tbuckley/cabot-search huggingface dataset:
Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice
Authors: Zhizhen Qin, Shoubao Wang, Yihuang Lin, Ying Zhao, Shengqian Yang, Junke Song, Tao Xie, Jinlong Tian, Song Wu, Guanhua Du
Journal: Acta Pharmaceutica Sinica B (2017)

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.
Abstract 1118: Synthetic lethality of CDK12 inhibition in tumors with EWS/FLI rearrangements
Authors: Amanda L. Balboni, Bjorn Stolte, Amy Saur Conway, Gabriela Alexe, Emily Jue Wang, Nicholas Kwiatkowski, Tinghu Zhang, Brian J. Abraham, Peter Kalev, Dipanjan Chowdhury, Cyril H. Benes, Richard A. Young, Nathanael S. Gray, Kimberly Stegmaier
Journal: Cancer Research (2017)

Abstract THZ1 is a potent, covalent inhibitor of the transcriptional CDKs, CDK7/12/13. Chemical genomic profiling of THZ1 across &amp;gt;1,000 diverse cancer cell lines revealed that EWS/FLI- rearranged Ewing sarcoma cells were remarkably sensitive to this molecule. We demonstrated that THZ1 inhibits the phosphorylation of the C-terminal domain of RNA Polymerase II, decreased colony formation capacity, and induced apoptosis in a dose-dependent manner in Ewing sarcoma cell lines. Using selective CDK7 and CDK12/13 inhibitors, we revealed that the primary target of THZ1 in Ewing sarcoma is CDK12/13. Genetic suppression of CDK12, but not CDK13, induced strong anti-viability effects, confirming CDK12 as the primary target. Treatment of Ewing sarcoma cell lines with THZ531, a novel CDK12/13 selective inhibitor, preferentially repressed genes involved in DNA damage repair. Additionally, suppression of EWS/FLI rendered Ewing sarcoma cells resistant to THZ531 and partially rescued the anti-viability effects of CDK12 knockdown. These results suggest that EWS/FLI imparts vulnerability to DNA damage repair inhibition and implicate a synthetic lethal relationship between the tumor-specific expression of EWS/FLI and CDK12 inhibition. Furthermore, we demonstrated that CDK12 and PARP inhibitors are highly synergistic in vitro, inducing widespread yH2AX foci formation. Interestingly, THZ531 impairs the ability of the PARP inhibitor, olaparib, to induce RAD51 foci formation, suggesting that THZ531 specifically causes a defect in homologous recombination repair. Moreover, we observed striking synergy of THZ1 and olaparib in two mouse models of Ewing sarcoma with limited toxicity observed. These findings have important translational significance as clinical trials with PARP inhibitors as single agents in Ewing sarcoma failed to demonstrate efficacy, highlighting the need to identify combination therapies that will enhance the activity of PARP inhibition. We anticipate that CDK12 and PARP inhibitor combinations will be of therapeutic interest in other ETS-rearranged tumors, as well as tumors with defects in DNA repair. Citation Format: Amanda L. Balboni, Bjorn Stolte, Amy Saur Conway, Gabriela Alexe, Emily Jue Wang, Nicholas Kwiatkowski, Tinghu Zhang, Brian J. Abraham, Peter Kalev, Dipanjan Chowdhury, Cyril H. Benes, Richard A. Young, Nathanael S. Gray, Kimberly Stegmaier. Synthetic lethality of CDK12 inhibition in tumors with EWS/FLI rearrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1118. doi:10.1158/1538-7445.AM2017-1118
Abstract 2023: Artemisinins enhanced the antileukemic efficacy of BCL2 inhibitors
Authors: Blake S. Moses, Jennifer M. Fox, Xiaochun Chen, Jeffrey W. Tyner, Gary H. Posner, Patrick Bailey, Curt I. Civin
Journal: Cancer Research (2017)

