tbuckley/cabot-search huggingface dataset:
Abstract A65: Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages
Authors: Hui-Ju Wen, Howard C. Crawford
Journal: Cancer Research (2016)

Abstract Acinar-to-ductal metaplasia (ADM) has been frequently seen in the damaged pancreatic tissues. It is also associated with PanIN lesions in PDAC samples derived from human and mouse and has been shown to act as a preneoplastic lesion in mice. Therefore, understanding the mechanisms of lesion formation at the earliest phase would provide needed information for studying pancreatic tumorigenesis. Previously, we have shown that EGFR activity is required for metaplastic duct formation and KRas-induced pancreatic tumorigenesis. In addition, a prominent macrophage infiltration has been shown to be important in the early phase of lesion formation. To investigate the origin of EGFR ligands for EGFR activation during ADM formation in vivo, we examined the metaplasia formation by administration of cerulein in the mice with the conditional knockout of a key EGFR ligand sheddase ADAM17 in the pancreas (ADAM17fl/fl;Ptf1aCre/+) or in the myeloid cells (ADAM17fl/fl;LysM-Cre). With 2 weeks cerulein treatment, wild type and ADAM17fl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response. However, the mice with ADAM17-null pancreas displayed significant protection from chronic pancreatitis induced by cerulein, including a lack of significant macrophage infiltration, making the analysis of any additional contribution from macrophage derived EGFR ligands. To remedy this, we conditionally knocked out HB-EGF (Heparin-binding EGF-like growth factor) one of the most robustly expressed EGFR ligands in macrophages using LysM-Cre. We examined cerulein-induced metaplasia in HB-EGFfl/fl;LysM-Cre mice. Compared to wild type mice, HB-EGFfl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response and a decrease in cell proliferation; moreover, myeloid cell-specific ablation of HB-EGF dramatically delayed the healing and the restoration of normal pancreatic epithelium after cessation of cerulein treatment. These results indicate that an ADAM17/EGFR ligand/EGFR autocrine loop derived from pancreatic parenchymal cells is required for metaplastic duct formation, and macrophage-derived HBEGF acting in a paracrine fashion contributes to cell survival and tissue remodeling. Citation Format: Hui-Ju Wen, Howard C. Crawford.{Authors}. Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages. [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 A65.
Sensitization of Leukemic Cells for Glucocorticoids by Inhibition of NFκB Activity.
Authors: Jacqueline Cloos, Josefien Vink, Marjolein van Miltenburg, Ruud Oerlemans, Joost van der Heijden, Ben A.C. Dijkmans, Gerrit Jansen, Gertjan J.L. Kaspers
Journal: Blood (2004)
Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines.
Authors: Markus Hermann Moehler, Annett Mueller, Erika Bachmann, Carl Christoph Schimanski, Peter Robert Galle
Journal: Journal of Clinical Oncology (2012)

522 Background: New targeted agents against tyrosine kinases expand the standard therapy in oncology. However, tumor resistance is still a challenge, particularly induced by mutations in growth-related signalling cascades. 20% and 10% of patients with human colon and gastric cancer carry PI3K mutations and do not react to receptor blocking therapies. Recently, selective tyrosine kinase inhibitors have been generated which block PI3K signalling pathways in tumor cells. Their therapeutically role has not yet been clarified. Methods: To define inhibitory and pro-apoptotic effects of the 2 PI3K inhibitors BEZ235 and BKM120 3 human colon cancer (HT-29, HCT-116, DLD-1) and 3 gastric cancer cell lines (NCI-n87, AGS, MKN-45) with different PIK3CA mutation status were used. First, viability, apoptosis and caspase assays were performed during incubation with inhibitors alone or combined with cytotoxic agents. Second, molecular consequences for cell cycle and the signalling pathways were analysed by defining the protein levels by FACS and Western blot. Results: Both PI3K inhibitors BEZ235 and BKM120 induced concentration dependently a significant reduction in viability and an increase in apoptotic death, while mutated cells reacted more sensitive to treatment. BKM120 had a higher efficiency than the dual PI3K/mTOR inhibitor BEZ235. BEZ235 alone caused a G1 arrest in tumor cells. In contrast, BKM120 induced a G2 shift in all gastrointestinal cancer cells. There was a clear downregulation in AKT signalling, and for BEZ235 an additional inhibition of mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis combined with irinotecan in colon cancer. Combinations with 5-fluoruracil and the 2 substances induced additive apoptotic effects. Human gastric cancer cells were less sensitive to BEZ235 and BKM120. Conclusions: In general, we found higher pro-apoptotic effects for all cell lines and in special cases a better response of resistant mutant cells. Our data support the clinical development of these PI3K inhibitors BEZ235 and BKM120 as potential targeting agents for patients with different wild-type or mutated gastrointestinal cancer cells.
