tbuckley/cabot-search huggingface dataset:
Can the well-credentialed neuroblastoma tumor antigen GD2 be exploited for T-cell-based immunotherapy of pediatric sarcomas?
Authors: S. Ramakrishna, S. Gottschalk, R. Morgan, G. Dotti, M. K. Brenner, R. Orentas, C. Mackall
Journal: Journal of Clinical Oncology (2011)

9531 Background: Genetic manipulation of T cells may provide promising new therapies for pediatric solid tumors. T cells can be modified to express chimeric antigen receptors (CAR), which link the antigen-recognition region of an antibody to a CD3-zeta signaling domain and various costimulatory domains. CARs allow for non-MHC-restricted tumor recognition, followed by T cell activation, expansion and cytolytic activity. We constructed a series of CARs specific for the disialoganglioside GD2. GD2 is a well-established target for neuroblastoma, with anti-GD2 moAb therapy improving survival in high risk neuroblastoma and GD2-CAR therapy showing clinical activity in this disease. GD2-CARs also have preclinical activity against melanoma and GD2 expression has been reported in some rhabdomyosarcomas, osteosarcomas and Ewing sarcomas. Methods: We observed that GD2 is overexpressed in the following established laboratory and recent patient-derived cell lines: Rh18 (rhabdomyosarcoma: 94.8% expression), 143B and MG63 (osteosarcoma: 78.5% and 98.2%, respectively) and Tc71 (Ewing sarcoma: 96.1%). These cell lines were used to evaluate our GD2-CARs in vitro. We compared activity between second generation, with one costimulatory molecule (CD28), and third generation, with two costimulatory molecules (CD28 & CD137), GD2-CAR constructs, with or without an extracellular CH2-CH3 hinge domain from human IgG1. Results: Second and third generation GD2-CAR modified T cells show similar high level lysis of GD2+ rhabdomyosarcoma, osteosarcoma and Ewing sarcoma cell lines as seen with neuroblastoma lines. Addition of the CH2-CH3 hinge region consistently improved cytolytic activity by 5-10%, measured by chromium-release assay, suggesting that this extracellular structural alteration may improve CAR function. Studies evaluating the expression of GD2 in tumor tissues and the efficacy of GD2-CAR modified T cells in osteosarcoma and rhabdomyosarcoma xenograft models are underway. Conclusions: GD2-CAR based therapy may prove effective for patients with GD2+ rhabdomyosarcoma, osteosarcoma and Ewing sarcoma in addition to patients with neuroblastoma and melanoma.
Abstract 5336: Improved antitumor effect of combining WNT/beta-catenin inhibition with sorafenib in hepatocellular carcinoma
Authors: Hsiao-Hui Lin, Wen-Chi Feng, Li-Chun Lu, Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Cancer Research (2015)

Abstract [Background] Sorafenib is currently the only approved systemic agent for advanced hepatocellular carcinoma (HCC); however, its efficacy is limited. Aberrant activation of WNT/β-catenin signaling pathway has been shown to mediate resistance to various types of anti-cancer therapy. We hypothesized that inhibition of WNT/β-catenin signaling pathway would improve the anti-tumor effect of sorafenib in HCC. [Materials and Methods] Human HCC cell lines, including Huh7, HepG2, PLC5, and Hep3B, were included. Inhibition of WNT/β-catenin pathway was achieved by ICG-001, a small molecule disrupting the interaction of cAMP-responsive element binding (CREB)-binding protein (CBP) and β-catenin and inhibiting the β-catenin-mediated transcription activities, or by RNA interference (RNAi)- downregulation of β-catenin. The efficacy of sorafenib combined with WNT/β-catenin pathway inhibition in HCC cells was determined by MTT for cell viability, and by flow cytometry and Western blotting for apoptosis. The in vivo efficacy was evaluated in a subcutaneous xenograft mode of Huh7 cells. [Results] In multiple HCC cell lines, ICG-001 enhanced the anti-proliferative effect of sorafenib dose-dependently; the combination of ICG-001 and sorafenib showed a synergistic antitumor effect. Downregulation of β-catenin by RNAi increased sorafenib sensitivity, whereas overexpression of β-catenin decreased sorafenib sensitivity in Huh7 cells. Furthermore, the sorafenib-sensitization effect by short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was offset by β-catenin overexpression. Mechanistically, sorafenib in combination of ICG-001 or shRNA- mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a more prominent downregulation of Mcl-1 in HCC cells. Finally, ICG-001 in combination of sorafenib showed a more significantly growth-retarding effect in Huh7 xenograft than either drug alone. [Conclusion] Our data indicate that inhibition of WNT/β- catenin signaling pathway improves the antitumor effect of sorafenib against HCC in vitro and in vivo.(This study was supported by grants NRPB-100CAP1020-2 and NSC-101-2314-B-002-141, 100CAP1020-2). Citation Format: Hsiao-Hui Lin, Wen-Chi Feng, Li-Chun Lu, Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu. Improved antitumor effect of combining WNT/beta-catenin inhibition with sorafenib in hepatocellular carcinoma. [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 5336. doi:10.1158/1538-7445.AM2015-5336
Subacute Cortical Infarct Showing Uptake on 68Ga-PSMA PET/CT
Authors: Mico Chan, Edward Hsiao
Journal: Clinical Nuclear Medicine (2016)

