tbuckley/cabot-search huggingface dataset:
Abstract 2913: Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor cells
Authors: Joelle Baddour, Lifeng Yang, Abhinav Achreja, Seth Padmabandu, Pari Shah, Rebecca N. Curtis, Thomas Plackemeier, Radina Khalid, Juan C. Marini, Janusz Franco-Barraza, Edna Cukierman, Chaoxin Hu, Anirban Maitra, Deepak Nagrath
Journal: Cancer Research (2015)

Abstract Pancreatic cancer remains one of the most lethal of all solid tumors largely due to an aggressive stroma that constitutes the bulk of the tumor. The notion of a reprogrammed stroma suggests the re-establishment of a physiologically normal tumor microenvironment with quiescent stellate cells and fibroblasts. The induction of a quiescent phenotype hinders the aberrant tumor-stroma crosstalk and enables the increased intratumoral delivery of chemo drugs. A combinatorial transcriptional therapy has proven successful at normalizing the tumor microenvironment by reverting the activated state of stromal cells back to quiescence, both at the phenotypic and genetic levels. Indeed, we have observed a reduction in the activation markers of primary human stellate cells and fibroblasts, accompanied by an increase in the quiescence markers. Observations from methylation/hydroxymethylation profiling and metabolic rewiring through isotopomer flux analysis revealed potential targets for therapeutic intervention. In addition, the differential metabolic rewiring induced by a quiescent stroma in cancer cells suggests a tumor suppressive environment aimed at weakening an otherwise aggressive cancer. Citation Format: Joelle Baddour, Lifeng Yang, Abhinav Achreja, Seth Padmabandu, Pari Shah, Rebecca N. Curtis, Thomas Plackemeier, Radina Khalid, Juan C. Marini, Janusz Franco-Barraza, Edna Cukierman, Chaoxin Hu, Anirban Maitra, Deepak Nagrath. Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2913. doi:10.1158/1538-7445.AM2015-2913
Sunitinib in BCG-refractory non-muscle-invasive transitional cell carcinoma of the bladder.
Authors: J. A. Garcia, A. J. Stephenson, J. Ireland, J. Finke, P. Elson, L. Schaaf, M. C. Gong, S. Campbell, R. Dreicer
Journal: Journal of Clinical Oncology (2011)

262 Background: Treatment options for pts with BCG-refractory NMITCC are limited and there is no established role for systemic chemotherapy in this setting. While cystectomy remains the gold standard, the vast majority of pts are unable or unwilling to have surgery. Sunitinib is an oral tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT and FLT3 with demonstrated antitumor activity in advanced TCC. To determine the clinical and biologic effects of sunitinib in BCG-refractory NMITCC pts a prospective phase II study was conducted. Methods: Pts with biopsy proven BCG- refractory NMITCC received three 28-day cycles of continuous sunitinib (37.5 mg PO). Subsequently, pts underwent cystoscopic evaluation. If no tumor was found, pts continued with standard cystoscopic surveillance. A single stage design was employed to test the hypothesis of a 25% improvement in the 12-month CR rate over the 20% CR historically observed in this setting. Overall response rate (ORR), disease-free recurrence (DFR) and safety were recorded. Exploratory endpoints included treatment effect on CTCs, type-1 response and immunosuppressive Treg cells. Results: To date 17 of a planned 31 pts are enrolled. Median age is 72 years (range, 54-82); 94% of pts were ECOG 0; 6 pts had received additional intravesical therapy other than BCG. Fourteen pts have already completed 3 cycles of treatment and 13 pts had at least once cystoscopic assessment. Among these, 8 pts (62%) were NED in their first cystoscopic evaluation. Most common treatment-related toxicity observed in both studies included fatigue, HTN, stomatitis, PPE, diarrhea and thrombocytopenia. Treatment with sunitinib also resulted in a sustained increase (compared to pre-treatment) in CD3+ and CD4+ IFN-g producing T-cells (p &lt; 0.07). In addition there was a significant decrease in CD33+ MDSC following 2 and 3 cycles of therapy (p &lt; 0.04). There was also a significant decrease in T regulatory cells following 2 cycles of therapy (p = 0.04); however it was not maintained during cycle 3 (p = 0.36). Conclusions: Sunitinib has modest clinical activity in pts with BCG-refractory NMITCC. Early immune studies also denote the ability of sunitinib to restore the balance of type-1 and type-2 immune response in bladder cancer. [Table: see text]
Abstract 18: Increasing in vivo Apoa1/HDL Levels Negates the Cardiotoxic Effects of Doxorubicin, and Involves Signalling Through SR-BI, PI3K, and AKT1
Authors: Kristina Durham, Cyrus Thomas, Bernardo L Trigatti
Journal: Circulation Research (2015)

