tbuckley/cabot-search huggingface dataset:
PWE-073 Gastro-oesophageal reflux symptoms and the development of oesophageal adenocarcinoma: comparison with community and reflux oesophagitis controls from MOSES (Midlands Oesophageal Adenocarcinoma Epidemiology Study)
Authors: S C Cooper, S Prew, L Podmore, N J Trudgill
Journal: Gut (2010)

<h3>Introduction</h3> Barrett9s oesophagus is the result of chronic gastro-oesophageal reflux disease (GORD) and is associated with the development of oesophageal adenocarcinoma (OAC). We have undertaken the largest case-control study to date to examine the relationship between GORD symptoms and the development of OAC. <h3>Methods</h3> Incident cases of OAC from 12 hospitals in the Midlands, UK and age-, gender-, ethnically- and geographically-matched community control (CC) subjects (from primary care) and reflux oesophagitis (RO) control patients (from endoscopy units) were recruited and interviewed. Logistic regression generated odds ratios (OR) for duration, frequency and nocturnal symptoms of heartburn and acid regurgitation 1 and 10 years prior to diagnosis of OAC or interview for the study for controls. <h3>Results</h3> 207 OAC (177 men, median (IQR) age 68 (60–75) years), 283 CC subjects (236 men, age 67 (60–74) years), and 224 RO patients (178 men, age 66 (59–75) years) were recruited. The presence of GORD symptoms was associated with OAC vs CC: OR (95% CI) 2.83 (1.94 to 4.14) (p&lt;0.0001), but there was no difference vs RO. A longer duration of heartburn was associated with OAC: vs CC 3.36 (1.6–7.04) (p=0.001) and vs RO 5.24 (2.41–11.38) (p&lt;0.0001). A longer duration of acid regurgitation was also associated with OAC: vs CC 2.95 (1.22–7.14) (p=0.017) and vs RO 9.16 (3.88-21.66) (p&lt;0.0001). Increasing frequency of GORD symptoms was also associated with OAC vs CC: 1 year prior to diagnosis – daily heartburn 2.96 (1.38–6.34) (p=0.005), daily acid regurgitation 11.66 (2.6-52.16) (p=0.001); 10 years prior to diagnosis – daily heartburn 2.66 (1.29–5.46) (p=0.008); and OAC vs RO, but only 10 years prior – daily heartburn 2.02 (1.1-3.71) (p=0.023). Nocturnal GORD symptoms were associated with OAC vs CC: 1 year prior to diagnosis acid regurgitation 2.25 (1.29–3.92) (p=0.004); 10 years prior to diagnosis heartburn 2.03 (1.2–3.43) (p=0.008) and acid regurgitation 2.19 (1.22–3.92) (p=0.009); and vs RO 10 years prior to diagnosis – heartburn 3.39 (1.98–5.78) and acid regurgitation 3.94 (2.23–6.98) (both p&lt;0.0001). Finally, antacid usage was also associated with OAC 10 years prior to diagnosis: vs CC 1.92 (1.5–2.46) (p&lt;0.0001) and vs RO 1.34 (1.06–1.68) (p=0.014). <h3>Conclusion</h3> Subjects with GORD symptoms are at increased risk of developing OAC. The increased risk of developing OAC is most marked in those whose symptoms occur daily, who have had symptoms for at least 10 years, who have required antacids for 10 years and whose symptoms wake them from sleep.
