expressed with the chimeric cytokine receptor 4αβ (combination termed “C4”), which allows for selective expansion and enrichment of CAR-transduced T-cells using IL-4. PBMCs of healthy donors were isolated and activated using anti-CD3/CD28 beads. Following retroviral T-cell transduction and 14 days expansion of C4+ T-cells in the presence of IL-4, co-cultures with a panel of ALCL cell lines (2 ALK positive and 2 ALK negative ALCL cell lines) were set up to test C4 efficacy in vitro. Successful re-targeting of C4+ T-cells was confirmed by monitoring target cell destruction. Conditioned media was collected and analysed for IFN-γ and IL-2 production. Cytotoxicity, cytokine release and T-cell proliferation data demonstrated Ag-specific activation of the C4+ cells, which contrasted with T-cells expressing a control CAR with truncated endodomain. This data provides for the first time the basis for successful application of CAR-based immunotherapy against CSF1R-expressing malignancies. Citation Format: Daniela Achkova, James Spicer, John Maher. Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes. [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 3144. doi:10.1158/1538-7445.AM2015-3144
298. Characterization of a Novel Anti-Sense Promoter Element in Adeno-Associated Virus: Implications for Hepatocellular Carcinoma
Authors: Grant Logan, Christine M. Smyth, Claus V. Hallwirth, Neeta Khandekar, Samantha L. Ginn, Sophia Laio, Allison P. Dane, Ian E. Alexander
Journal: Molecular Therapy (2016)

We have discovered a novel anti-sense promoter element in nucleotides proximal to the right ITR of AAV serotype 2. Presence of the element was initially detected using vector derived from psub201, a widely-used plasmid for AAV vectorization which carries an infectious wtAAV2 clone engineered such that the left ITR is replaced with the right ITR and 46 nucleotides (nt) of proximal AAV2 sequence. While preliminary studies using the psub201-derived vector showed promoter activity originated from a sequence containing 46-nt of wtAAV2 and 59-nt of poly-linker sequence, further investigation demonstrated 105 nucleotides proximal to the right wtAAV2 ITR to be optimal for activity, which was further enhanced by presence of ITR sequence. Demonstration of similar promoter activity in a phylogenetically-related AAV serotype (AAV7) but not a more distantly related serotype (AAV5) indicates potential conservation of the activity amongst related AAV, which may be important for the virus cycle. Activity of the element is restricted to cells of hepatic origin but also operates in a lung sarcoma cell line (A549). Our findings take on new significance in light of a recent study by Nault and colleagues (Nault et al. 2015 Nature Genetics) who have associated genomic integration of AAV with HCC in 11/193 patients. Cloncal expansion of AAV integration events occurred in known drivers of carcinogenesis leading to gene dysregulation at the site of integration. A striking feature of the study is that only a fragment of the AAV genome was integrated in the tumor genome with one patient showing a 1442 bp fragment spanning the rep-cap junction while the remaining 10/11 tumors contained fragments (201-1975 bp) from the 3' genome of which all contained the 105-nt element described in the current report. Conclusions drawn from the Nault study that AAV is involved in insertional mutagenesis have caused some contention in the field prompting two editorials with alternative interpretation of the data (Buning and Manfred 2015 Mol. Ther.; Berns et al. 2015 Human Gene Therapy). While the Nault report requires further scrutiny and confirmation, the nature of the findings may have implications for AAV gene therapy, especially in the liver over the longer term. Our findings delineating cell-restricted transcriptional activity from the 3' promoter element in AAV is of general interest to the fields of AAV biology and vectorology but, more importantly, are of specific significance to the HCC controversy and may provide insight and resolution over the matter of AAV-associated HCC.
Abstract 2936: Mitochondria dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African American prostate cancer
Authors: Ajay K. Chaudhary, Tariq A. Bhatt, Sandeep Kumar, Willie Underwood, Shahriar Koochekpour, Mojgan Shourideh, Neelu Yadav, Dhyan Chandra
Journal: Cancer Research (2015)