Doxorubicin (DOX) is a clinically used anti-tumor drug, though the use of DOX is limited by its potent cardiotoxic side effect that can lead to heart failure. HDL protects isolated cardiomyocytes against DOX induced apoptosis, though whether this effect translates in vivo has yet to be determined. Here we assess whether ApoA1/HDL overexpression can protect mice in vivo against DOX induced cardiotoxicity, and explore the intracellular signalling mechanisms involved in protection. Mice overexpressing human ApoA1 (ApoA1tg/tg) and ApoA1+/+ mice were treated chronically with DOX, and effects on cardiac function and cardiomyocyte health were assessed. Over expression of human ApoA1 in mice corresponded to ~2.5 fold increase in plasma HDL-C as compared to ApoA1+/+ mice. Following 5 weekly injections of 5mg/kg DOX, ApoA1+/+ mice displayed cardiac dysfunction as evidenced by reduced left ventricular developed pressure, and reduced rate of pressure development. In contrast, left ventricular function was maintained following DOX treatment in ApoA1tg/tg mice. Histological analysis revealed reduced cardiomyocyte cross-sectional area and increased cardiomyocyte apoptosis following DOX treatment in ApoA1+/+ mice. ApoA1tg/tg mice, on the other hand, were protected against DOX induced cardiomyocyte atrophy and apoptosis. Interestingly, pAKT:tAKT was reduced in ApoA1+/+ by treatment with DOX, but the ratio was maintained in ApoA1tg/tg mice. We evaluated the roles of SR-BI, PI3K, and AKT1/2 in the signalling cascade of HDL in neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes. Through inhibition of AKT and PI3K, and knockdown or knockout of SR-BI, AKT1, and AKT2, we demonstrated that SR-BI, PI3K and AKT1 are required for HDL mediated protection against DOX induced cardiomyocyte apoptosis. Our results provide evidence for ApoA1 mediated protection against DOX cardiotoxicity in vivo and demonstrate the roles of SR-BI, PI3K, and AKT1 as mediators in the protective effect.
First-in-human trial focusing on the immunologic effects of the survivin-derived multiepitope vaccine EMD640744.
Authors: S. Gross, V. Lennerz, E. Gallerani, C. Sessa, N. Mach, S. Boehm, D. Hess, L. von Boehmer, A. Knuth, A. Ochsenbein, U. Gnad-Vogt, J. Zieschang, U. Forssmann, T. Woelfel, E. Kaempgen
Journal: Journal of Clinical Oncology (2011)

2515 Background: Survivin is a promising antigen for cancer immunotherapy based on two major criteria: tumor cells depend on its actions, and it has demonstrated immunogenicity in patients with different cancers. Here we report immunomonitoring results of a first-in-man Phase I study (EMR 200032-001) with EMD640744, a cocktail of survivin-derived partially modified HLA class I-restricted peptides in Montanide ISA 51 VG. This multicenter, open-label, parallel group, randomized study compared the immunologic efficacy, safety, tolerability and clinical activity of 3 dosages of sc EMD640744 (30, 100 or 300 µg) in patients with different types of metastatic or locally advanced solid tumors positive for at least one relevant HLA antigen (A1, A2, A3, A24, B7). Methods: Routine immunomonitoring to analyze peptide-specific T cell responses at baseline and at weeks 4, 8, 12, 16, and 17 was performed by IFN-γ ELISpot and peptide/HLA-multimer staining (primary endpoint). Additional analyses were performed by intracellular cytokine staining (ICS) to IL-2, IFNγ, TNFα and degranulation marker CD107a after a single in vitro presensitization for 2 weeks with EMD640744. Results: Routine monitoring displayed T cell responses against the vaccine in 14 of 38 patients (37%) assessed by IFNγ-ELISpot and in 31 of 42 patients (74%) by HLA-multimer staining; 16 responses (38%) were clearly de novo induced. ICS revealed 3 relevant findings: 1) 15 of 22 (68%) analyzed patients showed vaccine-specific CD4+ T cells that could be blocked by anti-HLA-Class II antibodies; 2) survivin-specific CD8+ and CD4+ specific T cells often were polyfunctional, responding with degranulation and production of one or more cytokines; and 3) CD8+ responses against native homologues of modified vaccination peptides were demonstrated in 12 of 13 analyzed patients, and CD4+ responses in 5 of 9 patients. Dose dependency was not observed. Conclusions: Vaccination with EMD640744 elicited de novo T cell responses against survivin peptides in many patients, demonstrating immunological efficacy of EMD640744. The capability of EMD640744 to promote CD4-specific T cell help might explain the remarkable number of successfully induced immune responses.
PTH-092 Reproductive and hormonal risk factors for breast cancer among women with coeliac disease: a population-based questionnaire study
Authors: N R Lewis, R F A Logan, D S Sanders, G K Holmes, J West
Journal: Gut (2010)