Abstract 3923: A role for fibroblast growth factor receptors in growth of atypical teratoid rhabdoid tumor cells and as potential therapeutic targets
Authors: David O. Azorsa, Oliver B. Pepper, Madhavi Chakravadhanula, David W. Lee, Justin J. Montoya, Victor Ozols, Ratan Bhardwaj, Robert J. Arceci
Journal: Cancer Research (2015)

Abstract Malignant rhabdoid tumors are characterized by the loss of the SWI/SNF complex subunit SMARCB1. Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare form of pediatric MRT that occurs in the CNS. Current treatment modalities for this tumor type continue to be surgical resection, chemotherapy and radiotherapy, but overall survival is still relatively low for younger children with this disease. We initially tested the sensitivity of three ATRT cell lines to 48 chemotherapeutic agents and selective inhibitors. Our results indicated that two cell lines CHLA-04-ATRT and CHLA-05-ATRT were sensitive to FGFR inhibition. Further analysis of a panel of five ATRT cell lines indicated that the cell lines CHLA-04-ATRT, CHLA-05-ATRT, CHLA-266 and BT-12 were sensitive to the FGFR inhibitors PD173074, BGJ398 and AZD4547. Interestingly, the ATRT cell line CHLA-06-ATRT did not show sensitivity to FGFR inhibition. Analysis of FGFR protein expression by immunoblot analysis indicated that CHLA-04-ATRT and CHLA-266 cells expressed both FGFR1 and FGFR2, while the cell lines CHLA-05-ATRT and BT-12 expressed only FGFR1. The CHLA-06-ATRT cell line did not show expression of any FGFRs. We further demonstrated functional FGFR activity in the ATRT cell lines by treating growth factor-deprived ATRT cells with FGF-1 or FGF-2, both of which led to dose dependent cell growth only in the cell lines expressing FGFR1 or FGFR2. We are currently investigating the expression of FGFR isoforms in ATRT patient samples. Taken together, our results demonstrate a potential role for FGFR1 and FGFR2 in the survival and proliferation of ATRT cells and indicate that FGFRs could serve as potential targets for therapy in ATRT. Citation Format: David O. Azorsa, Oliver B. Pepper, Madhavi Chakravadhanula, David W. Lee, Justin J. Montoya, Victor Ozols, Ratan Bhardwaj, Robert J. Arceci. A role for fibroblast growth factor receptors in growth of atypical teratoid rhabdoid tumor cells and as potential therapeutic targets. [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 3923. doi:10.1158/1538-7445.AM2015-3923
Cross-Talk Between CLL Cells and Endothelial Cells in the Bone Marrow Microenvironment: Role of Signal Transducer and Activator of Transcription (Stat)-3.
Authors: Xavier C. Badoux, Carlos Bueso Ramos, David Harris, Ping Li, Zhiming Liu, Jan Burger, Susan O'Brien, Alessandra Ferrajoli, Michael Keating, Zeev Estrov
Journal: Blood (2009)
Assessment of T-Cell Receptor Repertoire and Clonal Expansion in Peripheral T-Cell Lymphoma Using RNA-Seq Data
Authors: Chao Wang, Qiang Gong, Weiwei Zhang, Javeed Iqbal, Yang Hu, Timothy C. Greiner, Adam Cornish, Raul Rabadan, Francesco Abate, Xin Wang, Giorgio Inghirami, McKeithan W. Timothy, Wing C Chan
Journal: Blood (2015)
Abstract 3619: Arsenic trioxide downregulates NPM-ALK and inhibits the proliferation of ALK-positive anaplastic large cell lymphoma
Authors: Wenying Piao, David HW Chau, Kevin LM Yue, Yok Lam Kwong, Eric WC Tse
Journal: Cancer Research (2015)

Abstract INTRODUCTION Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma. Depending on the presence or absence of chromosomal translocations involving the anaplastic lymphoma kinase ALK gene and hence the expression of ALK, ALCL is further subdivided into ALK positive (ALK+) or ALK negative (ALK-) types. NPM-ALK chimeric fusion oncogenic protein is found in around 80% of ALK+ ALCL, as a result of the chromosomal translocation t(2;5)(p23;q35). The current standard of treatment for ALK+ ALCL is combination chemotherapy. Crizotinib, an ALK tyrosine kinase inhibitor, is the only agent available to target NPM-ALK in ALCL. The identification of other targeting agents would potentially improve the treatment outcome of ALK+ ALCL especially for relapsed and/or refractory cases. In this study, we investigated the effect of arsenic trioxide (As2O3) on NPM-ALK in ALCL. Methods We treated ALK+ ALCL cell lines with various clinically achievable