bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2012: UVB-induced ULBP1 upregulation in melanocytes depends on HMGB1-mediated activation of NF-κB and IRF3
Authors: Wu Zhaohui , Wang Wei 
Published: July 2017

Abstract
Anti-tumor immune surveillance mediated by innate immunity cells such as NK cells plays a critical role in eliminating “damaged” cells at precancerous stage and preventing cancer progression. As a key epidemiological factor associated with melanoma, solar UV radiation also elicit immunosurveillance by upregulating ligands for NK cell activating receptor NKG2D. Nevertheless, how UVR upregulates NKG2DL in melanocytes is not completely understood. We found UVB exposure induced secretion of damage-associated molecular patterns molecule HMGB1 from skin cells. HMGB1 activates transcription factors NF-κB and IRF3 in melanocytes which synergistically enhances NKG2D ligand ULBP1 transcription. Moreover, RAGE is essential for HMGB1-induced activation of NF-κB and IRF3, which serves as the HMGB1 receptor and mediates activation of TBK1. Consistently, HMGB1 deficient melanoma cells are less susceptible to NK cells mediated cytotoxicity. Our study provides a mechanistic link between environmental UV radiation and antitumor immunosurveillance induced in melanocytes, which may play a critical role in the early stages of melanomagenesis.
Citation Format: Zhaohui Wu, Wei Wang. UVB-induced ULBP1 upregulation in melanocytes depends on HMGB1-mediated activation of NF-κB and IRF3 [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 2012. doi:10.1158/1538-7445.AM2017-2012
Abstract 2021: Ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis through upregulation of keratin-17
Authors: Lee Mee-Hyun , Lim Do Young , Lee Sung Young , Shim Jung Hyun , Liu Xuejiao , Zhao Ran , Huang Hai , Bowden G.Timothy , Surh Young-Joon , Cho Yong-Yeon , Bode Ann M. , Dong Zigang 
Published: July 2017

Abstract
Solar UV irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancerr and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic ablation of caspase-7 are significantly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and tumor numbers were increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation biomarkers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. 2-DE gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. Furthermore the expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study suggests that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17.
Citation Format: Mee-Hyun Lee, Do Young Lim, Sung Young Lee, Jung Hyun Shim, Xuejiao Liu, Ran Zhao, Hai Huang, G.Timothy Bowden, Young-Joon Surh, Yong-Yeon Cho, Ann M. Bode, Zigang Dong. Ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis through upregulation of keratin-17 [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 2021. doi:10.1158/1538-7445.AM2017-2021
Abstract 2025: A distinct role of RhoB in simvastatin-induced cytotoxicity in breast cancer cells
Authors: Seah Serena , Wang Tingting , Lee Soo Chin 
Published: July 2017

Abstract
Purpose Statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are initially developed as cholesterol-lowering drugs by inhibiting the mevalonate pathway. They have recently gained attention for their potential anticancer properties, but the mechanisms of their anticancer effects remain elusive. This study aims to investigate the antiproliferative effects of statins in breast cancer cell lines.
Methods We screened a panel of breast cancer cell lines (Estrogen receptor positive (ER+): CAMA1, MCF7, T47D, ZR-75-1 and Hcc1428; triple negative (TNBC): MDA MB231, MDA MB468, BT549, Hs578T and Hcc1806) and assessed the sensitivity of these cells to simvastatin in relation to their hormone receptor status using cell proliferation assay. Next, to elucidate the mechanisms underlying simvastatin sensitivity, we evaluated the (i) expression of key enzymes in the mevalonate pathway using qPCR and western blot analysis and (ii) the role of sterol biosynthesis metabolites by exogenously adding these compounds and testing their effects on simvastatin-induced cytotoxicity. Finally, we performed functional assays following siRNA knockout to identify the key small GTPase involved.
Results We found TNBC cell lines to be more susceptible to simvastatin compared to ER+ cell lines (mean IC50 of 7.98μM [95%CI 2.75-13.22] versus 41.74μM [95%CI 6.71-76.78]). Simvastatin treatment induced robust apoptosis in TNBC but not the ER+ cells. There was no significant difference in mRNA expression of HMGCR, HMGCS, MVK, MVD, IDI1 enzymes involved in the mevalonate pathway between TNBC and ER+ breast cancer cell lines. Supplementation with geranylgeranyl pyrophosphate but not farnesyl pyrophosphate, inhibited simvastatin-mediated cell death, suggesting the involvement of geranylgeranylated proteins such as Rho family of GTPases. Here, we identified RhoB to be a key player in simvastatin-mediated cytotoxicity. RhoB showed a significant increase in transcript and protein levels in response to simvastatin treatment in the TNBC cells. Interestingly, the increase in protein expression was not associated with an increase in its prenylation as the accumulation of RhoB was observed only in the cytosolic fraction. Finally, silencing RhoB was able to abrogate the cytotoxic effects mediated by simvastatin in TNBC cells.
Conclusions Taken together, our data reveals a critical role of RhoB in the anticancer activity of simvastatin, which appears to be exclusive to TNBC cells suggesting that HMG-CoA reductase inhibitors may provide new therapeutic strategies for TNBC treatment.
Citation Format: Serena Seah, Tingting Wang, Soo Chin Lee. A distinct role of RhoB in simvastatin-induced cytotoxicity in breast 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 2025. doi:10.1158/1538-7445.AM2017-2025
Abstract 2033: Testing the combined effects of low dose olaparib plus ibrutinib on MCL cytotoxicity
Authors: Curtis Adam D. , Hoffert Todd A. , Rajan Sheila S. , Rueter Jens , Shopland Lindsay S. 
Published: July 2017

