tbuckley/cabot-search huggingface dataset:
Abstract 1180: The TCA cycle transferase DLST is critical for MYC-mediated leukemogenesis
Authors: Nicole Anderson, Dun Li, H.L. Peng, Marc Mansour, Fabrice Laroche, Evisa Gjini, Daniel Helman, Itrat Harrold, Le Meng, Takaomi Sanda, Adam Amsterdam, Donna Neuberg, Travis Denton, Anurag Singh, A Thomas Look, Hui Feng
Journal: Cancer Research (2016)

Abstract The proto-oncogene MYC has been implicated in the pathogenesis of many human cancers, including hematological and solid malignancies1. In the majority of T-ALL cases, MYC is aberrantly expressed downstream of activated NOTCH1 mutations. Despite the pivotal role of MYC in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and many other cancers, the mechanisms underlying MYC-mediated tumorigenesis remain inadequately understood2. Here we utilized a well-characterized zebrafish model of Myc-induced T-ALL for genetic studies to identify novel genes contributing to disease onset. We found that heterozygous inactivation of a tricarboxylic acid (TCA) cycle enzyme, dihydrolipoamide S-succinyltransferase (Dlst), significantly delayed tumor onset. Concordant with our zebrafish results, RNAi knockdown of DLST led to decreased cell viability and induction of apoptosis in human T-ALL cell lines. DLST is the E2 transferase of the -ketoglutarate dehydrogenase complex (KGDHC), which converts -ketoglutarate (-KG) to succinyl-CoA in the TCA cycle3. Polar metabolomics profiling revealed that the TCA cycle was disrupted by DLST knockdown in human T-ALL cells, as demonstrated by an accumulation of -KG and its precursor glutamine, as well as a loss of succinyl-CoA. Addition of succinate, the downstream TCA cycle intermediate, to human T-ALL cells was sufficient to rescue defects in cell viability caused by DLST inactivation. Taken together, our studies identify DLST as an important mediator of MYC-driven leukemogenesis and provide compelling evidence for the metabolic dependence of T-ALL cells on the TCA cycle. 1. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene 1999 May 13; 18(19): 3004-3016. 2. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Molecular and cellular biology 2006 Nov; 26(21): 8022-8031. 3. Sheu KF, Blass JP. The alpha-ketoglutarate dehydrogenase complex. Ann N Y Acad Sci 1999; 893: 61-78. Citation Format: Nicole Anderson, Dun Li, H.L. Peng, Marc Mansour, Fabrice Laroche, Evisa Gjini, Daniel Helman, Itrat Harrold, Le Meng, Takaomi Sanda, Adam Amsterdam, Donna Neuberg, Travis Denton, Anurag Singh, A Thomas Look, Hui Feng. The TCA cycle transferase DLST is critical for MYC-mediated leukemogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1180.
Association of Radical Local Treatment with Mortality in Men with Very High-risk Prostate Cancer: A Semiecologic, Nationwide, Population-based Study
Authors: Pär Stattin, Fredrik Sandin, Frederik Birkebæk Thomsen, Hans Garmo, David Robinson, Ingela Franck Lissbrant, Håkan Jonsson, Ola Bratt
Journal: European Urology (2016)

Current guidelines recommend androgen deprivation therapy only for men with very high-risk prostate cancer (PCa), but there is little evidence to support this stance. To investigate the association between radical local treatment and mortality in men with very high-risk PCa. Semiecologic study of men aged <80 yr within the Prostate Cancer data Base Sweden, diagnosed in 1998–2012 with very high-risk PCa (local clinical stage T4 and/or prostate-specific antigen [PSA] level 50–200 ng/ml, any N, and M0). Men with locally advanced PCa (local clinical stage T3 and PSA level <50 ng/ml, any N, and M0) were used as positive controls. Proportion of men who received prostatectomy or full-dose radiotherapy in 640 experimental units defined by county, diagnostic period, and age at diagnosis. PCa and all-cause mortality rate ratios (MRRs). Both PCa and all-cause mortality were half as high in units in the highest tertile of exposure to radical local treatment compared with units in the lowest tertile (PCa MRR: 0.51; 95% confidence interval [CI], 0.28–0.95; and all-cause MRR: 0.56; 95% CI, 0.33–0.92). The results observed for locally advanced PCa for highest versus lowest tertile of exposure were in agreement with results from randomized trials (PCa MRR: 0.75; 95% CI, 0.60–0.94; and all-cause MRR: 0.85; 95% CI, 0.72–1.00). Although the semiecologic design minimized selection bias on an individual level, the effect of high therapeutic activity could not be separated from that of high diagnostic activity. The substantially lower mortality in units with the highest exposure to radical local treatment suggests that radical treatment decreases mortality even in men with very high-risk PCa for whom such treatment has been considered ineffective. Men with very high-risk prostate cancer diagnosed and treated in units with the highest exposure to surgery or radiotherapy had a substantially lower mortality.
Abstract 3195: Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in brainstem glioma
Authors: Seung Ah Choi, Chanhee Lee, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Seung-Ki Kim
Journal: Cancer Research (2016)