concentrations of As2O3 (0, 0.5, 1 and 2μM) for 24 hours and examined its effects on NPM-ALK mRNA expression by semi-quantitative RT-PCR and protein expression by Western immunoblotting. The downstream signaling pathway of NPM-ALK, phosphorylation of STAT3 on Tyr705, was also examined. Next, we analyzed apoptotic cell death and growth arrest induced by As2O3 in ALK+ and ALK- ALCL cell lines using Annexin V-7AAD staining and cell cycle analysis. The effect of As2O3 on cell viability was also measured with WST-1 assay. RESULTS Our data showed that As2O3 downregulated NPM-ALK at the protein level without affecting the transcription. It also inhibited the phosphorylation of STAT3 in all ALK+ ALCL cell lines. We also found that blocking protein degradation through proteasome with MG132 abrogated the effect of As2O3 on NPM-ALK. Furthermore, As2O3 induced apoptotic cell death, cell cycle arrest at G2/M phase and growth inhibition in ALK+ but not in ALK- ALCL cell lines, with a GI50 of less than 1μM, which was a level achievable with clinical use of As2O3. CONCLUSIONS. Our data demonstrated that As2O3 downregulated NPM-ALK by facilitating protein degradation through the proteasomal pathway, thereby inhibited cell proliferation and induced cell death in ALK+ ALCL. As2O3 may therefore represent a potential therapeutic agent for the treatment of ALK+ ALCL. Citation Format: Wenying Piao, David HW Chau, Kevin LM Yue, Yok Lam Kwong, Eric WC Tse. Arsenic trioxide downregulates NPM-ALK and inhibits the proliferation of ALK-positive anaplastic large cell lymphoma. [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 3619. doi:10.1158/1538-7445.AM2015-3619
557. Targeted CYBB Minigene Insertion into the CYBB Locus for Correction of X-CGD iPSCs Requires Intronic Elements for Expression
Authors: Colin L. Sweeney, Uimook Choi, Jizhong Zou, Randall K. Merling, Suk See De Ravin, Harry L. Malech
Journal: Molecular Therapy (2016)

X-linked chronic granulomatous disease (X-CGD) is an immune deficiency characterized by defective phagocyte production of microbicidal reactive oxygen species (ROS), resulting in recurring, life-threatening infections and hyper-inflammation. Mutations causing X-CGD span the entire 13 exons or intronic splice sites of the >30-kb CYBB gene encoding gp91phox, resulting in a loss of gp91phox protein expression. We previously tested a TALEN-mediated targeted gene therapy approach to insert a codon-optimized CYBB minigene into the start site of endogenous CYBB. Although targeted insertion into the endogenous start site was achieved in X-CGD patient iPSCs, little or no gp91phox expression or ROS activity was observed upon granulocyte differentiation, suggesting that downstream intronic or regulatory elements may be necessary for efficient gene expression from the CYBB promoter. To test this hypothesis, we tested CRISPR-mediated targeted insertion of a codon-optimized CYBB cDNA consisting of exons 2 through 13 (CYBB2-13) together with a puromycin-resistance gene cassette into exon 2 of the CYBB locus. In iPSCs from X-CGD patients with a CYBB mutation in exon 5, exon 7, or intron 10, the efficiency of targeted insertion of the CYBB2-13 plasmid donor without random inserts in puromycin-selected clones was 50-66%. Upon granulocyte differentiation of CYBB2-13 corrected X-CGD iPSCs, gp91phox expression and ROS production were restored to levels 64-100% (gp91phox) and 68-76% (DHR) of normal healthy donor controls. As expected for expression from the endogenous CYBB promoter, expression of gp91phox was specific to CD13+ granulocytes, and was undetected in undifferentiated iPSCs. This targeted gene therapy approach should allow correction of ~90% of X-CGD patient mutations (those involving mutations in exons 2 through 13), to restore ROS activity while maintaining normal regulation of CYBB expression. Further, these findings demonstrate a key issue for the design of targeted gene insertion to capture expression from an endogenous promoter: for some endogenous promoters, the inclusion of intronic elements is necessary for efficient expression of the insert.
Normal Presence of Tissue Inhibitors of Matrix Metalloproteinases in Platelets of Patients with the Gray Platelet Syndrome Suggests a Novel Organization for These Secreted Proteins.