Ga prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate extent of disease in prostate carcinoma. We present a case of subacute cortical cerebral infarct showing focal uptake on PSMA PET/CT. It is an important potential cause of false-positive uptake in this imaging cohort. The patient is an 85-year-old man with a background of nonbacterial thrombotic endocarditis and previous cerebrovascular events. He was referred for PSMA PET/CT for staging of high-risk prostate cancer.
216. Exploiting Redox-Based Vulnerabilities in Field Cancerization by Targeting Cancer Associated Fibroblasts
Authors: Jeremy Soon Kiat Chan, Ming Jie Tan, Nguan Soon Tan
Journal: Molecular Therapy (2016)

Tumor development and progression to malignancy is increasingly viewed as a consequence of disrupted homeostatic interactions between epithelial cells and the underlying stromal elements. In squamous cell carcinoma of the skin, genomic and histological abnormalities have been observed in keratinocytes and stroma bordering multifocal neoplastic lesions, suggesting a regional carcinogenic signal that promotes aberrant cellular behavior within the tumor microenvironment. This has been termed field cancerization. Cancer associated fibroblasts (CAFs) are the major cell type in the tumor stroma and are known producers of extracellular pro-tumor signaling molecules. While growth factors and cytokines are candidate molecules for targeted therapy, reactive oxygen species (ROS) are gaining attention for their roles in heterotypic paracrine signaling in cancer. The importance of ROS in field cancerization remains poorly understood. Histological analysis of on sections of patient tumor biopsies revealed that ROS was elevated in the tumor stroma. CAFs explanted from patient tumors also released high levels of hydrogen peroxide into the extracellular space. Interestingly, normal fibroblasts exposed to CAF-conditioned medium displayed increased ROS production, an observation that could be reversed by the antioxidant N-acetyl cysteine. Exposure to hydrogen peroxide also resulted in elevated ROS production in normal fibroblasts. Taken together, these findings suggest that CAFs are a potent source of ROS in the tumor microenvironment and can induce a field effect that transforms adjacent normal fibroblasts into a CAF-like state. Transformed fibroblasts in turn produce ROS to spread oxidative stress in the microenvironment, potentially exacerbating field cancerization. Therefore, antioxidant-based therapies targeting the tumor microenvironment may be important adjuvant treatments to current anticancer chemotherapy or targeted therapy.
573. Vector Free Genome Editing of Immune Cells for Cell Therapy
Authors: Tia DiTommaso, Jonathan Gilbert, Howard Bernstein, Armon Sharei
Journal: Molecular Therapy (2016)