Abstract
Mantle cell lymphoma (MCL) presents a therapeutic challenge, with frequent relapses after therapy due to high levels of DNA damage and disease evolution. One currently approved MCL therapeutic, ibrutinib, is a tissue-specific agent with relatively few adverse effects. However, ibrutinib is administered at high dose for MCL and provides only a short progression-free survival time. To potentially improve ibrutinib therapy for MCL, we tested the effects of combining ibrutinib with the DNA damage response inhibitor, olaparib, on MCL cells in vitro. We confirmed that ibrutinib monotherapy is cytotoxic to MCL cell lines only at high doses (&gt; 25 μM). In contrast, single-agent olaparib treatment is cytotoxic at lower concentrations (10 μM). Importantly, the addition of low dose olaparib to ibrutinib has an additive cytotoxic effect. Notably, the effects of ibrutinib alone and in combination are dependent on cell medium composition. Our findings support clinical testing of ibrutinib plus olaparib therapy to reduce MCL cell burden initially and to potentially slow MCL cell evolution in the longer term. Our data also suggest the possibility for more effective ibrutinib-based therapy via manipulation of the MCL cell niche.
Citation Format: Adam D. Curtis, Todd A. Hoffert, Sheila S. Rajan, Jens Rueter, Lindsay S. Shopland. Testing the combined effects of low dose olaparib plus ibrutinib on MCL cytotoxicity [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 2033. doi:10.1158/1538-7445.AM2017-2033
Abstract 204: In vitro metabolomics of mesothelioma: Challenges and outcomes
Authors: Lagniau Sabrina , Lamote Kevin , Vandermeersch Lore , Langenhove Herman Van , Meerbeeck Jan P. van , Vermaelen Karim Y. 
Published: July 2017

Abstract
Introduction
Early detection of malignant pleural mesothelioma (MPM) is likely to improve outcome in affected patients. From our previous studies (MesoBreath 1 & 2) we developed a screening tool in which volatile organic compounds (VOCs) in breath allowed discrimination of MPM patients from at risk controls. However it is not yet clear which VOCs arise from the neoplastic cells themselves or from the host response. Identifying the cancer cell-specific compounds should increase the specificity of our breathomic signature model. Therefore, we set up an in vitro experimental setup model for VOC analysis from the headspace of mesothelioma cell lines.
Methods
Standard polystyrene culture flasks (NunclonTM Delta Surface, Thermo Scientific) were mounted with an adapted cap accommodating teflon inlet and outlet tubes. The inlet tube provides environmental air while an external pump (Gilian GilAir Plus, Sensidyne) draws headspace air from the outlet tube over an adsorption column (Tenax GR, Markes International, UK). The adsorption columns were further processed on a GC-MS platform (GC: Focus GC, Thermo Finnigan, Milan, Italy; DSQII Single Quadrupole MS, Thermo Finnigan, Austin, TX, USA). VOC profiles were processed using supervised clustering algorithms and principal component analysis.
Results
Using this setup, we have investigated the impact of flow and total sampled volume on the concentration and range of VOCs detected. For a constant flow, VOCs were detected in higher concentrations with increasing sample volume. For a constant volume, a lower sampling flow yielded a higher concentration of detected VOCs. Most of the VOCs obtained were alkanes and ketones. We will show data illustrating the differential VOC profiles of container plastic, cell culture medium and growing mesothelioma cancer cells, as well as the differential VOC output of epithelioid vs sarcomatoid mesothelioma cell lines.
Conclusions
We have succesfully developed an in vitro experimental setup allowing collection and analysis of VOCs emanating from mesothelioma cancer cell line cultures. This platform will allow us to investigate how VOC profiles are impacted in different experimental conditions (e.g. hypoxia, nutrient deprivation, cytostatics, co-culture with leukocytes). The data collected will help us to pinpoint the cancer cell-derived VOCs from patient exhaled breath, and increase the robustness of our mesothelioma breathomic signature.
Note: This abstract was not presented at the meeting.
Citation Format: Sabrina Lagniau, Kevin Lamote, Lore Vandermeersch, Herman Van Langenhove, Jan P. van Meerbeeck, Karim Y. Vermaelen. In vitro metabolomics of mesothelioma: Challenges and outcomes [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 204. doi:10.1158/1538-7445.AM2017-204
Abstract 2041: High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy
Authors: Kita Yuki , Kobayashi Takashi , Saito Ryouichi , Yamasaki Toshinari , Inoue Takahiro , Ogawa Osamu 
Published: July 2017