Abstract African American (AA) patients with prostate cancer (PCa) respond poorly to current therapy compared to Caucasian American (CA) patients. Although underlying mechanisms are not clearly defined, mitochondria dysfunction is a key reason for PCa disparity. We observed that glycolytic pathway inhibitor dichloroacetate (DCA) inhibited cell proliferation in both AA PCa cells (AA cells) and CA PCa cells (CA cells). CA cells were arrested at G1 and G2/M phases whereas S-phase arrest was observed in AA cells. AA cells showed resistance to cell death upon DCA exposure in spite of higher caspase activation than in CA cells. AA cells possess reduced level of reactive oxygen species (ROS) and mitochondrial membrane potential (mtMP) compared to CA cells. DCA induced cellular and mitochondrial ROS in AA cells but were unchanged in CA cells. DCA upregulated the levels of mtMP in both cell types. DCA enhanced taxol-induced cell death only in CA cells, but DCA sensitized doxorubicin-induced AA cell death. Expression of heat shock proteins (HSPs) were inhibited only in AA cells upon doxorubicin alone or combined treatment of DCA with doxorubicin, whereas Taxol alone or in combination with DCA did not show any changes in the levels of HSPs. DCA suppressed the metastatic features and reduced the population of cancer stem cell-like cells in CA cells but had a little effect on AA cells. Therefore, anticancer agents that can effectively restore mitochondria function may provide new therapeutic potential in reducing PCa health disparity and poor prognosis in AA men with PCa. Citation Format: Ajay K. Chaudhary, Tariq A. Bhatt, Sandeep Kumar, Willie Underwood, Shahriar Koochekpour, Mojgan Shourideh, Neelu Yadav, Dhyan Chandra. Mitochondria dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African American prostate cancer. [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 2936. doi:10.1158/1538-7445.AM2015-2936
413. Pre-Clinical Preparation and Validation of Tumor Cell-Based IL-12 Immunotherapy for Acute Myeloid Leukemia
Authors: Bryan C. Au, Yuanfeng Liu, Ju Huang, Megan Nelles, Andrea Arruda, Michael Rothe, Gabi Paul, Axel Schambach, Dwayne L. Barber, Mark D. Minden, Christopher J. Paige, Jeffrey A. Medin
Journal: Molecular Therapy (2015)

Interleukin(IL)-12 is a potent pro-inflammatory cytokine that stimulates a variety of effector cells involved in anti-tumor immunity. Systemic administration of IL-12 has associated toxicities, however. Various strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Options here include generating fusions with tumor-targeting molecules and directing gene delivery to specific cells. First – we used lentivirus vectors (LVs) to engineer expression of murine IL-12 in tumor cells ex vivo and subsequently infused such modified cells into recipient mice. This strategy restricts IL-12 to the local tumor microenvironment thereby promoting immune activation in the context of tumor-associated antigens (TAAs). Using mouse models of both leukemia and solid tumors, we found that this cell-based approach generated effective anti-tumor protection when as little as 1% of the tumor burden expressed IL-12 as long as threshold expression levels on a per cell basis were reached. Second – our groups showed that anti-tumor mechanisms here involve CD4+ killer T cells, dendritic cells, and direct cell-cell contact with effectors. Clinical translation of this cell-based IL-12 therapy is in progress in Toronto for AML using a novel LV to modify patients' own blast cells. Patient AML cells collected to date (n = 21) were stratified based on in vivo growth kinetics and transduced with a near-GMP-grade bicistronic LV that encodes the human IL-12 cDNA as a p40-p70 fusion, as well as a mutant thymidylate kinase (tmpK) fused to the ectodomain of LNGFR (trLNGFR) as a suicide (cell-fate control) cassette. The trLNGFR/tmpK element allows selection and also selective ablation of transduced cells by administration of AZT. Furthermore, it also allows tracking of transduced cells and quantification of transduction frequencies/transgene expression levels. With our current protocol, functional transduction efficiencies of primary patient AML blasts ranged from 20% to 70% (n=17). Transduced AML cells displayed a strong correlation between vector copy number and trLNGFR/tmpK + IL-12 levels and dose-dependent sensitivity to AZT. In vitro immortalization (IVIM) assays determined that the near-GMP LV/IL-12 vector displayed minimal genotoxic risk in transduced lin- cells; insertion site analyses carried out on expanded clones displayed poly-to oligo-clonality patterns. Pre-clinical data on toxicity and scale-up considerations are being accumulated in preparation for a Clinical Trial Application to Health Canada targeting AML. This LV/IL-12 immunotherapy platform targeting tumor cells themselves thus holds potential to be effective against a wide variety of cancers.
Differences in regulatory T cells (Tregs) in responding and non-responding patients with indolent B-cell or mantle cell lymphoma during treatment with lenalidomide and rituximab ± dexamethasone.
Authors: N. Aqui, A. Gordon, Y. Xu, E. A. Chong, L. Leinbach, T. Ahmadi, S. Nasta, J. Svoboda, S. J. Schuster
Journal: Journal of Clinical Oncology (2011)