Abstract 2019: Photoimmunotherapy with an anti-EGFR antibody conjugated to an IRDye700 results in extensive and rapid cell death in vitro and in vivo in human pancreatic cancer cell lines
Authors: Nzola de Magalhães, Takashi Murakami, Roger Heim, Lew Makings, Miguel Garcia-Guzman, Hisataka Kobayashi, Robert M. Hoffman, Michael Bouvet
Journal: Cancer Research (2015)

Abstract Photoimmunotherapy (PIT) of cancer utilizes tumor-specific monoclonal antibodies conjugated to a photosensitizer phthalocyanine dye IR700 which becomes cytotoxic upon irradiation with near infrared light. In this study, we aimed to evaluate the efficacy of PIT on human pancreatic cancer cells in vitro and in vivo in a nude mouse model. An in vitro cytotoxicity assay was used to determine cell death following treatment with PIT for Panc-1, MiaPaCa2, and BxPC-3 human pancreatic cancer cells. For in vivo determination of PIT efficacy, nude mice were implanted with BxPC-3 pancreatic tumors expressing green fluorescent protein (GFP). After tumor engraftment, the mice were divided into two groups: treatment with anti-EGFR-IR700 + 690 nm laser and treatment with 690 nm laser only. Anti-EGFR-IR700 (100 μg) was administered to the treatment group via tail vein injection 24 hours prior to therapy. Tumors were then exposed and treated with phototherapy at an intensity of 150 mW/cm2 for 30 minutes. Whole body imaging was done using an OV-100 small animal imaging system. Anti-EGFR-IR700 antibody bound to the BxPC3 cells to a high degree based on image co-localization. Anti-EGFR-IR700 caused extensive cancer cell killing after light activation compared to control cells in cytotoxicity assays. In the mouse experiments, the treatment group had significantly smaller tumors as measured by GFP than the control after just 96 hours. The present results indicate the high potential of PIT for pancreatic cancer therapy. Citation Format: Nzola de Magalhães, Takashi Murakami, Roger Heim, Lew Makings, Miguel Garcia-Guzman, Hisataka Kobayashi, Robert M. Hoffman, Michael Bouvet. Photoimmunotherapy with an anti-EGFR antibody conjugated to an IRDye700 results in extensive and rapid cell death in vitro and in vivo in human pancreatic cancer cell lines. [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 2019. doi:10.1158/1538-7445.AM2015-2019
Rapid and Potent Mobilization of Murine Hematopoietic Stem and Progenitor Cells by the Novel CXCR4 Antagonist POL5551
Authors: Darja Karpova, Katrin Dauber, Gabriele Spohn, Doreen Chudziak, Eliza Wiercinska, Miriam Schulz, Barbara Romagnoli, Eric Chevalier, Kalpana Patel, Halvard Bonig
Journal: Blood (2012)
Abstract 4135: A polyclonal origin for pancreatic cancer metastases
Authors: Ravikanth Maddipati, Ben Z. Stanger
Journal: Cancer Research (2015)

Abstract Cancer genome studies demonstrate that tumors are comprised of multiple sub-clones with varied genetic and phenotypic properties. Metastases are often depicted as arising from these subpopulations through seeding by single cells, leading to clonally-derived lesions at distant sites. Alternatively, it has been suggested that metastases can also arise from the collective migration of tumor cells, resulting in formation of polyclonal metastases. To better understand the dynamics of metastasis formation in native tumors, we employed the multi-color “Confetti” lineage tracing system, in an autochthonous mouse model of pancreatic ductal adenocarcinoma (PDAC). Through the stochastic expression of distinct fluorescent proteins in any given cell, we tracked the contribution of different tumor subpopulations to malignant progression. We find that early pre-malignant lesions exhibit significant clonal heterogeneity but this clonal diversity decreases during progression to frank carcinoma. Furthermore our data provide the first direct evidence for polyclonal metastasis in the context of a naturally-evolving tumor and suggest that seeding and colonization of metastatic sites involves interactions between at least two distinct tumor populations. We also observe that clonal evolution during metastatic growth varies significantly between the sites of metastatic invasion, resulting in either monoclonal or polyclonal outgrowth. These results provide and unprecedented window into the dynamic changes in clonality that accompany tumor progression and suggest that heterotypic interactions between tumor subpopulations and microenvironmental factors unique to each tissue site contribute to the clonal evolution of metastases. Citation Format: Ravikanth Maddipati, Ben Z. Stanger. A polyclonal origin for pancreatic cancer metastases. [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 4135. doi:10.1158/1538-7445.AM2015-4135