Abstract
Introduction and Objectives Gemcitabine and cisplatin chemotherapy (GC) is the current standard regimen for locally advanced and metastatic bladder cancer (BC). Despite a relatively high initial response rate, some cases do not regress (intrinsic resistance) and the remaining cases often show regrowth after initial shrinkage (acquired resistance). To identify novel therapeutic agents for overcoming these resistances, we applied a high-throughput screening of chemicals administered in combination with GC.
Methods As a high-throughput screening, 2100 compounds were administered alone or in combination with GC to human BC cell lines (J82, UMUC-3). Cell viability was determined after 3-day incubation and chemicals that enhanced inhibitory effect of GC were screened. The in vivo effect of disulfiram (DSF) was studied in UMUC-3 cell xenografts, and western blot, immunofluorescence, induced coupled plasma spectrometry and measurement of reactive oxygen species (ROS) were done in vitro for mechanistic exploration.
Results The initial screening identified 26 compounds and further validation narrowed them into the most synergistic agent DSF, an FDA-approved drug for alcoholism. Combination index assay showed synergistic effects of DSF with cisplatin but not with gemcitabine in J82, UMUC-3, T24, HT1197 and HT1376 cells. Co-administration of DSF significantly increased DNA-platinum adducts by regulating cisplatin efflux transporter ATP7A and enhanced apoptosis by GC treatment in UMUC-3 cells, with significant increase of ROS production. Use of DSF in combination with GC (GCD) significantly inhibited tumor growth of UMUC-3 subcutaneous xenograft on athymic mice (by 39% compared with GC alone, p = 0.02). GCD regimen was as tolerable as GC and no significant differences were observed in body weight of treated mice between the two regimens.
Conclusions Repositioning of DSF to a chemotherapy sensitizer is a promising treatment strategy, which can be translated rapidly in the future.
Citation Format: Yuki Kita, Takashi Kobayashi, Ryouichi Saito, Toshinari Yamasaki, Takahiro Inoue, Osamu Ogawa. High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy [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 2041. doi:10.1158/1538-7445.AM2017-2041
Abstract 2060: Characterizing acquired resistance to palbociclib in breast cancer
Authors: Vijayaraghavan Smruthi , Doostan Iman , Carey Jason P.W. , Keyomarsi Khandan 
Published: July 2017

Abstract
The CDK4/6 inhibitor palbociclib is currently being used in combination with endocrine therapy to treat advanced ER positive breast cancer patients. While this treatment has shown great promise in the clinic, about 25% of the patients do not respond, and almost all patients eventually acquire resistance to palbociclib treatment. Hence, understanding the mechanism(s) of acquired resistance to CDK4/6 inhibition is crucial to devise alternate treatment strategies. To interrogate this, we developed MCF7 and T47D resistant cells by treating them with increasing doses of palbociclib over a 6-month period. After confirming that these cells were resistant to palbociclib, we performed genome-wide expression analysis via RNA-seq, in comparison with the parental (sensitive) cells. RNA- seq analysis revealed 2888 differentially expressed genes (p&lt;0.05) in the resistant cells when compared to parental. Further, gene set enrichment analysis (GSEA) revealed enrichment of immune pathways (interferon alpha and gamma response, immune response) and pathways known to regulate EMT and cancer stem cells (IL-6/Stat3, IL-2/STAT-5, Notch, Wnt) in the resistant cells. Additionally, GSEA analysis revealed downregulation of G2/M checkpoint, estrogen response and DNA repair pathways (double strand break repair). Thus, this data suggests that combined targeting of two or more pathways that are altered in the resistant cells can provide a novel therapeutic strategy to combat CDK4/6 inhibitor resistance.
Citation Format: Smruthi Vijayaraghavan, Iman Doostan, Jason P.W. Carey, Khandan Keyomarsi. Characterizing acquired resistance to palbociclib in breast 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 2060. doi:10.1158/1538-7445.AM2017-2060
Abstract 2066: Delivery of 2`F-PS2 PTGER3 siRNA-DOPC enhances anti-tumoral activity in cisplatin resistant ovarian cancer model
Authors: Bayraktar Emine , Rodriguez-Aguayo Cristian , Siddik Zahid , Lopez-Berestein Gabriel 
Published: July 2017