<h3>Introduction</h3> Several studies have observed that coeliac disease is associated with more than a 50% reduced risk of breast cancer1–4 though the reasons for this reduction are unclear. We determined the conventional breast cancer risk factors reported by women with coeliac disease in comparison to the general population. <h3>Methods</h3> 9000 women who were members of Coeliac UK, the national society for people with coeliac disease in the UK and 1193 women with coeliac disease who had attended Nottingham University Hospital, Royal Hallamshire Hospital, Derbyshire Royal Infirmary between January 2000 and December 2006 were invited to complete a questionnaire relating to known risk factors for breast cancer. Data from British birth cohort studies were used as a general population comparison.5–7 <h3>Results</h3> 7416 women (mean age 58.7 (SD 12.4) years) with coeliac disease completed the questionnaire. The mean age at adult diagnosis was 44.8 (SD 12.8) years with 424 (6%) being diagnosed in childhood. The higher proportion of women being parous (91% vs 88%, OR 1.39, 95% CI 1.11 to 1.73), having their first full-term pregnancy before 30 years (89% vs 79%, OR 2.00, 95% CI 1.75 to 2.29) and breastfeeding (73% vs 68%, OR 1.29, 95% CI 1.02 to 1.63) in addition to the younger mean age at menopause (47.8 vs 49.0 years, p=0.00001) suggests women with coeliac disease have favourable breast cancer risk profile features in comparison to the general population. However, the higher likelihood of being Caucasian (98% vs 90%, OR 7.22, 95% CI 5.90 to 8.83) and of affluent social class (26% vs 20%, OR 1.40, 95% CI 1.19 to 1.64) together with higher proportion having menarche before 11 years (15% vs 2%, OR 7.87, 95% CI 5.90 to 8.83) and irregular menstrual cycles (22% vs 19%, OR 1.22, 95% CI 1.05 to 1.43) suggests there are also potentially adverse breast cancer risk profile features associated with coeliac disease. Having similar height to the general population (162.8 (SD 7) cm) and BMI within normal range suggests anthropometric exposures may not explain the apparent reduced risk of breast cancer in women with coeliac disease to the general population. <h3>Conclusion</h3> The breast cancer risk profile suggests both protective and adverse associations of coeliac disease. Reduced risk of breast cancer in women with coeliac disease may be related to differences in menstrual and reproductive factors.
Abstract A15: In vivo efficacy of a CD38-specific engineered toxin body.
Authors: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney Flores, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert
Journal: Clinical Cancer Research (2015)