Risk of Non-Hodgkin lymphoma (NHL) in relation to germline variation in DNA repair genes
Authors: Deirdre A. Hill, Sophia S. Wang, Patricia Hartge, James R. Cerhan, Scott Davis, Wendy Cozen, Richard K. Severson, Meredith Yeager, Stephen J. Chanock, Nathaniel Rothman
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

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Introduction: DNA repair genes may influence chromosomal translocation, an early event in carcinogenesis for some NHL subtypes, and also respond to damage induced by UV, which has been implicated in NHL etiology. Methods: We examined DNA repair gene variants in blood or buccal cells from up to 1,172 incident lymphoma cases and 982 controls who participated in a population-based study of NHL in Los Angeles, Seattle, Detroit and Iowa from 1998-2000. Participants were genotyped for variants in five DNA repair pathways: Non-homologous end joining(NHEJ): RAG1 (K820R), LIG4 (-176), XRCC4 (N298S, S307, A247S); Homologous repair: BRCA1 (L77I, P871L, K1183R, S1613G); BRCA2 (N372H, K1132, S2414, 105bp3’ of STP, N289H, N991D), NBS1 (Q185E), TP53 (P72R), WRN (V114I, M387I, L1048F, C1341R), XRCC2 (R186H), XRCC3 (T241M); Nucleotide excision repair: ERCC1 (IVS5+33A>C ), ERCC2 (D312N, K751Q), ERCC4 (P379S), ERCC5 (H1104D), XPC (K939Q), Rad23B (A249V); Base excision repair:ADPRT (V762A), APEX (D148E), XRCC1 (Q399R, R280H, R194W); Direct reversal: MGMT (I143V, K178R, L84F). Discordance rates for blinded replicates were ≤ 1%. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for the matching factors of age, race, gender and study site. Among white non-Hispanic participants, relative odds of specific NHL subtypes (follicular, diffuse, T-cell, other) were also examined. Results: Overall, NHL cases were more likely than controls to be carriers of the RAG1 820 variant allele (Lys/Arg OR 1.3; 95% CI 1.0-1.6; Arg/Arg OR 2.7; 95% CI 1.4-5.0; p-trend=0.001) as were follicular lymphoma cases (Lys/Arg OR 1.4; 95% CI 1.0-2.0; Arg/Arg OR 3.4; 95% CI 1.0-12.0; p-trend=0.04). The Lig4 -176 variant allele was less common among cases than controls for all NHL (-176 CT OR 0.9; 95% CI 0.7-1.1; -176 TT OR 0.5; 95% CI 0.3-0.9; p-trend=0.04) and for follicular lymphoma (-176 CT OR 0.8; 95% CI 0.6-1.1; -176 TT OR 0.2; 95% CI 0.1-1.0; n=2, p-trend=0.08). Carriers of the BRCA2 372 His/His polymorphism had a slightly elevated NHL risk (OR 1.4; 95% CI 1.0-2.0); predominantly of follicular (OR 1.5; 95% CI 0.9-2.6) and T-cell lymphoma subtypes (OR 2.8; 95% CI 1.2-6.9;n=8). Risks of follicular (OR 1.4; 95% CI 1.0-2.0) and T-cell lymphoma (OR 1.8; 95% CI 1.0-3.3) were also increased among those with either MGMT 143 Val/Ile or Val/Val genotypes. Conclusion: Our results support the possibility that variants in RAG1 and Lig4, which act in the NHEJ repair pathway, may be related to risk of NHL, particularly of follicular lymphoma. As many relationships were tested, results will be presented with consideration of the number of tests performed and the prior probability of a false positive result.
Rapid NKG2D Reconstitution on NK Cells Possibly Plays a Major Role in the Development of Graft-Versus-Leukemia Effect in the Early Period after Unrelated Cord Blood Transplantation.
Authors: Zimin Sun, Jie Chen, Huilan Liu, Xingbing Wang, Liangquan Geng, Wen Yao, Juan Tong
Journal: Blood (2008)
The Anti-CD19 Bispecific T-Cell Engager (BiTE) MT103 (MEDI-538), Induces Dose-Dependent Complete and Partial Responses in Relapsed Non-Hodgkin Lymphoma (NHL): Phase I Study MT103-104.