Abstract
RNAi-based therapeutics approaches holds a big promise for clinical translation. However, siRNAs are very weak and highly susceptible to degradation by nucleases. Nanoparticle delivery systems and chemical modifications of small interfering RNA (siRNA) can enhance efficient intracellular delivery and resistance to degradation for various siRNAs resulting in an increase in their clinical therapeutic potential. Here, we hypothesized that DOPC nanoparticles incorporated with a chemically fluoro phosphorodithioate (2`F-PS2) modified-PTGER3 siRNA will enhance the stability, prolong the silencing effect in vitro and increase the anti-tumoral effect when is combined with cisplatin in vivo. We screened 51 different chemically modified PTGER3-siRNAs which have 2'-F-PS2 or 2'-O-methyl modification on selectively protected nuclease-sensitive sites. We determined PTGER3 gene expression after siRNA-2'-F-PS2 or 2'-O-methyl modified mediated silencing, stability, time-response silencing effect and the therapeutic effect in xenograft OC in vivo model. We demonstrated that siRNA-2'-F-PS2 prolong the stability for more than 24 hours and enhance the silencing for more than 96 hours. Moreover, we found that PTGER3-silencing effect can control the expression of CFTR multidrug resistant pump by regulating ERK-ELK1-ETS1-CFTR axis, resulting in an increase of the cisplatin uptake, decreased the tumor-associated angiogenesis and tumor growth in xenograft OC in vivo model. SiRNA-PTGER3-2'-F-PS2 modification increase the stability and time-response silencing effect, leading to a synergistic anti-tumor in combination with cisplatin in ovarian cancer models.
Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Zahid Siddik, Gabriel Lopez-Berestein. Delivery of 2`F-PS2 PTGER3 siRNA-DOPC enhances anti-tumoral activity in cisplatin resistant ovarian cancer model [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 2066. doi:10.1158/1538-7445.AM2017-2066
Abstract 2068: Development of a rational triple combination therapy for castration-resistant prostate cancer
Authors: Qiao Yuanyuan , Morgan Todd M. , Chinnaiyan Arul M. 
Published: July 2017

Abstract
Background The androgen receptor (AR) signaling pathway drives prostate cancer development and progression, making it a major target for drug development. However, resistance to AR targeted therapies invariably develops and eventually leads to an aggressive, castrate-resistant prostate cancer (CRPC). Although CRPC often remains dependent on AR signaling, anti-androgen therapies can lead to the development of AR independent disease and metastatic CRPC. Understanding the molecular basis of this transition and resistance to current anti-androgen therapy will provide important insight and reveal novel therapeutic strategies for both AR-positive and -negative disease pathways.
Methods and Results We analyzed in silico data of AR (signaling)-positive or -negative human CRPC tissue samples and discovered that MET expression is specifically increased only in AR-negative CRPC samples. When AR-positive CRPC models are subjected to AR signaling inhibition (by the AR antagonist enzalutamide or androgen deprivation), MET is increased and susceptible to activation by its ligand HGF. Therefore, we postulate that dual targeting of AR and MET signaling pathways may be a better approach to prevent and overcome resistance-related disease progression. Our preliminary AR ChIP-seq data suggested that MET transcription is not affected by AR directly rather, MET protein is modulated by AR signaling at the post-translational level. Therefore, we hypothesize that a combination therapy of a proteasome inhibitor and MET inhibitor may have potential therapeutic benefit for some CRPC patients. By using in vitro and in vivo models of AR-dependent CRPC, we have showed that combination of the dual MET/VEGFR2 inhibitor cabozantinib and enzalutamide treatment is more efficacious than either inhibitor alone. In addition, Bortezomib, an FDA-approved proteasome inhibitor, showed significant synergistic effect when paired with cabozantinib in our preliminary data using in vitro and in vivo CRPC models. In vitro results suggest that triple combination of anti-androgen, MET inhibitor and proteasome inhibitor therapies will maximize inhibition in CRPC.
Conclusion MET is a compensatory survival pathway in AR+ CRPC upon anti-androgen therapy. The rational for triple combination of anti-androgen, MET inhibitor and proteasome inhibitor therapies is a feasible approach to maximize inhibition in CRPC while minimizing development of drug resistance to any single agent.
Citation Format: Yuanyuan Qiao, Todd M. Morgan, Arul M. Chinnaiyan. Development of a rational triple combination therapy for castration-resistant prostate 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 2068. doi:10.1158/1538-7445.AM2017-2068