Abstract More effective, less toxic treatments are needed to improve longevity and quality of life for patients with acute leukemias. Artesunate (AS), the current WHO-recommended drug for severe malaria, is a semi-synthetic derivative of the natural compound Artemisinin. AS has broad antineoplastic activity in vitro, and is well tolerated, inexpensive, and can be parenterally or orally administered in humans. Both AS and a more potent synthetic derivative, artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838), substantially inhibited acute leukemia growth in vivo and in vitro, at doses where normal CD34+ hematopoietic stem-progenitor cell clonogenicity was essentially unaffected. Moreover, AS and ART-838 synergized with several current antileukemic drugs (Fox et al, Oncotarget, 2015). To identify additional potential antileukemic drug combinations, we screened for the growth inhibitory effects of AS and ART-838 against 3 acute leukemia cell lines co-treated with a panel of 122 antileukemic compounds (mainly emerging antineoplastic drugs). Both AS and ART-838 showed synergistic or additive growth inhibition with several compounds. Two BCL2 protein family inhibitors demonstrated among the highest levels of synergy. One of these, ABT-199 (venetoclax), was recently approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL) and received breakthrough designation for acute myeloid leukemia (AML). Therefore, we decided to further investigate the combination of ABT-199 with AS or ART-838. Synergy between AS (or ART-838) and ABT-199 was confirmed across several acute leukemia cell lines with varying sensitivities to each drug. Both leukemia cell proliferation and survival were affected synergistically by exposure to the combination of AS (or ART-838) plus ABT-199. Utilizing in vivo imaging, we assessed changes in growth kinetics of tail vein-injected acute leukemia cell lines and primary patient-derived samples constitutively expressing luciferase in mice treated with AS, ABT-199, or the combination. The combination of AS plus ABT-199 had the greatest antileukemic effect. Based on these data, we propose that Artemisinins plus BCL2 inhibitors comprise an antileukemic drug pair with high potential for incorporation into acute leukemia therapeutic regimens. Citation Format: Blake S. Moses, Jennifer M. Fox, Xiaochun Chen, Jeffrey W. Tyner, Gary H. Posner, Patrick Bailey, Curt I. Civin. Artemisinins enhanced the antileukemic efficacy of BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2023. doi:10.1158/1538-7445.AM2017-2023
Abstract 4009: Characterization of M2 macrophage subtype content in cancer and normal tissues
Authors: Lisa M. Dauffenbach, Gela C. Sia, Jianping Zheng, Natalia Jun, Eric P. Olsen, Christopher A. Kerfoot
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages play an important role in presenting tumor antigens to T cells and are being investigated for their role in sensitivity to immune checkpoint inhibitors such as PD-1 inhibitors. The M2 macrophage subtype, characterized by CD163 expression, is immunosuppressive and associated with poor prognosis. A multiplex CD68/CD163 immunohistochemical assay was developed to characterize the density of cells expressing each marker and determine the percentage of macrophages that are of the M2 subtype. The assay was used to analyze 22 normal tissue types and 50 tumor tissues within 5 different indications. The results were analyzed by image analysis and results were analyzed as percent positive and density per mm2. Cancer tissues expressed a greater percentage of CD163+ macrophages than normal tissues. Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Jianping Zheng, Natalia Jun, Eric P. Olsen, Christopher A. Kerfoot. Characterization of M2 macrophage subtype content in cancer and normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4009. doi:10.1158/1538-7445.AM2017-4009
Zwitterionic hydrogels enhance angiogenic response, promote complete skin regeneration during full-thickness wound healing
Authors: Zecong Xiao, Chaochao He, Jingjing Zhu, Jingjing Ye, Yi Li, Anqi Chen, Hongxue Shi, Hongyu Zhang, Xiaokun Li, Jian Xiao, Jiang Wu
Journal: Journal of Controlled Release (2017)
Abstract 3170: MCAM modulates small cell lung cancer chemoresistance via PI3k/Akt/Sox2 signaling pathway
Authors: Satyendra C. Tripathi, Johannes F. Fahrmann, Muge Celiktas, Mitzi Aguilar, Kieren D. Marini, Mohit K. Jolly, Hiroyuki Katayama, Hong Wang, Eunice N. Murage, Jennifer B. Dennison, D. Neil Watkins, Herbert Levine, Edwin J. Ostrin, Ayumu Taguchi, Samir M. Hanash
Journal: Cancer Research (2017)

Abstract Despite favorable responses to initial therapy SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. We sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is still not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3K/AKT pathway in a SOX2 dependent manner. Metabolomic profiling revealed that MCAM can modulate glutamic acid and lactate production in chemoresistant cells with a distinct metabolic phenotype sustaining low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC. Citation Format: Satyendra C. Tripathi, Johannes F. Fahrmann, Muge Celiktas, Mitzi Aguilar, Kieren D. Marini, Mohit K. Jolly, Hiroyuki Katayama, Hong Wang, Eunice N. Murage, Jennifer B. Dennison, D. Neil Watkins, Herbert Levine, Edwin J. Ostrin, Ayumu Taguchi, Samir M. Hanash. MCAM modulates small cell lung cancer chemoresistance via PI3k/Akt/Sox2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3170. doi:10.1158/1538-7445.AM2017-3170
Abstract 5523: Loss of RAB25 cooperates with oncogenes in the transformation of human mammary epithelial cells
Authors: Krishna Rao, Pooja Sridhar Joshi
Journal: Cancer Research (2017)