While the ex vivo manipulation of primary cells has signaled a new era in the application of cell-based therapies, common methods to manipulate primary cells have limitations. To overcome the limitations associated with conventional cell delivery and engineering systems, we have developed a microfluidic approach to delivery where cells are mechanically deformed as they pass through constricting channels. This deforms the cell membrane resulting in the diffusion of material from the surrounding buffer directly into the cytosol. This system has demonstrated efficacy in patient-derived cells, such as stem cells and immune cells and with a variety of target molecules that are difficult to address with alternative methods. Moreover, by eliminating the need for electrical fields or exogenous materials such as viral vectors and plasmids, it minimizes the potential for cell toxicity and off-target effects. Here, we present evidence detailing our ability to deliver functional material to primary human T cells via membrane deformation with little detectable perturbation in baseline gene expression, cell function, and viability. To determine effect of membrane deformation on gene expression and to compare to other delivery systems, human T cells were subjected to membrane deformation or electroporation and gene expression changes were compared to unmanipulated control cells using microarray analysis. Differential gene expression with respect to both methods of delivery was assessed by performing t tests on the coefficient of a linear mixed-effects model that treated delivery method as a fixed effect and donor as a random effect. Electroporation produced substantially more changes in gene expression than membrane deformation. Subsequently, we designed a series of experiments to manipulate gene expression with the CRISPR-CAS9 system using membrane deformation to deliver CAS9 ribonucleoproteins (RNPs; recombinant CAS9 protein complexed with a single-guide RNA) designed to edit a model locus, the B2 microglobulin component of MHC class 1 (B2M). Here, we show that the delivery of the CRISPR-CAS9 system via membrane deformation results in a significant reduction in B2M surface protein expression by FACS analysis. Taken together, these data suggest that membrane deformation is a viable delivery method for genetic engineering of primary human cells with little off target effects on baseline gene expression. Indeed, the ability to deliver structurally diverse materials to difficult-to-transfect primary cells indicate that this method could potentially enable many novel clinical applications.
Pretransplant Parathyroid Hormone Level Has No Correlation with Platelet Recovery After Stem Cell
Authors: Soo-Jeong Kim, Yundeok Kim, Shin-Young Hyun, Ji-Eun Jang, Doh Yu Hwang, June-Won Cheong, Jin Seok Kim, Yu Ri Kim, Hye Won Lee, Yoo-Hong Min
Journal: Blood (2012)
Abstract 1334: Chemotherapy regulated microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung cancer
Authors: Shigehiro Yagishita, Yu Fujita, Yuichi Fujimoto, Fumiyuki Takahashi, Kazuhisa Takahashi, Tomohide Tamura, Fumiaki Koizumi
Journal: Cancer Research (2015)

Abstract Small-cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. Human epidermal growth factor receptor 2 (HER2) is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we firstly identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3′-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay we demonstrated a significant synergistic cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the synergistic anti-tumor effect of these agents in an orthotopic lung cancer model in vivo. Our result offer a novel therapeutic strategy for HER2-positive SCLC by using trastuzumab combined with cytotoxic drugs. Citation Format: Shigehiro Yagishita, Yu Fujita, Yuichi Fujimoto, Fumiyuki Takahashi, Kazuhisa Takahashi, Tomohide Tamura, Fumiaki Koizumi. Chemotherapy regulated microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung 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 1334. doi:10.1158/1538-7445.AM2015-1334
Abstract 415: Cardioprotective Effects of Interleukin-15 in Immortalized Human Ventricular Cardiomyocytes
Authors: Marin Jane McBride, Kristina Durham, Bernardo L Trigatti
Journal: Circulation Research (2015)