Abstract The cell surface glycoprotein CD38 is highly expressed on the surface of several B cell lineage cancers, such as the plasma cell malignancy multiple myeloma, some lymphomas and chronic lymphocytic leukemia (CLL), where it is a marker of unfavorable prognosis. CD38 is a transmembrane receptor and ectoenzyme that is absent or expressed at a low level on most resting leukocytes under normal conditions, making this an appealing target for directed therapy for hematological malignancies. Recent clinical trials with antibodies to CD38 have shown promise in multiple myeloma. While these antibodies rely on the recruitment of an immune response for cytotoxicity, we have developed an engineered toxin body (ETB) comprising a CD38 binding scFv and a modified Shiga-like Toxin A subunit capable of specifically recognizing and directly killing CD38 expressing cells. The CD38 targeted ETB has a different mechanism of action than current treatments for multiple myeloma (such as immunomodulatory agents, protease inhibitors and chemotherapies). Our CD38 targeted ETB has shown to be well tolerated in mice and displays dose dependent efficacy in a CD38 positive tumor setting. The CD38 targeted ETB significantly reduced tumor burden and increased survival over a 40-fold dose range in a disseminated Daudi xenograft, early treatment model. In this setting, the mean tumor burden at day 28 was reduced to 29% of control for the lowest dose group (0.05 mg/kg) and less than 1% of control for the two higher doses (0.5 and 2 mg/kg). Median survival of the control, untreated group was 34 days; the low dose group had extended median survival to 59.5 days and, at the day 60 study end, 90 or 100% of mice were alive in the higher two dosing groups. Our results show that the CD38 targeted ETB is a promising targeted therapeutic agent against CD38 positive cancer cells and is currently under further development. Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney Flores, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert. In vivo efficacy of a CD38-specific engineered toxin body. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A15.
Abstract 4222: Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity
Authors: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Laura Asnaghi, Fausto Rodriguez, Brent A. Orr, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2015)

Abstract Glioblastoma Multiforme (GBM) causes the majority of brain tumor-related deaths in the United States. The high invasiveness of GBM prevents complete surgical resection, allowing tumor recurrence. The lack of curative treatment highlights a dire need to develop specific targeted therapeutics. Identifying and targeting novel molecular markers in glioma stem-like cells (GSCs) thought to be critical for tumor invasion and recurrence could lead to development of better therapies. HMGA2, a non-histone transcriptional modulator, is a regulator of normal and cancer stem cells. The significance of HMGA2 as a potential therapeutic target in GBM has not been investigated. We found increased HMGA2 expression in a subset of primary human GBM tumors, in multiple patient-derived GBM neurosphere and adherent cell lines, and in the mesenchymal subgroup of GBM in The Cancer Genome Atlas (TCGA) database. Lentiviral short hairpin RNA (shRNA)-lowered HMGA2 protein levels and significantly reduced invasion and clonogenicity of GBM cell lines in transwell invasion and soft agar colony formation assays. Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited growth of the U-87 MG GBM cell line (P&amp;lt;0.01) in MTS assays. Mice bearing orthotopic GBM neurosphere xenograft lines transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (median survival = 67.5 days) (P&amp;lt;0.0001 by log-rank analysis). Conversely, lentiviral-mediated overexpression of HMGA2 in GBM cell lines increased invasion, clonogenicity and resistance to radiation in vitro (P&amp;lt;0.01). Overexpression of HMGA2 also promoted GBM tumor formation in vivo in orthotopic xenografts. To elucidate the molecular mechanism by which HMGA2 promotes invasion and stemness in GBM, we performed mRNA expression profiling on GBM neurosphere lines lentivirally transduced to express HMGA2 or empty vector control. We found increased CD44 expression in HMGA2-overexpressing GBM neurosphere lines compared to control, and confirmed this result by western blotting. Together, our results suggest an oncogenic role of HMGA2 in promoting GBM tumorigenicity by increasing invasiveness and a stem cell-like state, and show that HMGA2 is a potential therapeutic target in GBM. Citation Format: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Laura Asnaghi, Fausto Rodriguez, Brent A. Orr, Charles G. Eberhart, Eric H. Raabe. Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity. [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 4222. doi:10.1158/1538-7445.AM2015-4222
136. Nuclease-Assisted Vector Integration (NAVI): A Robust Platform for Multiplexed Targeted Genome Engineering
Authors: Alexander Brown, Wendy S. Woods, Pablo Perez-Pinera
Journal: Molecular Therapy (2016)