Authors: Ralf C. Bargou, Peter Kufer, Mariele Goebeler, Stefan Knop, Hermann Einsele, Rudolf Noppeney, Andreas Viardot, Georg Hess, Gert Riethmueller, Dirk Reitsma, Eugen Leo, Carsten Reinhardt, Gerhard Zugmaier
Journal: Blood (2007)
Abstract 2799: Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated cancer
Authors: Débora Barbosa Vendramini Costa, Ralph A. Francescone, Oxana Dmitrieva, Vivi Hou, David Posocco, Ronaldo A. Pilli, Sergei Grivennikov
Journal: Cancer Research (2015)

Abstract Despite anticancer drug discovery advances, the worldwide cancer incidence is remarkable. Thus, there is continuous necessity on new therapies development and tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nature has been a source of new therapeutic and preventive agents and the styryl-lactone goniothalamin (GTN) has shown to be a promising anti-proliferative and anti-inflammatory agent. In previous studies we showed that GTN has pro-apoptotic activity, gastroprotective effects and inhibits tumor development and acute inflammation in mice. Thus, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on colitis and colitis-associate cancer (CAC) models, focusing on the elucidation of the relationship between the anti-proliferative and anti-inflammatory activities. GTN was synthesized and evaluated in vitro in LPS-stimulated RAW 264.7 murine macrophages. Cells were pre-treated with GTN (20 μM) for 3 hours and then stimulated with LPS (1 μg/mL) for 4 hours. Gene expression was analyzed by real-time PCR and cytokines production by ELISA. Experimental colitis was induced by 3.5% dextran sulfate sodium (DSS) for 7 days and animals (mice, C57-BL/6) were treated with GTN daily by oral route (30 and 100 mg/kg). CAC was induced by Azoxymethane (AOM, 10 mg/kg) followed by 3 cycles of DSS (3.0%) and treatments with GTN (30 mg/kg) were conducted by oral route, twice week. Body weight was checked every week and in the end of experiments, colon tissues were collected and processed for microscopic, biochemical and gene expression evaluations. GTN significantly reduced IL-1β, IL-6, TNF-α, IL-23, CXCL2 and iNOS expression on RAW cells, as well as levels of secreted IL-6 and TNF-α. Treatments with GTN also reduced inflammation severity on DSS-induced colitis model by reducing cytokines expression, thus suggesting a modulatory activity of the inflammatory environment. GTN treatment modulated tumor development in a mouse model of CAC. Together with previous data, these results highlight that goniothalamin can be used as a preventive and therapeutic agent to inhibit inflammation in colitis and cancer. Citation Format: Débora Barbosa Vendramini Costa, Ralph A. Francescone, Oxana Dmitrieva, Vivi Hou, David Posocco, Ronaldo A. Pilli, Sergei Grivennikov. Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated 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 2799. doi:10.1158/1538-7445.AM2015-2799
Abstract 593: Kinetic risk assessment with biomarkers of systemic inflammation in patients with metastatic renal cell carcinoma
Authors: Wayne B. Harris, Omer Kucuk, Bradley Carthon, Yuan Liu, John Pattaras, Kenneth Ogan, Viraj Master
Journal: Cancer Research (2015)

Abstract Background: Empiric prognostic scoring systems for metastatic renal cell carcinoma (mRCC) are routinely employed as baseline risk stratification tools for clinical trials. However, these systems have limited clinical utility after therapeutic intervention has begun. The goal of the current study was to develop clinically useful, hypothesis-driven, kinetic risk assessment tools based exclusively on biomarkers of systemic inflammation. Methods: A retrospective chart review was conducted with authorization from the Emory University Institutional Review Board. Inclusion criteria included treatment at the Winship Cancer Institute with a targeted agent for mRCC as well as concomitant serum C-reactive protein (CRP) and albumin levels on at least three occasions that were at least 10 days apart. The modified Glasgow Prognostic Score (mGPS) was used to quantify the intensity of systemic inflammation and to formulate the Inflammation Intensity Index for kinetic risk assessment. Findings: Intensity of systemic inflammation was assessed 2465 times in 135 patients with cohorts used for training (n = 55; cutoff date 06/30/2012) and validation (n = 80; cutoff date 06/30/2014). Kinetic risk was assigned on the basis of time to onset of refractory systemic inflammation. The median overall survival (OS) was 44.7, 19.8, 13.0, and 6.7 months for kinetic risk categories A, B, C and D, respectively, with a median follow up of 29.3 months for the combined cohorts and none lost to follow up (censored log rank p &amp;lt;.0001). OS was 40.6 months for whites (n = 99) vs. 9.8 months for blacks (n = 30; p &amp;lt;.0001). Conclusions: The correlation of dramatic differences in OS with the onset of refractory systemic inflammation provides strong evidence in support of the clinical utility of the Inflammation Intensity Index and, as a consequence, the underlying theoretical constructs, including a plausible biological hypothesis for differences in clinical outcome by race. Citation Format: Wayne B. Harris, Omer Kucuk, Bradley Carthon, Yuan Liu, John Pattaras, Kenneth Ogan, Viraj Master. Kinetic risk assessment with biomarkers of systemic inflammation in patients with metastatic renal cell 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 593. doi:10.1158/1538-7445.AM2015-593
Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial
Authors: Séverine Vermeire, Stefan Schreiber, Robert Petryka, Tanja Kuehbacher, Xavier Hebuterne, Xavier Roblin, Maria Klopocka, Adrian Goldis, Maria Wisniewska-Jarosinska, Andrey Baranovsky, Robert Sike, Kremena Stoyanova, Chantal Tasset, Annegret Van der Aa, Pille Harrison
Journal: The Lancet (2016)
Cerebral Thromboses during Treatment of Childhood Acute Lymphoblastic Leukaemia.