Abstract Human adipose-derived mesenchymal stem cells expressing secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (hAT-MSC.sTRAIL) have demonstrated therapeutic activity against various tumors. However, sTRAIL resistance remains a challenge in developing anticancer strategies. To solve this problem, many studies have tried to combine drugs to produce synergism or sensitize resistant cancer cells. Histone deacetylase inhibitors (HDACi) have been known to induce expression of TRAIL death receptors 4 and 5 (DR4/DR5). Herein, we evaluated the use of combined therapy of hAT-MSC.sTRAIL with HDAC inhibitor, panobinostat, in enhancing sensitivity to hAT-MSC.sTRAIL mediated apoptosis against the brainstem glioma. A sTRAIL was introduced into the characterized hAT-MSCs using electroporation. To confirm appropriate treatment concentration of panobinostat to the glioblastoma cells, dose titration was tested using cell viability assay. The therapeutic effect of single or combination treatment against glioblastoma was evaluated using primary cultured glioblastoma cells and cell lines. Orthotopic xenograft brainstem glioma mouse model was established using engineered firefly luciferase expressing tumor cells for bioluminescence in vivo imaging. Panobinostat induced anti-proliferative effects in dose and time-dependent manner (IC50 range, 0.05-0.2 μM) and effectively enhanced the expression of TRAIL DR4 and DR5, but not decoy receptors. Combined hAT-MSC.sTRAIL and panobinostat significantly decreased the tumor cell growth compared to each alone. Intriguingly, the combination treatment not only induced apoptosis but also autophagy. Using a preclinical brainstem mouse model, we confirmed that the combination of hAT-MSC.sTRAIL and panobinostat was safe and induced regression of tumor volume. Furthermore, the combination therapy prolonged the survival of brainstem glioma-bearing mice. Our results suggested that combination therapy of panobinostat enhanced the anti-cancer effect of hAT-MSC.sTRAIL and represent potential therapeutic approach to the brainstem glioma. Citation Format: Seung Ah Choi, Chanhee Lee, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Seung-Ki Kim. Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in brainstem glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3195.
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
Authors: Meenakshi Hegde, Malini Mukherjee, Zakaria Grada, Antonella Pignata, Daniel Landi, Shoba A. Navai, Amanda Wakefield, Kristen Fousek, Kevin Bielamowicz, Kevin K.H. Chow, Vita S. Brawley, Tiara T. Byrd, Simone Krebs, Stephen Gottschalk, Winfried S. Wels, Matthew L. Baker, Gianpietro Dotti, Maksim Mamonkin, Malcolm K. Brenner, Jordan S. Orange, Nabil Ahmed
Journal: Journal of Clinical Investigation (2016)

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease
Authors: William L. Roberts
Journal: Circulation (2004)

Inflammation plays a key role in atherosclerosis. A number of different biomarkers of inflammation are measurable in blood. These include cytokines, chemokines, soluble adhesion molecules, and acute-phase reactants. The first 3 groups of molecules are not routinely measured in clinical laboratories. The acute-phase reactants include C-reactive protein (CRP). This analyte is stable and is readily measured by several commercial high-sensitivity (hs) assays, and numerous clinical studies have demonstrated its usefulness as an atherosclerotic risk marker. For these reasons, CRP is currently the inflammatory marker of choice. Comparison of commercial hsCRP assays has demonstrated that many are capable of imprecision of <7% at a CRP concentration of <1 mg/L. Method comparability studies have shown good agreement among some commercial hsCRP assays in terms of quartile assignments, whereas additional standardization efforts are necessary for others. The first goal of standardization is to develop a secondary reference material with a CRP of approximately 4 mg/L. This material can be used to assist diagnostic vendors in calibrator value assignment and assay harmonization. Another project is to define clearly what performance characteristics are necessary for hsCRP assays. Preliminary estimates based on the biological variability of CRP indicate that the total allowable analytical error is between 15% and 32%. The former requirement can be met with accuracy and imprecision of <5% and the latter requirement with accuracy and imprecision of <11%. If 2 hsCRP results are averaged, then the imprecision requirements are relaxed slightly. Clinical validation of these performance requirements is also required.
Abstract 3849: The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells
Authors: Elena Strekalova, Dmitry Malin, Vincent Cryns
Journal: Cancer Research (2016)

