tbuckley/cabot-search huggingface dataset:
Abstract 5250: Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia
Authors: Alok R. Khandelwal, Rong Xiaohua, Tara Moore-Medlin, Oleksandr Ekshyyan, Abreo Fleurette, Xin Gu, Cherie-Ann O. Nathan
Journal: Cancer Research (2016)

Abstract Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the USA due to high exposure to ultraviolet-B (UVB) radiation. In our previous studies Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling both of which play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against UVB-induced hyper proliferation by targeting the mTOR and FGFR signaling pathways. Pre-treatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced colony formation, mTORC1 and mTORC2 activation and FGFR2 phosphorylation in promotion sensitive JB6 epithelial cells. Further, FGFR2 was required for UVB-induced mTOR activation suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pre-treated with C3 (15mg/kg/b.w) for 2 weeks followed by a single exposure to UVB (50mj/cm2) significantly attenuated UVB-induced mTOR and FGFR activation. To further assess the role of FGFR in UVB-induced hyper proliferation, SKH-1 mice were pre-treated with AZD4547; a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (50mj/cm2). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyper proliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR pathway in mediating the effects of C3 complex in the pathogenesis of skin cancer. Citation Format: Alok R. Khandelwal, Rong Xiaohua, Tara Moore-Medlin, Oleksandr Ekshyyan, Abreo Fleurette, Xin Gu, Cherie-Ann O. Nathan. Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia. [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 5250.
Crossover pharmacokinetics (PK) study to assess oral administration of abiraterone acetate capsule and tablet formulations in fasted and fed states in patients with prostate cancer
Authors: C. P. Carden, F. I. Raynaud, R. L. Jones, S. B. Riggs, V. Martins, N. Oommen, D. McIntosh, G. Lee, J. S. De Bono, F. F. Kabbinavar
Journal: Journal of Clinical Oncology (2008)

5168 Background: Abiraterone acetate (A) is an oral compound with metabolites that selectively inhibit CYP 17(17OH/ 17,20 lyase), blocking adrenal androgen synthesis and exhibiting anti-tumor activity in castration resistant prostate cancer (CRPC). Methods: Patients were divided into fed or fasted groups, and treated at 1000mg/day as a single dose in either capsule or tablet formulation on day 1, then the opposite formulation one week later on day 8, and from day 15, continuous dosing of 1000mg of the tablet formulation. PK samples were taken pre-dose and 1, 2, 4, 6, 8, 24, 48 and 72 hr post dose on days 1 and 8. Statistical analysis employed a two- period crossover model, using non-compartmental analysis. Results: A was well tolerated and side effects readily managed by mineralocorticoid antagonists. Overall 31 patients were enrolled, with PK results from 19 patients presented here. Area under the curve (AUC), was not significantly different between the two formulations for either the fed (p=0.412) or the fasted (p=0.334) states. However, there was a significantly higher mean Cmax in the fed state compared with the fasted state for both formulations: mean Cmax (nmol/l) capsules: (fed) 1469 vs (fasted) 286, p= 0.005; mean Cmax (nmol/l) tablets: (fed) 1573 vs (fasted) 324, p=0.004. AUC was also significantly higher in the fed state than in the fasted state for both formulations: AUC (hr*nmol/l) capsules: (fed) 10978 vs (fasted) 3249, p<0.001; AUC (hr*nmol/l) tablets: (fed) 10782 vs (fasted) 3090, p<0.001. Antitumor activity was observed as indicated by PSA declines, radiological responses, and symptomatic benefit. Conclusions: Similar Cmax and AUC were observed after administration of capsule and tablet formulations of A irrespective of fed or fasted state, suggesting bioequivalence. However both of these PK parameters were significantly higher in fed patients. Pharmacokinetic parameters comparing capsules with tablets Tmac (hr) Cmax (nmol/l) Terminal half life (hr) AUC (hr*nmol/l) Total body clearance (L/hr) Volume of distribution (L) Capsules (Fed) Mean 3.491 1469 13.8 10978 307 6254 Standard deviation (SD) 2.25 1156 2.35 3602 194 4686 Tablets (fed) Mean 3.176 1573 16.8 10782 341 7546 SD 1.69 1218 6.17 4732 255 4251 Capsules (fasted) Mean 3.068 286 16.8 3249 2094 30566 SD 1.64 161 11.4 2005 2846 35337 Tablets (fasted) Mean 2.098 324 16.7 3090 1308 35566 SD 0.70 215 10.4 2127 866 44766 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology Cougar Biotechnology
Assessment of central nervous system (CNS) and dose reduction events in patients treated with abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ).
Authors: Dominic Pilon, Ajay S. Behl, Laurence Gozalo, Bruno Emond, Yongling Xiao, Patrick Lefebvre, Christopher J. Kane
Journal: Journal of Clinical Oncology (2016)