Authors: Julien Villeneuve, Anna Block, Caroline Le Bousse, Sebastien Lepreux, Jean-Max Pasquet, Paquita Nurden, Jean Ripoche, Alan T. Nurden
Journal: Blood (2007)
Abstract A14: Engineering pancreatic cancer through molecular and cellular reconstruction
Authors: Naoki Akanuma, Jun Liu, Pei Wang
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignancies characterized by the accumulation of a series of genetic mutations during disease progression. Despite significant amount of studies using genetically engineered mouse PDAC models, human PDAC still has a dismal prognosis, and there are few models for human PDAC tumorigenesis. To establish a genetic modification system for human pancreatic tissue, we made lentiviral CRISPR to target CDKN2A/p16, p53 and SMAD4. We have confirmed the efficiency of the p16 CRISPR, p53 CRISPR and SMAD4 CRISPR constructs in editing the genome to delete the respective gene loci. We then generated a lentiviral vector to express KRASG12D-mCherry and transduced normal human primary pancreatic exocrine cells with single or multiple viral vector combinations. After one week of culture, two million of the cells were transplanted into the renal sub-capsular space of NOD-SCID mice. The engraftments were harvested 4 months after transplantation. We observed two PanIN lesions in kidneys where KRASG12D mutant cells were transplanted. Human cells were detected using anti-human nuclear antigen antibody (anti-HuNu). Anti-Pan cytokeratin staining proved that the lesions were made up of epithelial cells. The histologic appearance of the lesion from the cells with all four mutations, KRASG12D p16-/- p53-/- SMAD4-/-, differed from that of the two PanIN lesions in that has a single, much larger cyst with mucin rich cytoplasm reminiscent of mucinous cystic neoplasm (MCN). To further define the cellular origin of PDAC initiation, we also developed a flow cytometry-based method to sort viable ductal cells and acinar cells from primary normal human pancreatic cells for genetic modifications. In summary, we have successfully generated PDAC-associated-precancerous lesions from primary normal human pancreatic tissues. The system established in this study could be a valuable platform to address the fundamental mechanisms for the human PDAC tumorigenesis process. Citation Format: Naoki Akanuma, Jun Liu, Pei Wang.{Authors}. Engineering pancreatic cancer through molecular and cellular reconstruction. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A14.
Fully Functional NK Cells Promote Graft-to-Leukemia Effect, after Cord Blood Transplantation.
Authors: Vivien Beziat, Stéphanie Nguyen, Simona Lapusan, Baptiste Hervier, Nathalie Dhedin, Dominique Bories, Madalina Uzunov, Hélène Treberden-Negre, Françoise Norol, Zora Marjanovic, Jean-Pierre Marie, Jean-Paul Vernant, Patrice Debre, Bernard Rio, Vincent Vieillard
Journal: Blood (2008)
507. Chondroitin Sulfate Proteoglycan 4 (CSPG4)-Redirected T Cells Eliminate Glioblastoma-Derived Neurospheres
Authors: Serena Pellegatta, Barbara Savoldo, Chuang Su, Soldano Ferrone, Gaetano Finocchiaro, Gianpietro Dotti
Journal: Molecular Therapy (2016)

Adoptive therapy with chimeric antigen receptor-redirected T cells (CAR-Ts) remains challenging for the treatment of glioblastoma (GBM) because of the heterogeneous expression of targetable tumor antigens, which leads to the selection of antigen-loss variants. In addition, the emerging role of GBM-derived neurospheres (GBM-NS) as a critical cell subset in causing GBM recurrence highlights the need to eradicate these cells to achieve sustained responses. By exploiting a well-established culture system, we generated and expanded GBM-NS from 23 surgical samples, and tested them using flow cytometry for the expression of CSPG4, a membrane bound tumor antigen found to be overexpressed in GBM by mRNA profiling. We observed that 70% of GBM-NS displayed high expression of CSPG4 (from 71% to 99%), 17% moderate-high expression (from 51% to 70%), and 13% moderate-low expression (<50%). Based on these results, we hypothesized that CSPG4-specific CAR-Ts would represent a broadly applicable strategy for the treatment of GBM. We generated CSPG4. CAR-Ts, encoding the 4-1BB endodomain, from 6 healthy donors and tested them against 19 of the 23 generated GBM-NS that robustly grow in vitro. CSPG4.CAR-Ts efficiently eliminated all GBM-NS, with high to moderate-low CSPG4 expression, in co-culture experiments at E:T ratios ranging from 2:5 to 1:5 (0.2±0.5% and 0.6±0.9% residual GBM-NS, respectively). By contrast, GBM-NS continued to grow in the presence of control T cells (60.7±17.6% residual GBM-NS). CSPG4.CAR-Ts, but not control T cells, also rapidly proliferated in response to GBM-NS as evaluated by the CFSE assay. CSPG4. CAR-Ts showed a Th1 cytokine profile in response to GBM-NS, releasing significantly more IFN-γ (3593.8±1718.1 pg/ml/2×10^5 cells) and IL-2 (258.8±153.3 pg/ml/2×10^5 cells) than control T cells (1.8±2.5 and 0.9±1.2 pg/ml/2×10^5 cells, respectively). For the in vivo experiments we compared CSPG4.CAR-Ts encoding CD28, 4-1BB, or CD28-4-1BB co-stimulatory endodomains. Two GBM-NS with moderate-low and high CSPG4 expression, respectively were selected and transduced to express the FFluciferase gene to monitor the tumor growth by in vivo bioluminescence imaging. Both GBM-NS and T cells were intracranially injected in 5 wks old female nude mice. CSPG4.CAR-Ts were efficient in controlling tumor growth of both moderate-low and high CSPG4-expressing GBM-NS. We observed an early eradication of the tumor mass in high-CSPG4 expressing GBM-NS, and a significant improved survival in both mice bearing high or moderate-low CSPG4-expressing GBM-NS. CAR-Ts encoding 4-1BB were significantly more efficient than those encoding CD28 or CD28-4-1BB in prolonging tumor free survival (p=0.04). Our data suggest that CSPG4 is an attractive target for CAR-Ts in GBM and that the strategy we have shown to be effective in mice has the potential to be translated to a clinical setting.