Authors: Brigitte Pautard, Julie Micheli, Marie-Françoise Auclerc, Valérie Li Thiao Te, Thierry Leblanc, Barbara Horle, Judith Landman Parker, Claudine Schmitt, Gérard Michel, Pascale Schneider, Geneviève Margueritte, Anne Notz, Virginie Gandemer, Guy Leverger, André Baruchel
Journal: Blood (2005)
Allogeneic Hematopoietic Cell Transplantation Is a Curative Treatment Option for Advanced-Stage Chronic Myeloid Leukemia in the TKI Era, a Single Institution Retrospective Study of 29 Post AP/BC Cases
Authors: Hiroki Mizumaki, Shinsuke Takagi, Naoyuki Uchida, Sachie Wada, Kosei Kageyama, Daisuke Kaji, Aya Nishida, Kazuya Ishiwata, Masanori Tsuji, Hisashi Yamamoto, Go Yamamoto, Yuki Asano-Mori, Shigeyoshi Makino, Akiko Yoneyama, Atsushi Wake, Koji Izutsu, Shuichi Taniguchi
Journal: Blood (2014)
Gamma-Retroviral and Lentiviral Vectors Have Different Preferences for Specific Classes of Genes and Specific Genomic Features in Human Hematopoietic Cells
Authors: Alessandra Recchia, Anna Testa, Davide Cittaro, Barbara Felice, Claudia Cattoglio, Lucilla Luzi, Fulvio Mavilio
Journal: Blood (2007)
Attempting to Redefine Renal Involvement by Utilizing 3D Reconstruction Models of CT Imagings in Pediatric Acute Leukemia
Authors: Toshihiro Fujiki, Raita Araki, Shintaro Mase, Rie Kuroda, Hideaki Maeba, Akihiro Yachie, Ryosei Nishimura
Journal: Blood (2012)
153. Third Generation Antisense Targeted to Double Homeobox Protein 4 (DUX4) Reduced DUX4 Expression and Improved Differentiation of FSHD Myoblasts
Authors: Sachchida Nand Pandey, Kelly Murphy, Hunain Khawaja, Mallikarjuna Putta, Lakshmi Bhagat, Sudhir Agrawal, Yi-Wen Chen
Journal: Molecular Therapy (2016)

Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of double homeobox protein 4 (DUX4) gene at chromosome 4q35. To date there is no effective treatment for the disease. In the current study, we have evaluated selected Third Generation Antisense compounds (3GAs) targeted to DUX4 for their effectiveness in knocking-down DUX4 in FSHD myoblasts. In addition, we examined the effects of the treatments on myogenic differentiation of FSHD myoblasts. Multiple 3GA compounds (3GA1-5) showed significant knock-down of DUX4 in the FSHD myoblasts, as examined by quantitative RT-PCR. We evaluated two 3GA candidates (3GA3 and 3GA5) at 4 different concentrations, 2.5 nM, 5nM, 25nM, and 50nM, and observed dose-response effects. One of the 3GA compounds completely knocked-down DUX4 expression at 50nM. The effects of 3GAs at25nM on cell differentiation were determined by fusion index, myotube size and number of atrophic myotubes after 7 days of muscle differentiation in culture. Our results showed that the treatments increased fusion index and reduced the number of atrophic myotubes. The studies showed that 3GAs successfully knocked-down DUX4, which improved the myogenic capacity of FSHD myoblasts. The findings demonstrated that the 3GAs are promising therapeutic molecules to be further developed for FSHD treatment.