5078 Background: The prognosis of patients with metastatic castrate resistant prostate cancer (PC) has improved with the availability of recent treatments such as AA+P or ENZ. However, concerns regarding adverse events such as CNS conditions, fatigue, and pain potentially leading to dose reductions or treatment interruption are rising. This study assessed CNS, fatigue, pain, and dose reduction events in AA+P or ENZ-treated patients. Methods: The MarketScan databases were used to conduct a retrospective analysis, in which patients initiated on AA+P or ENZ (index date) after 10/2012 with ≥ 6 months of continuous eligibility prior to index date and ≥ 1 PC diagnosis were included. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Weighted Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare the occurrence of CNS, pain, fatigue, or dose reduction (i.e., relative dose intensity [RDI] ≤ 80%, and ≤ 85%) events between groups. CNS, pain, and fatigue events were assessed in patients without respective event at baseline. Results: A total of 2,196 AA+P and 807 ENZ patients were identified. IPTW resulted in balanced baseline demographic, comorbidities, and disease characteristics (AA+P = 1,493 and ENZ = 1,510). At 12 months, 30.3% of patients on AA+P had a CNS event compared to 37.5% of patients on ENZ (P = 0.005). Similarly, 25.0% of patients on AA+P had a fatigue event compared to 28.6% of patients on ENZ (P = 0.013). Respectively, 13.6% and 20.0% of AA+P and ENZ patients had a dose reduction event (RDI ≤ 80%, P < 0.001; Table). Conclusions: This national study showed that mCRPC patients treated with ENZ were more likely to experience a CNS or fatigue event, and to reduce their treatment dose than patients treated with AA+P. Event KM Rates HRs for Development of Event AA+P ENZ Log-Rank P-value ENZ vs. AA+P (95% CI) P-value CNS 30.3% 37.5% 0.005 1.32 (1.05, 1.66) 0.017 Fatigue 25.0% 28.6% 0.013 1.30 (1.02, 1.66) 0.033 Pain 12.9% 15.3% 0.267 1.17 (0.84, 1.63) 0.351 RDI ≤ 85% 19.4% 24.4% 0.006 1.29 (1.04, 1.61) 0.022 RDI ≤ 80% 13.6% 20.0% < .001 1.44 (1.11, 1.86) 0.006
Abstract 3335: The high cMyc expression characterizes a small cell subpopulation in ALK-positive anaplastic large cell lymphoma that carry cancer stem-like properties
Authors: Chengsheng Wu, Haifeng Zhang, Nidhi Gupta, Alshareef Abdulraheem, Qian Wang, Yunghsin Huang, Raymond Lai
Journal: Cancer Research (2016)