Abstract Most metastatic tumors, such as triple negative breast cancer (TNBC) respond poorly to conventional chemotherapy. We have previously demonstrated that targeting TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) might be an effective pathway against metastatic TNBC. However, many TNBCs are resistant to TRAIL receptor agonists. Here we demonstrate that diabetes drug metformin, previously linked to preventing and treating several types of cancer, enhances sensitivity of TNBC cells to recombinant TRAIL and TRAIL-R2 agonistic humanized monoclonal antibody (lexatumumab)-induced apoptosis. We have demonstrated that combination of metformin with lexatumumab or TRAIL augments response to TRAIL therapy and reduce cancer cell viability via induction of apoptosis and inhibiting long-term survival of three different metastatic TNBC cell lines. Intriguingly, metformin treatment also sensitized transformed MCF10A-RasV12 cells, but not untransformed MCF10A-Vector cells, to TRAIL agonist therapy. This effect was associated with reduction of X-linked Inhibitor of Apoptosis Protein (XIAP) levels after metformin treatment. Similar to metformin treatment, inhibition of XIAP by small interfering RNA sensitized breast cancer cells to TRAIL-induced apoptosis. Moreover, metformin treatment in combination with TRAIL more efficiently inhibited primary tumor growth and lung metastases in orthotopic model of TNBC. Overall, our results demonstrate that metformin treatment in combination with targeting TRAIL receptors may be a good strategy to augment the antitumor effects of TRAIL receptors agonistic therapy and provide the foundation for a clinical trial combining dietary metfomin and TRAIL agonists. Citation Format: Elena Strekalova, Dmitry Malin, Vincent Cryns. The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3849.
Serum Levels Of Vitamin D In Patients Undergoing Hematopoietic Stem Cell Transplantation
Authors: Andrea Z Pereira, Juliana Bernardo Silva, Silvia MF Pivocari, Marcia Tanaka, Fabiana Lucio, Ana Paula N Barrere, Claudio Galvão Castro, Andreza Alice Feitosa Ribeiro, Nelson Hamerschlak
Journal: Blood (2013)
Prevalence and Determinants of Bleeding in Severe Von Willebrand Disease Type 3: Results of Retro/Prospective Studies in a Cohort of 105/52 Italian Patients.
Authors: Augusto B. Federici, Paolo Bucciarelli, Alfonso Iorio, Giancarlo Castaman, Maria Gabriella Mazzucconi, Massimo Morfini, Angiola Rocino, Pier M. Mannucci
Journal: Blood (2009)
Abstract LB-056: Discovery of novel small molecule inhibitors of the DCN1-Ubc12 interaction by high throughput screening technology
Authors: Jaeki Min, Daniel C. Scott, Sergio C. Chai, Asli N. Goktug, Jared T. Hammill, Guochang Huang, Michele C. Connelly, Amy Matheny, Anang Shelat, Bhuvanesh Singh, Taosheng Chen, Brenda A. Schulman, R. Kiplin Guy
Journal: Cancer Research (2016)