Interleukin-15 (IL-15) is a pleotropic cytokine that has a profound effect on the proliferation, survival and differentiation of many distinct cell types. The IL-15 receptor complex has 3 subunits: the unique receptor chain IL-15 receptor alpha (IL-15Rα), and two receptor chains shared with interleukin-2 (IL-2) and/or other cytokines, referred to as IL-2 receptor beta (IL-2Rβ) and IL-2 receptor gamma/gamma common chain (IL-2Rγ/γc), respectively. To our knowledge, this is the first study to examine the effects of IL-15 in immortalized human cardiomyocytes. Data collected by RT-PCR shows mRNA expression of IL-15Rα, IL-2Rβ and IL-2 Rγ/γc in these cells. Additionally, western blotting for IL-15Rα, IL-2Rβ and IL-2 Rγ/γc confirms the presence of all three IL-15 receptors. Early experiments examining the effect of IL-15 on cardiomyocyte cell survival show a statistically significant protective effect of IL-15 on the survival of cells exposed to tunicamycin, a pharamacological endoplasmic reticulum (ER) stress inducing agent. These findings suggest that IL-15 signaling may be an important cardioprotective pathway that is involved in the cardiac ER stress response. As ER stress is a major component of multiple different cardiac pathologies, such as myocardial infarction, heart failure and diabetes, uncovering the molecular mechanism by which IL-15 protects the heart will allow for deeper understanding of the cardiac ER stress response.
Difference in Outcome of Adolescents with Acute Lymphoblastic Leukemia (ALL) Enrolled in Pediatric (AIEOP) and Adult (GIMEMA) Protocols.
Authors: Anna Maria Testi, Maria Grazia Valsecchi, Valentino Conter, Marco Vignetti, Francesca Paoloni, Fiorina Giona, Maria Luisa Moleti, Luca Lo Nigro, Franco Locatelli, Saverio La Dogana, Giorgina Specchia, Francesca Fabiano, Anna Recchia, Franco Mandelli, Robert Foa’, Giuseppe Masera
Journal: Blood (2004)
Abstract 580: hENT1 testing in pancreatic ductal adenocarcinoma: Are we ready yet? A comparative analysis of the murine and the rabbit antibodies
Authors: Jerome Cros, Raphael Marechal, Jean Baptiste Bachet, Pierre Laurent-Puig, Jean Francois Flejou, Pieter Demetter, Magali Svrcek
Journal: Cancer Research (2015)

Abstract Introduction Human equilibrative nucleoside transporter 1 (hENT1) level of expression in pancreatic adenocarcinoma (PAC) may predict survival in gemcitabine-treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2), which is not commercially available. Another antibody, rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PAC. This raises the question of the equivalence of the antibodies. Patients and Methods Murine (10D7G2) and rabbit (SP120) monoclonal anti-hENT1 antibodies were applied on the same tissue microarrays of resected PAC. Two sets of patients from 2 separate institutions (n = 147 each) were used to compared hENT1 expression with both antibodies on two different immunochemistry automates. An additional amplification technique was performed on the second set. hENT1 expression was scored as previously reported. Results were correlated with overall survival (OS) following gemcitabine treatment. Results The rate of “hENT1 high” cases was lower with the SP120 clone (set 1: 7 versus 48%, set 2:11 versus 38%). With the amplification technique, the rate of “hENT1 high” cases was globally similar between both antibodies. However, the concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS with the 10D7G2 antibody (HR = 0.49; 95% CI: 0.24-0.98; P = 0.045) but not with the SP120 (HR = 1.61; 95% CI: 0.80-3.21; P = 0.18). Conclusion Our data suggest that the two antibodies are not equivalent. Further studies are ongoing and will be presented at the meeting: 1/ Comparative analysis of the rabbit antibody on a larger series (n = 471) with staining performed by Ventana® (Roche®), 2/ Comparative analysis of 3 additional anti-hENT1 antibody together with mRNA level correlation, 3/ Comparative expression of hENT1 in a series of matched primary tumors-metastases. Citation Format: Jerome Cros, Raphael Marechal, Jean Baptiste Bachet, Pierre Laurent-Puig, Jean Francois Flejou, Pieter Demetter, Magali Svrcek. hENT1 testing in pancreatic ductal adenocarcinoma: Are we ready yet? A comparative analysis of the murine and the rabbit antibodies. [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 580. doi:10.1158/1538-7445.AM2015-580
Abstract 714: Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers
Authors: Ye Zhang, Xiujuan Qu, Yuee Teng, Ling Xu, Jing Liu, Zhi Li, Xuejun Hu, Yunpeng Liu
Journal: Cancer Research (2015)