Abstract We have previously identified two phenotypically distinct cell subpopulations in ALK+ anaplastic large cell lymphoma (ALK+ALCL) based on their differential response to a Sox2 reporter (SRR2), with reporter responsive (RR) cells being more tumorigenic and chemoresistant than reporter unresponsive (RU) cells. The regulation of the RU/RR dichotomy remains to be elusive. Our bioinformatics analysis of the SRR2 sequence suggests that cMyc may be an important factor. In support of this concept, we found a substantially higher expression of cMyc and more cMyc and Sox2-SRR2 probe bindings in RR cells than in RU cells. Inhibition of cMyc in RR cells significantly decreased SRR2 luciferase activity, and overexpression of cMyc in RU cells significantly increased SRR2 luciferase activity. Correlating with this, cMyc inhibition in RR cells significantly attenuated the clonogenicity and sensitized cells to doxorubicin; while overexpression of cMyc in RU cells conferred to the potentiated clonogenicity and chemoresistance. Importantly, we found cMyc not only maintains Sox2 protein expression, but also promotes Sox2 SRR2 probe binding and its transcriptional activity. Moreover, we found the highly active Wnt canonical pathway (WCP) contributes to the high expression of cMyc in RR cells. Intriguingly, we observed a positive regulatory loop in RR cells, in which Sox2 up-regulates Wnt2B, which can activate the WCP and cMyc. Furthermore, the significance of cMyc in this context was further highlighted by the fact that RU cells with stably transfected c-MYC are phenotypically similar with RR cells in terms of the elevated activation of WCP and increased tumorigenicity in vivo. Lastly, we found cMyc is heterogeneously expressed in ALK+ALCL tumor cells (n = 5) by immunohistochemcial staining, and it co-localizes with active β-catenin, a marker of active WCP, in tumor cells by immunofluorescence assay. In conclusion, cMyc is a key regulatory factor in the determination of RU/RR dichotomy, which is linked to tumorigenic potential and chemo-resistance in ALK+ALCL. Citation Format: Chengsheng Wu, Haifeng Zhang, Nidhi Gupta, Alshareef Abdulraheem, Qian Wang, Yunghsin Huang, Raymond Lai. The high cMyc expression characterizes a small cell subpopulation in ALK-positive anaplastic large cell lymphoma that carry cancer stem-like properties. [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 3335.
Abstract 3270: Myriocin, an inhibitor of serine palmitoyltransferase activity, has the anti-angiogenic effect by attenuating VEGF-induced angiogenesis signaling pathway
Authors: Sun Hee Lee, Yuk Dong Jung, Hye-Eun Lee, You Mie Lee
Journal: Cancer Research (2016)

Abstract Myriocin is a powerful serine palmitoyl transferase inhibitor, by inhibiting of sphingosine biosynthesis. Myriocin is also known to have immunosuppressive activity. Here, we demonstrate the anti-angiogenic effect of myriocin. Myriocin decreased vascular endothelial cell growth factor (VEGF)-induced angiogenic process, that include proliferation, migration, invasion, tube formation and cell adhesion in human umbilical vein endothelial cells (HUVECs). Myriocin down-regulated VEGF-induced VEGFR2, focal adhesion kinase, AKT kinase, rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and matrix metalloproteinase-2 (MMP2) expression. Myriocin greatly reduced new vessel formation in chick chorioallantoic membrane and vessel sprouting in mouse aortic ring assay. Furthermore, VEGF-induced phalloidin expression was inhibited by miyriocin in HUVECs. Our result indicated that myriocin inhibited VEGF-induced proliferation, migration, invasion, tube formation and cell adhesion in vitro by inhibiting VEGFR2-mediated activation of FAK, AKT, ROCK1 and MMP2. Taken together, we suggest that myriocin may act as significant angiogenic inhibitor by inhibiting VEGF-induced signaling pathway. Citation Format: Sun Hee Lee, Yuk Dong Jung, Hye-Eun Lee, You Mie Lee. Myriocin, an inhibitor of serine palmitoyltransferase activity, has the anti-angiogenic effect by attenuating VEGF-induced angiogenesis signaling pathway. [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 3270.
Abstract 4166: Role of calreticulin in the spontaneous development of lung adenocarcinoma: Evidence from a novel transgenic mouse model
Authors: Nasrin Mesaeli, Hamid Massaeli, Divya Viswanathan, Dhanya Pillai, Mercy Anna Thomas
Journal: Cancer Research (2016)