Abstract Ubiquitination of protein is well known mechanism for the regulation of cellular proteins by the ubiquitin-proteasome system (UPS). The ubiquitin-proteasome system (UPS) plays a crucial role in regulating cellular protein degradation and turnover. Dysregulation of the UPS has been associated with a wide variety of diseases including cancers, neurodegenerative disorders, and viral and bacterial infections. Recently, there are emerging evidences show that targeting this UPS by small molecule modulator is a useful anticancer strategy based on the previous successes of proteasome inhibitors, E3 inhibitors and the NEDD8 E1 inhibitor. In particular, we are targeting NEDD8 ligation to cullins via inhibition of DCN1 as a small molecule target. DCN1 was known to interacts with cullins and is required for neddylation in vivo. Furthermore, dysregulation of DCN1 is associated with a number of human cancers. DCN1 activity is controlled by its interaction with UBC12. Therefore, we have developed biochemical assay utilizing TR-FRET technology for the purpose of high-throughput screening (HTS) to identify the small molecule inhibitors that disrupt the DCN1-UBC12 protein-protein interaction and use them to elucidate the biological effects of DCN1 mediated UPS regulation. Herein, we report our progress including design, procedure and result of HTS with post-screen analysis to discover small molecule inhibitors of the DCN1 from our in-house library compounds (∼600K). Following hit identification and validation, we identified three novel scaffolds as novel DCN1 inhibitors by biochemical, biophysical, and crystallographic studies to follow for further hit optimization. To the best of our knowledge, this is the first work to report small molecule DCN1 inhibitors. Citation Format: Jaeki Min, Daniel C. Scott, Sergio C. Chai, Asli N. Goktug, Jared T. Hammill, Guochang Huang, Michele C. Connelly, Amy Matheny, Anang Shelat, Bhuvanesh Singh, Taosheng Chen, Brenda A. Schulman, R. Kiplin Guy. Discovery of novel small molecule inhibitors of the DCN1-Ubc12 interaction by high throughput screening technology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-056.
Abstract 4723: Innovative cancer treatment of human lung cancer cells PC-9 with a synthetic retinoid Am80 and EGCG via inhibition of HDAC4 and HDAC5
Authors: Masami Suganuma, Yukiko Oya, Sonthaya Umsumarng, Keisuke Iida, Anchalee Rawangkhan, Ryo Sakai, Hiroyuki Kagechika, Koichi Shudo, Hirota Fujiki
Journal: Cancer Research (2016)

Abstract A synthetic new retinoid Am80 (tamibarotene) is used for treatment of acute promyelocytic leukemia (APL) patients with resistance of all-trans-retinoic acid (ATRA). To potentiate efficacy of Am80, we challenged combination treatment of Am80 and EGCG on human lung cancer cell line PC-9. It is now well accepted that EGCG acts as synergist with numerous anticancer compounds, and that the average reduction of tumor volume for in vivo genograft mouse models implanted using various human cancer cell lines was 70.3% with combinations of 13 anticancer compounds and EGCG. We previously reported that combinations of NSAIDs (sulindac and celecoxib) or other retinoids (ATRA, 13-cis-RA and 9-cis-RA) and EGCG synergistically induced apoptosis of the cells along with strong expression of growth arrest and DNA-damage inducible gene 153 (GADD153) and death receptor (DR5) gene. Our objective was to investigate the mechanism of the synergistic induction for GADD153-DR5 apoptosis pathway. The proteomic analysis of lysine-acetylated proteins was conducted with a shotgun analysis using nanoLC-ESI-MS/MS in PC-9 cells. We found that the numbers of acetylated proteins were different: 551 acetylated proteins were found in non-treated cells, 331 proteins in cells treated with combination, and 59 proteins were common in both cases. Acetylation was mainly found in non-histone proteins, chaperons, transcription factors, and enzymes. The combination increased acetylated p53 (Lys382) about 3-fold compared with non-treated cells. In addition, combination significantly decreased the protein amounts of histone deacetylase (HDAC) 4 and HDAC 5 to 50% and 20%, respectively, but not HDAC6 among Class II HDACs. Class I HDACs (HDAC1, 2, and 3) were not decreased. All the results suggest that combination of Am80 and EGCG induces GADD153-DR5 apoptotic pathway, and reduces the amounts of HDAC4 and HDAC5 resulting in changing protein acetylation. Citation Format: Masami Suganuma, Yukiko Oya, Sonthaya Umsumarng, Keisuke Iida, Anchalee Rawangkhan, Ryo Sakai, Hiroyuki Kagechika, Koichi Shudo, Hirota Fujiki. Innovative cancer treatment of human lung cancer cells PC-9 with a synthetic retinoid Am80 and EGCG via inhibition of HDAC4 and HDAC5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4723.
MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action
Authors: Lucile Amrouche, Geoffroy Desbuissons, Marion Rabant, Virginia Sauvaget, Clément Nguyen, Aurélien Benon, Pauline Barre, Clémentine Rabaté, Xavier Lebreton, Morgan Gallazzini, Christophe Legendre, Fabiola Terzi, Dany Anglicheau
Journal: Journal of the American Society of Nephrology (2016)

AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a-/- mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a-/- mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.
Reply to Lars Egevad, Hemamali Samaratunga, John R. Srigley, Brett Delahunt's Letter to the Editor re: Anthony Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto. Describing the Grade of Prostate Cancer: Consistent Use of Contemporary Terminology Is Now Required. Eur Urol 2016;70:1
Authors: Anthony Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto
Journal: European Urology (2016)