8060 Background: Lenalidomide may enhance anti-tumor immune responses by inhibiting Tregs and by augmenting NK-cell mediated antibody-dependent cytotoxicity. These immunologic effects may synergize when lenalidomide is combined with rituximab. Methods: We are conducting a single center, open label phase II trial of lenalidomide and rituximab +/- dexamethasone in patients (pts) with indolent B-cell lymphomas or mantle cell lymphoma refractory to rituximab, defined as failure to respond to or progression within 6 months of rituximab-monotherapy, rituximab-containing chemotherapy, or rituximab-maintenance. The regimen consists of two 28-day treatment cycles of lenalidomide 10 mg daily +/- dexamethasone 8 mg once weekly (Part 1). During cycle 3, pts receive 4 weekly doses of rituximab 375 mg/m2 while continuing lenalidomide +/- dexamethasone (Part 2). After cycle 3, lenalidomide +/- dexamethasone is continued until disease progression, as tolerated. Peripheral blood is collected for immune assessment by flow cytometry at enrollment and after Parts 1 and 2. Results: 37 pts enrolled on study; 23 pts completed Parts 1 and 2. Pts with CR or PR after Part 2 were analyzed as responders (N=16); pts with stable/progressive disease as nonresponders (N=7). After Part 1, CD4+FOXP3+ Tregs were increased in non-responders (median 1.3 fold change, range: 0.85, 4.6) but decreased or unchanged in responders (median 0.73 fold change, range: 0.02, 3.3); p = 0.07. The CD4+FOXP3+CD39+ Treg subset increased significantly in non-responders compared to responders (median fold change: non-responders 3.3, range: 2.8, 4.2; responders 0.98, range: 0.40, 3.5; p = 0.004). After Part 2, no further changes in CD4+FOXP3+ and CD4+FOXP3+CD39+ Tregs were observed. Conclusions: Non-responding patients appear to have an increase in CD4+FOXP3+ Tregs after two months of lenalidomide +/- dexamethasone, particularly in the CD4+FOXP3+CD39+ subset. Responding patients exhibit no change in Tregs during lenalidomide and rituximab +/- dexamethasone therapy. Functional studies are underway to determine the significance of these findings.
674. Development of the Retroviral Vector Manufacturing Process for MM-TK Therapy
Authors: Simona La Seta Catamancio, Manuela Cota, Patrizia Mangia, Ralitsa Arnaudova, Paolo Morandi, Marisa Marzocca, Michele Manfredini, Francesca Rossetti, Elena Spoldi, Giuliana Vallanti, Gian-Paolo Rizzardi, Catia Traversari
Journal: Molecular Therapy (2015)

The MM-TK Drug Product (DP) is a medicinal product used as adjunctive therapy in leukaemia patients undergoing stem cell transplantation. It is constituted of T lymphocytes genetically modified ex vivo with the γ retroviral vector SFCMM-3 Mut2 #48 encoding the HSV-TK Mut2 suicide gene and the cell surface marker ΔLNGFR. During clinical development, different improvements were introduced in retroviral vector (RVV) manufacturing in order to obtain simple and robust processes producing RVV with low level of impurities and high performance in lymphocyte transduction. Single-use bioreactors are currently replacing conventional bioreactors also for mammalian cell culture. They allow to increase biological and process safety by reducing cleaning and sterilization procedures and the risk of cross contaminations. In this context, we are currently evaluating different single-use, closed-system bioreactors for the manipulation of adherent packaging cell lines. A feasibility study is on-going, using a single-use bioreactor based on the 2D multi-tray stacks technology Xpantion system (Pall LifeSciences). This study explores the role of gas control on cell growth and its impact on the RVV quality attributes evaluating key metabolites, as glucose and lactate, and viral titer during cell expansion. In parallel a manufacturing process in 10-layers cell factories (CFs) has been developed and validated. The results obtained with the Am12/SFCMM-3 Mut2 #48 producer cell line grown up to 10 days in XP10 and in XP50 bioreactors showed an infectious viral titer on the reference cell line CEM A3.01, a transduction efficiency on T cells and an impurities level close to those obtained with the CFs. Process development and comparability data will be presented in more detail.
Personality Changes, Executive Dysfunction, and Motor and Memory Impairment
Authors: Alfonso Sebastian López-Chiriboga, Takuya Konno, Jay A. van Gerpen
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Abstract 824: A novel mechanism of areca nut-induced oral cancer is through the conversion of cancer stem cells to acquire malignant phenotypes
Authors: Yi-Chen Li, Ann-Joy Cheng
Journal: Cancer Research (2015)