Abstract 2271: Peptidylarginine deiminase 2 as a novel therapeutic target for breast cancer
Authors: Sachi Horibata, John L. McElwee, David Sadegh, Katherine Rogers, Dalton McLean, Scott A. Coonrod
Journal: Cancer Research (2015)

Abstract Peptidylarginine deiminases (PADIs) enzymes are calcium-dependent enzymes that post-translationally convert positively charged protein arginine residues to a neutrally charged citrulline in a process known as citrullination or deimination. This loss of charge can alter the tertiary structure of proteins and affect protein-protein and protein-DNA interactions. We, and others, have found that PADI-mediated histone tail citrullination alters chromatin structure and regulates gene expression. For example, we found that PADI2 interacts with estrogen receptor (ERα) and that PADI2-mediated citrullination of histone H3 arginine 26 residues at ERα binding sites regulates target gene expression. In addition, we also found that PADI2 is often co-expressed with HER2 in both breast cancer cell lines and in tumor tissue. Our molecular studies suggest that PADI2 activates HER2 expression via histone citrullination at the HER2 gene locus and that HER2 signaling appears to induce PADI2 expression, thus potentially forming an oncogenic positive feedback loop with HER2. These findings suggest an important role for PADI2 in breast cancer progression. This prediction is supported by our finding that PADI2 expression is upregulated in cancer cells and that depletion of PADI2 from breast cancer cells results in reduced tumorigenicity. In addition, we found that transgenic overexpression of PADI2 promotes carcinogenesis and that the PADI inhibitor, Cl-Amidine, slows tumor growth in mouse models of breast cancer. Furthermore, we found that Cl-Amidine also maintains basement membrane integrity in xenograft tumors, preventing initiation of metastasis. Together, these findings suggest that PADI2 represents a novel therapeutic target and biomarker for early stage breast cancer. Citation Format: Sachi Horibata, John L. McElwee, David Sadegh, Katherine Rogers, Dalton McLean, Scott A. Coonrod. Peptidylarginine deiminase 2 as a novel therapeutic target for breast 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 2271. doi:10.1158/1538-7445.AM2015-2271
Neural Stem Cell–Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients
Authors: Jana Portnow, Timothy W. Synold, Behnam Badie, Revathiswari Tirughana, Simon F. Lacey, Massimo D'Apuzzo, Marianne Z. Metz, Joseph Najbauer, Victoria Bedell, Tien Vo, Margarita Gutova, Paul Frankel, Mike Chen, Karen S. Aboody
Journal: Clinical Cancer Research (2016)

Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 107 to 5 × 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.Results: Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951-60. ©2016 AACR.
Clinical Activity of Flavopiridol in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL) with High-Risk Cytogenetic Abnormalities: Updated Data on 89 Patients (Pts).
Authors: Nyla A. Heerema, John C. Byrd, Leslie A. Andritsos, Gerard Lozanski, Kristie Blum, Beth Fischer, Jeffrey A. Jones, Mollie E. Moran, Sarah Groering, Larry J. Schaaf, Linda S. Mahoney, Amy J. Johnson, Lisa L. Smith, Amy J. Wagner, Chelsey A. Raymond, Mitch A. Phelps, James T. Dalton, Michael R. Grever, Thomas S. Lin
Journal: Blood (2007)