Abstract The RAB guanosine triphosphates (RAS-related in brain) belong to the Ras superfamily of GTPases, and loss of RAB 25 expression has been reported in a number of breast cancer cases containing H-Ras point mutations, particularly triple negative breast cancers (TNBC), one of the most aggressive subtypes of breast cancer and associated with a poor prognosis. The mechanism involved in the progression of these tumors is poorly understood. In this study, we are trying to understand if loss of RAB25 expression in Human Mammary Epithelial Cell (HMEC) lines co-operates with H-Ras mutations and contributes to tumorigenesis. HMEC were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, catalytic subunit of the telomerase enzyme that permits the cells to exceed the Hayflick Limit and become immortal. We have found that with loss of RAB25 and over expression of mutant H-Ras61L, immortal HMEC undergo transformation. We have looked into the co-operativity between loss of Rab25 and H-Ras61L mutant by in-vitro studies to show their anchorage independent growth and increased ability to migrate. Furthermore, cells express low CD24, high CD44, and very low levels of Claudin indicating that cells acquire stem-like properties upon transformation. Loss of RAB25 and over-expression of H-ras61L resulted in increased expression of transcription markers Snail and Slug that drive these cells to lose E-cadherin and undergo Epithelial Mesenchymal Transition (EMT). We also intend to carry out nude mice studies to look for the potential of these cells to form tumors and metastasize. This study shows that loss of RAB25 and over-expression of mutant H-Ras can transform HMEC and give rise to mesenchymal stem-like tumors. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker in the prognosis of Claudin-low type of TNBC. Citation Format: Krishna Rao, Pooja Sridhar Joshi. Loss of RAB25 cooperates with oncogenes in the transformation of human mammary epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2017-5523
Abstract 763: Analytical validation of Ki67/CD8 duplex IHC assay using computational tissue analysis (cTATM)
Authors: Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani
Journal: Cancer Research (2017)

Abstract Chromogenic multiplex immunohistochemistry (IHC) assays enable investigation of the spatial relationships between tumor and immune cells, which is thought to be important for understanding and predicting therapeutic response. Development and analytical validation of multiplex IHC assays enables the use of such assays to simultaneously investigate multiple biomarkers as predictors of clinical response. In this study, we analytically validated a chromogenic duplex IHC assay that quantifies Ki67 and CD8 in formalin-fixed, paraffin-embedded non-small cell lung cancer tissues. Five performance criteria were selected and evaluated based on Clinical Laboratory Standards Institute guidelines: reportable range, analytical sensitivity, analytical specificity, accuracy, and precision. Similar to analytical validation studies for monoplex IHC assays, this study utilized a reference method and multiple days of staining. The percentage of cells positive for Ki67 nuclear staining and/or CD8 membrane staining were quantified using our computational Tissue Analysis (cTATM) platform. Performance of the Ki67/CD8 chromogenic duplex IHC assay was considered acceptable for the five criteria evaluated. Once the performance of the assay was established, additional exploratory cTA-based endpoints were examined, including the quantification of each biomarker in the tumor compartment and the tumor microenvironment, and analysis of the spatial arrangement of immune cells relative to tumor cells. In conclusion, Flagship’s cTA platform allows for more consistent quantification of individual analytes on dual-stained tissue sections, enabling investigation of complex biological questions that cannot be achieved with traditional tissue-based manual endpoints. Citation Format: Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani. Analytical validation of Ki67/CD8 duplex IHC assay using computational tissue analysis (cTATM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 763. doi:10.1158/1538-7445.AM2017-763
Abstract 3989: Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer
Authors: Yunpeng Liu, Shuo Wang, Xiujuan Qu, Zhi Liu, Xiaofang Che, Xu Ling, Kezuo Hou, Yibo Fan, Na Song, Ti Wen, Ce Li
Journal: Cancer Research (2017)