Abstract Lung cancer is the most common cause of cancer related deaths in both men and women worldiwide. The overall 5 year survival rate of lung cancer ranges between 5-15% (depending on the subtype). Based on histopathological criteria, lung cancer is subdivided into two main subtypes: small cell lung cancer (15%) and non-small cell lung cancer (NSCLC 85%). Adenocarcinoma a subtype of NSCLC is the most common type in both sexes, and it has a poor response to chemotherapy. We recently developed a transgenic mouse model of lung adenocarcinoma by overexpressing calreticulin (CRT) under the control of Tie2-promotor. The main phenotype of these mice is high incidence of metastatic lung adenocarcinoma similar to human patients. Immunohistological analysis showed these tumors to be SP-C+ve and CC10-ve phenotype. At the initial stages most of cells in the hyperplegic area and adenoma stained positive for exogenous CRT and HSCs markers, and as the tumor differentiated to carcinoma there were a significant loss of exogenous CRT and HSCs markers and increased expression of SP-C. The aim of our current project was therefore to identify the mechanism of development of metastatic lung adenocarcinoma in this mouse model. To address this objective we carried out microarray and quantitative proteomic analysis of tissue and cell lines isolated from lungs of this transgenic mouse model. Microarray analysis showed activation of cluster of genes involved in cellular development, growth and proliferation. Some of these pathways include genes invlved in VEGF signal transduction pathways and Epherin receptor signaling, at the same time there were decreased expression of cell-cell interaction and communication (needed for metastasis). At the protein level we observed a significant increase in proteins involved in tumor progression, invasion and metastasis. In addition we observed a significant change in the expression of genes invloved in lipid metabolism (both at protein and RNA level) in the lung of these mice. The change in the expression of lipid metabolizing genes suggest the metabolic shift needed during tumor progression. In conclusion, our data suggests that CRT as an endoplasmic reticulum chaperone and a regulator of intracellular calcium homeostasis affects multiple genes invivo resulting in the development of tumor. This research was funded by Qatar National Research Fund (NPRP4-043-3-016). Citation Format: Nasrin Mesaeli, Hamid Massaeli, Divya Viswanathan, Dhanya Pillai, Mercy Anna Thomas. Role of calreticulin in the spontaneous development of lung adenocarcinoma: Evidence from a novel transgenic mouse model. [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 4166.
Abstract IA08: The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets.
Authors: Jan A. Burger
Journal: Clinical Cancer Research (2015)

Abstract The tissue microenvironment plays an important role of in the pathogenesis of chronic lymphocytic leukemia (CLL), delivering signals that promote the clonal expansion of the malignant B cells, as well as drug resistance. The complex cross talk between neoplastic B cells and the microenvironment, for example in secondary lymphoid organs, has been increasingly well characterized, and several cellular and molecular key players have emerged. Important cells in the CLL microenvironment are monocyte-derived nurselike cells (NLC), mesenchymal stromal cells (MSC), and T cells, which engage in a dialogue with the neoplastic CLL cells, often via specific receptor-ligand pairs. Engagement of CLL surface receptors by ligands in the tissue microenvironment, for example activation of B cell receptor (BCR) signaling, triggering of TNF family members (i.e. BAFF, APRIL), and activation of chemokine receptors and adhesion molecules result in the activation of signaling cascades that support the maintenance and expansion of the CLL clone. BCR signaling plays a particularly important pathogenic role in CLL, based on structural restrictions of the BCR, and signs of BCR-dependent survival and growth of the malignant B cells. Ligand-independent (“autonomous”) and ligand-dependent BCR signaling have been characterized, the latter triggered by (auto-) antigens present in the tissue microenvironment. Based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases (BTK, PI3Kδ), which currently are changing treatment paradigms in CLL. Clinical and translational aspects of these new targeted therapeutics will be discussed, along with an outlook into future therapeutic strategies. Citation Format: Jan A. Burger. The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets. [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 IA08.
Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study
Authors: Kathleen F Pirollo, John Nemunaitis, Po Ki Leung, Robert Nunan, Jana Adams, Esther H Chang
Journal: Molecular Therapy (2016)

Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m2/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of −47%, −51%, and −79%. Two others had stable disease with significant shrinkage (−25% and −16%). These results support phase 2 testing of SGT-53 in combination with docetaxel. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m2/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of −47%, −51%, and −79%. Two others had stable disease with significant shrinkage (−25% and −16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.
A Novel Cross-Talk Between Epicardial Adipose Tissue and the Human Heart Regulates Myocardial Redox State in Ischaemic Heart Disease
Authors: A S Antonopoulos, M Margaritis, J Digby, M Petrou, P Ciccone, C Psarros, R Sayeed, B Casadei, K M Channon, C Antoniades
Journal: Circulation (2013)
Abstract 13498: Global Changes in Cardiovascular Endurance of Children and Youth Since 1964: Systematic Analysis of 25 Million Fitness Test Results from 28 Countries
Authors: Grant R Tomkinson, Madison Annandale, Katia Ferrar
Journal: Circulation (2013)

Introduction: Cardiovascular endurance is considered to be an important marker of current health and even a predictor of future health. Aim/hypothesis: This study aimed to systematically analyze th...
Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial
Authors: Mark A. Schroeder, Marcus Grillot, Teresa Reineck, Meagan A Jacoby, Rizwan Romee, Iskra Pusic, John Welch, Geoffrey L. Uy, Amanda F Cashen, Keith E. Stockerl-Goldstein, Ravi Vij, Shashikant Kulkarni, Peter Westervelt, Matthew J. Walter, John F. Dipersio
Journal: Blood (2013)
Acute appendicitis in an overweight and obese Mexican population: A retrospective cohort study
Authors: Eduardo Sotelo-Anaya, Martha Patricia Sánchez-Muñoz, César Felipe Ploneda-Valencia, Liliana Faviola de la Cerda-Trujillo, Oscar Varela-Muñoz, Carlos Gutiérrez-Chávez, Carlos Rene López-Lizarraga
Journal: International Journal of Surgery (2016)
GATA3 immunohistochemical expression in urothelial carcinoma.
Authors: Frederick Edem Doamekpor, AMR Mohamed, Momin Siddiqui, AlKhoder Ayman, Tengteng Wang, Khuram Ashraf, Omer Kucuk, Cynthia Cohen
Journal: Journal of Clinical Oncology (2016)

e16135 Background: GATA binding protein 3 (GATA3) is a transcription factor, which belongs to a distinct family of tumor suppressor genes. It is involved in human cancer cell growth and differentiation, and plays an important role in cell proliferation and apoptosis. Although its expression has been reported in various cancers, there is limited data in genitourinary malignancies. Recent studies found GATA3 to be a sensitive marker for urothelial carcinoma and is associated with prognostic pathologic features. Its level of expression was found to be an independent factor predicting cancer recurrence. Methods: In this study, immunohistochemical evaluation of GATA3 expression in genitourinary malignancies (urothelial carcinoma, renal cell carcinoma and prostatic adenocarcinomas) was performed. Results: GATA3 was positive in 56/79 (70.8%) of urothelial carcinoma, and was negative in all renal cell carcinoma and prostatic adenocarcinomas. The pattern of GATA3 staining when positive was intensely nuclear, within the clusters of malignant cells. No cytoplasmic staining was noted. Negative controls were negative for all cases. GATA3 high expression was associated with larger tumor size in urothelial carcinoma (3.19 cm vs 1.65 cm, P = 0.01). GATA3 expression did not correlate with other clinicopathologic parameters in urothelial carcinoma. Conclusions: These data suggested that GATA3 is a sensitive marker in confirming primary urothelial carcinoma, and may be helpful in differentiating it from metastatic tumors of renal and prostatic origin. Also, high GATA3 expression was noted to have an impact on tumor size in patients with urothelial carcinoma.