The expansion of genome engineering spurred by CRISPR/Cas9 continues to accelerate. While mutagenesis generated via NHEJ remains a highly efficient and effective strategy for select applications, the insertion of large or complex sequences and the ability to easily select for modified cells often necessitates the use of homology directed repair (HDR) based strategies. The time-consuming construction of donor vectors for HDR gene editing is often technically challenging, costly, and leads to poor modification rates. By using customized single-stranded oligonucleotides (ssODN) the efficiency of gene editing increases, but the scale of possible genetic changes is greatly diminished. Additionally, as both donor vectors and ssODN require two discontiguous regions of homology, neither is well suited to multiplexing. Here, we present Nuclease-Assisted Vector Integration (NAVI) as a unique strategy to bypass HDR and the need for customized donor vectors required for traditional genome editing technologies. We demonstrate, through multiplexed insertion of a single plasmid into multiple loci, that NAVI eliminates the need for homologous sequence within donor vectors. Furthermore, by employing a single and universal guide-RNA, multiple vectors harboring different selection markers were integrated into distinct loci simultaneously, greatly facilitating production of isogenic mammalian cell lines. We were able to integrate sequences ranging from 3-50 kbp, but no upper limit was identified. Through the elimination of the HDR bottleneck and increased efficiency of editing, generation of double knockouts within two loci using NAVI takes approximately 3 weeks from design to completion, at minimal cost. Additionally, as NAVI is independent of homology, vector integration at double strand breaks occurs in either the plus or minus orientation. Finally, the resulting sequence of the juncture of genomic DNA with the vector is variable. We conclude that NAVI, despite sacrificing single base pair resolution, can be readily adapted for use in a variety of research and therapeutic platforms, due to its greatly enhanced versatility, ease of use, efficiency, and robust multiplexing capabilities for targeted integration of large sequences within mammalian genomes.
Recommendations for Clinical Trial Development in Mantle Cell Lymphoma
Authors: Stephen E Spurgeon, Brian G Till, Peter Martin, Andre H Goy, Martin P Dreyling, Ajay K Gopal, Michael LeBlanc, John P Leonard, Jonathan W Friedberg, Lawrence Baizer, Richard F Little, Brad S Kahl, Mitchell R Smith
Journal: JNCI Journal of the National Cancer Institute (2016)

Mantle cell lymphoma (MCL) comprises around 6% of all non-Hodgkin's lymphoma (NHL) diagnoses. In younger patients, age less than 60 to 65 years, aggressive induction often followed by consolidation with autologous stem cell transplant has suggested improved outcomes in this population. Less intensive therapies in older patients often followed by maintenance have been studied or are under active investigation. However, despite recent advances, MCL remains incurable, with a median overall survival of around five years. Patients with high-risk disease have particularly poor outcomes. Treatment varies widely across institutions, and to date no randomized trials comparing intensive vs less intensive approaches have been reported. Although recent data have highlighted the heterogeneity of MCL outcomes, patient assessment for treatment selection has largely been driven by patient age with little regard to fitness, disease biology, or disease risk. One critical advance is the finding that minimal residual disease status (MRD) after induction correlates with long-term outcomes. As such, its use as a potential end point could inform clinical trial design. In order to more rapidly improve the outcomes of MCL patients, clinical trials are needed that prospectively stratify patients on the basis of MCL biology and disease risk, incorporate novel agents, and use MRD to guide the need for additional therapy.
Concordance of local and central HER2 status in 1597 patients participating in German neoadjuvant breast cancer studies
Authors: B.M. Pfitzner, S. Loibl, J. Lindner, P. Sinn, B. Lederer, S. Braun, K.W. Schmid, C. Denkert, G. von Minckwitz
Journal: Annals of Oncology (2015)
PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease
Authors: Kun Huang, Meng Du, Xin Tan, Ling Yang, Xiangrao Li, Yuhan Jiang, Cheng Wang, Fengxiao Zhang, Feng Zhu, Min Cheng, Qinglin Yang, Liqing Yu, Lin Wang, Dan Huang, Kai Huang
Journal: Journal of Hepatology (2016)
Roscovitine Sensitizes Leukemia and Lymphoma Cells to TRAIL-Induced Apoptosis and Enhances Cell-Mediated Cytotoxicity
Authors: Jan Molinsky, Marie Markova, Magdalena Klanova, Michal Koc, Lenka Beranova, Ladislav Andera, Zdenka Ludvikova, Martina Bohmova, Zdenka Gasova, Marek Trneny, Emanuel Necas, Jan Zivny, Pavel Klener
Journal: Blood (2010)