Abstract Although checkpoint inhibitors targeting PD-1/PD-L1 pathway have demonstrated similar clinical activity in treatment of NSCLC both for squamous(SCC) and non-squamous carcinoma (non-SCC) patients, the predictive role of PD-L1 expression is distinct between two histologies in clinical trials. In order to investigated the expression and prognostic roles of PD-1/PD-L1, data from TCGA and GEO database were analyzed and further validated with our original data by IHC in 133 resected NSCLC tumor tissue(49 SCC and 84 non-SCC). Through the analysis of online data, we concluded that PD-L1 expression in SCC was significantly higher than that of non-SCC. In addition, in non-SCC, PD-L1 was associated with immune response and indicated worse prognosis while no such results were observed in SCC. Further, our original data demonstrated PD-L1 expression in tumor cells(TC) and immune cells(IC) were significantly more often and more intense in SCC(P&amp;lt;0.001). In survival analysis, PD-L1 expression in TC and IC were associated with shorter overall survival in non-SCC (P=0.019 and 0.003, respectively). However, in SCC, PD-L1 did not demonstrate any significant effect neither in TC or IC (P=0.526 and 0.674, respectively) which consistent with online data. Contrary to PD-L1, no significant differences of PD-1 expression in tumor infiltrating lymphocytes(TILs) were showed between two histologies. PD-1 in TILs of SCC correlated with worse prognosis (P=0.025) while in non-SCC there was no correlation(P=0.986). Taken together, these findings suggest distinct regulation mechanisms and clinical significance of PD-L1/PD-1 pathway in NSCLC subgroups. Citation Format: Yunpeng Liu, Shuo Wang, Xiujuan Qu, Zhi Liu, Xiaofang Che, Xu Ling, Kezuo Hou, Yibo Fan, Na Song, Ti Wen, Ce Li. Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2017-3989
Abstract 2311: A peptide derived from a photosynthetic cupredoxin protein, auracyanin, induces a p53-independent apoptosis in cancer cells
Authors: Samer A. Naffouje, Tohru Yamada, Tapas K. Das Gupta
Journal: Cancer Research (2017)

Abstract Cupredoxins are a family of low-molecular weight, water soluble, copper-containing redox proteins involved mainly in the electron transfer chain in prokaryotes. Azurin is a member of the cupredoxin family secreted by Pseudomonas aeruginosa, of which a 28-amino acid sequence (p28) was identified to acquire the capability of preferential entry into cancer cells of various histogenesis. Upon entry, it exerts a cytostatic effect in these cancer cells via a p53-mediated pathway. Our aim was to study whether the other members of the cupredoxin family possess a similar function to that of azurin in the eukaryotic cancer cells. Based on structural and sequence analyses, helical regions of auracyanin A &amp; B were shown to resemble p28 closely. Thus, we studied the biologic function of two 28-amino-acid peptides derived from auracyanin A (aurA; pI 4.5, MW 2.6 kD), and auracyanin B (aurB; pI 3.4, MW 2.7 kD). Cancer growth and MTT assays demonstrated that aurB, but not aurA, induced cytotoxicity in various cancer cell lines in a dose-dependent (range 0.1uM-100uM) and time-dependent (~72 hours) pattern, including p53-null (prostate cancer PC-3) and dn-p53 (breast cancer MDD-2 and ovarian cancer SKOV-3) in which p28 did not demonstrate a significant growth inhibition. Annexin-V assays showed a dose-dependent apoptosis in prostate cancer cell lines of various p53 statuses (wt-p53 LNCaP, mut-p53 DU-145, p53-null PC-3) following treatment with aurB at 5-50uM for 48 hours, whereas p28 did not demonstrate an apoptotic activity in p53-null cell lines, suggesting an aurB-induced apoptosis via a p53-indepdnent pathway. In contrast, aurA did not appear to induce apoptosis in any of the above cell lines. Induction of apoptosis was mediated through depolarization of the mitochondrial membrane and caspase cascade activation in cancer cells. Moreover, fluorescence microscopy demonstrated that aurB, unlike p28, does not acquire a similar pattern of preferential entry into cancer cells. This proposes that aurB acquires the potential as an anticancer cell penetrating peptide, and differs from p28 in its mode of entry and p53-mediated action. Our studies pertaining to azurin and auracyanin, suggest that cupredoxins, as a family of prokaryotic metalloproteins, could represent a fountainhead of numerous derived peptides that hold promise as novel and efficient antineoplastic agents against various cancer cell lines. Citation Format: Samer A. Naffouje, Tohru Yamada, Tapas K. Das Gupta. A peptide derived from a photosynthetic cupredoxin protein, auracyanin, induces a p53-independent apoptosis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2311. doi:10.1158/1538-7445.AM2017-2311