Abstract Background The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. Methods Immunofluorescence microscopy and proximity ligation assays were used to analyze the translocation of P-gp into caveolae. Nude mice (n = 7 mice per group) were injected with SGC7901/Adr vector, SGC7901/Adr + Cbl-b cells and/or Dox and tumor growth was assessed. Immunoprecipitation and western blotting were used to examine the effects of Cbl-b mediated ubiquitination and degradation of c-Src. Immunochemistry was performed on primary tumor specimens from breast cancer patients (n = 319) to determine the relationship of Cbl-b with overall survival. Results c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance (MDR) in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae, resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Conclusions Our findings reveal a new regulatory mechanism of P-gp transport function. Citation Format: Ye Zhang, Xiujuan Qu, Yuee Teng, Ling Xu, Jing Liu, Zhi Li, Xuejun Hu, Yunpeng Liu. Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers. [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 714. doi:10.1158/1538-7445.AM2015-714
PP-018 What is the most cost-effective therapy for high-grade dysplasia in Barrett's oesophagus?: Abstract PP-018
Authors: S Menon, N Trudgill
Journal: Gut (2010)

<h3>Introduction</h3> High grade dysplasia (HGD) in Barrett9s oesophagus (BO) has been regarded as an indication for oesophagectomy. However, the introduction of endoscopic mucosal resection (EMR), radiofrequency ablation (RFA) and photodynamic therapy (PDT) is changing practice. The cost-effectiveness of these strategies was compared with oesophagectomy. <h3>Methods</h3> Decision analysis (Markov) models were developed to examine EMR, RFA and PDT in managing HGD in BO. Two separate models were developed for endoscopically visible HGD and flat HGD. The models assumed that HGD was present at two separate endoscopies, that intramucosal cancer had been excluded and that staging modalities (EUS and CT) had been performed. Competing clinical strategies included a baseline strategy of oesophagectomy and other strategies involving EMR only (up to two resections were modelled), EMR followed by RFA and EMR followed by PDT, respectively, for visible HGD and RFA or PDT for flat HGD. Cost-effectiveness was expressed as net amount per quality adjusted life year (QALY) and base-costs for treatment were obtained from the Department of Health HRG tariffs for 2007/8. A cohort of 1000 50-year-old Caucasian males with BO and HGD followed until 75 years old was modelled. All patients were assumed to be fit for oesophagectomy. Monte Carlo simulation and sensitivity analysis were carried out. <h3>Results</h3> Treatment of visible HGD utilising EMR followed by RFA to ablate residual BO yielded a total cost per patient of £12 424 for 26 QALYs and was the most cost-effective strategy (Abstract 018). The incremental cost-effectiveness ratio (ICER) for this strategy compared to oesophagectomy was £7554. A strategy of treating flat HGD with RFA was more cost-effective than PDT or oesophagectomy (Abstract 10) and yielded an ICER of £4596 compared to oesophagectomy. All variables in the model were tested in a one-way sensitivity analyses and strategies involving EMR and RFA for visible HGD and RFA for flat HGD remained superior to competing strategies in the model. <h3>Conclusion</h3> A combination of EMR and RFA to treat visible HGD and RFA for flat HGD appear to be the most cost-effective strategies to treat HGD due to lower mortality and morbidity than oesophagectomy and less morbidity than PDT. This combination remained more cost-effective even if mortality due to oesophagectomy were to fall from 5 to 0%.
Mitochondrial Donation — Clearing the Final Regulatory Hurdle in the United Kingdom
Authors: Mary Herbert, Doug Turnbull
Journal: New England Journal of Medicine (2016)

A study uncovers aspects of mtDNA replication in cell lines derived from earlystage embryos; meanwhile, a regulatory authority in the United Kingdom has given the green light to “mitochondrial donation” techniques to reduce risk of transmitting mitochondrial disorders.
A Novel Enumeration Method for Hematopoietic Progenitor Cells in Collecting Peripheral Blood Stem Cell for Transplantation
Authors: Ryuji Tanosaki, Tomoko Kumazawa, Shigehisa Yoshida, Atsuya Nakano, Shizuka Yamagata, Noriko Takahashi, Saiko Kurosawa, Shin-Ichiro Mori, Yuji Heike, Takahiro Fukuda, Ko Furuta, Hitoshi Tsuda
Journal: Blood (2011)