Abstract Areca nut is one of the most commonly used psychoactive substance worldwide. It is has been identified as a primary carcinogen of oral cancer in Southeast Asia. Previous studies to examine the effects of this carcinogen often used short-term and high-dose treatment of area nut extract (ANE) as a research model. To elucidate the molecular effects of areca nut and mimic patient chronic exposure situation, we established four areca nut extract (ANE)-trained oral cancer sublines by treating cells with low-dose of ANE (IC30, dose for 30% growth inhibition) for 2 months. Without evidence of cellular senescence, these sublines exhibited significant increases in invasive ability, along with the up-regulation of MMP1 and the reversed expression of epithelial-mesenchymal transition markers. These sublines also showed more resistant to chemotherapeutics and irradiation, which was associated with the over-expression of ABCG2 transporters, increased production of anti-oxidative enzymes, and insensitive to ROS induction. Furthermore, these chronically treated cells possessed characteristics of cancer stem cells, as indicated by enrichment of CD24-/CD44+ population, enhancing spheroid cell formation, and increasing expressions of stemness associated molecules, including Slug, Twist1, Sox9, and Grp78. Thus, we concluded that chronic areca nut exposure induces a pleotropic effect on stemness regulators that facilitates the conversion of cancer stem cells to acquire malignant transformation in oral cancer. This novel finding provides valuable knowledge on areca nut-induced oral carcinogenesis. Citation Format: Yi-Chen Li, Ann-Joy Cheng. A novel mechanism of areca nut-induced oral cancer is through the conversion of cancer stem cells to acquire malignant phenotypes. [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 824. doi:10.1158/1538-7445.AM2015-824
Assessment of neratinib-resistance and cross-resistance in HER2-overexpressing breast cancer cells.
Authors: Susan Breslin, Claire Corcoran, Sweta Rani, John Crown, Lorraine O'Driscoll
Journal: Journal of Clinical Oncology (2013)

e11520 Background: While current therapies approved for HER2-overexpressing breast cancer (BC) treatment has led to advances in treatment of this BC subtype, issues of innate/acquired drug resistance are evolving. Neratinib (N) is an irreversible EGFR, HER2 and HER4 tyrosine kinase inhibitor currently in phase III clinical trials for BC treatment. We aimed to investigate the ability of BC cells to acquire resistance to N and the implications of this in terms of potential cross-resistance to other drugs and phenotypic changes in cells. Methods: Neratinib-resistant (NR) cell line variants were developed by exposing HER2-overexpressing BC cell lines, HCC1954 and SKBR3, to increasing concentrations of N over several months. Proliferation assays were used to establish IC 50 values for N in parent and NR variants; as well as to assess possible cross-resistance to lapatinib (L), afatinib (A) and docetaxel (D). Phenotypic changes in NR cell variants were examined using invasion, migration and anoikis assays. IGF1R expression was determined using immunoblots. Results: HCC1954-NR and SKBR3-NR cell variants were 6.5±0.4 and 194±47 fold more resistant to neratinib than parent cells, respectively. Furthermore, HCC1954-NR variants were cross-resistant to afatinib (37±7.23 fold) and lapatinib (10±0.8 fold). SKBR3-NR variants were cross-resistant to afatinib by &gt;163.3±22.7 fold (IC 50 not reached at 9µM afatinib where, on average, 65.5 % cell growth is maintained) and lapatinib (162.3±22 fold). No cross-resistance to docetaxel was observed. Cells that have acquired N resistance are more invasive, migratory and resistant to anoikis than their parent controls. IGF1R expression is increased in NR cell variants compared to parent cells. Conclusions: Chronic exposure of BC cells to N results in acquired resistance to the drug. N resistance conferred cross-resistance to other HER2-targeting drugs and induced a more aggressive phenotype. Overexpression of IGF1R in NR variants suggested its role in the mechanism of N resistance.
OP02ADOLESCENT/YOUNG ADULT MEDULLOBLASTOMA: TIME FOR A CHANGE IN MANAGEMENT STRATEGY
Authors: Jonathan L. Finlay, Arnab Charkavarti, Anita Mahajan, Kevin C. De Braganca, Karla Bellman, Minesh Mehta, Sharon Gardner, Stephen Sands, Roger Packer, Michael Prados
Journal: Neuro-Oncology (2015)