bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2243: Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach.
Authors: Koundinya Malvika , Sudhalter Judith , Courjaud Albane , Lionne Bruno , Touyer Gaetan , Bonnet Luc , Menguy Isabelle , Schreiber Isabelle , Perrault Christelle , Vougier Stephanie , Benhamou Brigitte , Simard Daniel , Castaldi Maria Paola , Tomlinson Ronald , Reiling Stephan , Cao Hui , Harper David , Bouaboula Monsif , Pollard Jack , Grepin Claudine , Garcia-Echeverria Carlos , Adrian Francisco , Cornella-Taracido Ivan , Arrebola Rosalia , Morris Aaron J. 
Published: August 2014

Abstract
Activating KRAS mutations are oncogenic and prevalent in multiple tumor types, being found in as high as 90% of pancreatic carcinomas and 50% of colorectal carcinomas. In spite of its attractiveness for therapeutic intervention to date no KRAS-targeted drug therapies have been approved. Most of the reported mutant KRAS directed cellular screening efforts utilize 2-dimensional assays. Because mutant KRAS driven tumor cell lines are much more strongly dependent on activated K-Ras signaling for anchorage independent growth relative to growth when anchored to plastic, we report herein a screening strategy that leverages a 3-dimensional clonogenic growth assay in soft agar. We have performed a multi-cell line parallel phenotypic high throughput screen with our proprietary compound collection to identify pathways, targets and chemical matter with selective anti-tumor activity in mutant KRAS dependent cell lines - a Synthetic Lethal approach.
Our strategy has led to the identification of several chemical classes that inhibit the growth of multiple mutant KRAS cell lines of pancreatic and colorectal carcinoma origin, while sparing multiple wild-type KRAS cancer cell lines. Studies to elucidate their molecular mechanisms of action are underway.
Citation Format: Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Daniel Simard, Maria Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Hui Cao, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Francisco Adrian, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron J. Morris. Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2013-2243
Abstract 2245: Overcoming cisplatin resistance by celastrol in cancer cells.
Authors: Shi Zhi 
Published: August 2014

Abstract
Cisplatin is one of the most widely used cytotoxic anticancer drugs for the treatment of solid malignancies, including lung, testicular, ovarian, head and neck, colorectal, bladder cancers, etc. However, its clinical efficacy is often limited by the development of chemoresistance. Several mechanisms have been implicated in cisplatin resistance, such as reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. Celastrol, a quinone methide triterpene, is an active compenent of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo. In this study, we sought to determine the effect of celastrol on cisplatin resistance cancer cells and the possible involved molecular mechanism. Our data show that celastrol had similar cytotoxic effects on both A549 parental and A549/DDP cisplatin resistant cells. The IC50 values of celastrol to both cell lines are at the concentration of μM range. Celastrol also induced cell apoptosis with ROS accumulation, loss of mitochondrial membrane potentials, cleavage of PARP and caspases in a dose- and time-dependent manner in both cell lines. These findings might provide significant strategy for overcoming cisplatin resistance in clinic, and define the novel mechanism of celastrol-induced anticancer activity.
Citation Format: Zhi Shi. Overcoming cisplatin resistance by celastrol in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2013-2245
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2251: Induction of apoptosis in breast cancer cells using Kedrostis foetidissima.
Authors: Motadi Lesetja Raymond 
Published: August 2014

Abstract
Kedrostis foetidissima has been used by tribes throught Africa to treat various human livestock ailments. K. foetidissima, has been shown to inhibit the growth of breast cancer cell lines in vitro by induction of apoptosis in previous studies of our group1. With current chemotherapy and radiotherapy continuing to show unwanted side effects the only hope to a better safer medicinal target would include that uses medical plants that induces apoptosis with or without inducing p53 gene2,3. However, the mechanisms of action are not completely understood. In this study we are looking at the role and expressional levels of RBBp6 in breast cancer following treatment with the plant extract. In trying to achieve our objective both human breast cancer tissue and MCF7 cell lines were used to first establish the pattern of expression and then cell lines were treated with medicinal plant to evaluate the expressional patterns using both the immunohistochemistry, RTPCR and Flow cytometer.
We observed that protein as well as mRNA level of RBBP6 was inhibited by K. foetidissima in a dose-dependent manner (Fig. 1). However, in both untreated and human breast cancer tissues RBBp6 was found to be highly expressed around cells undergoing cell division. In recent studies, an apoptosis-related gene expression profiling analysis provided a clue that both p53 and bax gene were slightly upregulated at least 2 to 3 fold in response to K. foetidissima treatment in MCF7 cell2. On the other had we have reported in the past that RBBp6 acted as inhibitor of p53 gene. The findings in this study suggest that downregulation of RBBp6 may through small molecules might be a potential therapy in cancer.
Citation Format: Lesetja Raymond Motadi. Induction of apoptosis in breast cancer cells using Kedrostis foetidissima. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2013-2251
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2258: Celastrol shows chemopreventive properties in an inflammatory driven model for colon cancer via induction of Nrf2 transcription.
Authors: Barker Emily , Letterio John J. , Tochtrop Gregory P. 
Published: August 2014

Abstract
Celastrol is a natural triterpenoid isolated from the medicinal herb Triptyrgium wilfordii or Thunder of God vine. Celastrol has been shown to have a broad range of anti-inflammatory and anti-cancer activities. A mouse model for inflammatory-driven colon carcinogenesis combines a conditional T-cell deletion of the Smad4 gene with germ line deletion of the p27Kip1 gene. These genetic deletions result in spontaneous inflammation of the intestinal tract and associated early and aggressive development of cancer in the epithelia of both the small intestine and colon. In this study, administration of celastrol as a dietary supplement at a dose of 2 mg/kg is shown to be an effective strategy for cancer chemoprevention in this mouse model of colon carcinogenesis. Mice of this strain on a celastrol-supplemented diet had increased overall health and increased survival compared to mice receiving control diet. In vivo, celastrol was observed to increase the otherwise suppressed expression of cytoprotective Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) target genes (in comparison to wild type) and also to decrease expression of inducible nitric oxide synthase and accumulation of circulating nitric oxide in serum. In vitro, celastrol also induces antioxidant and cytoprotective activity through the induction of Nrf2 transcription as confirmed using macrophages derived from bone marrow of Nrf2-/- mice compared to wildtype. Celastrol induces the expression of many known Nrf2 target genes, including Hemeoxygenase-1, NAD(P)H quinone reductase-1, glutathione-S reductase, catalase and Nrf2 itself. This activity is abrogated in macrophages from Nrf2-/- mice. These data provide additional mechanistic insight on the potent anti-inflammatory activity of celastrol and present a rationale to further explore the capacity of dietary celastrol to suppress carcinogenesis in other, classical models of colon carcinogenesis with an emphasis on future potential for clinical translation.
Citation Format: Emily Barker, John J. Letterio, Gregory P. Tochtrop. Celastrol shows chemopreventive properties in an inflammatory driven model for colon cancer via induction of Nrf2 transcription. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2258. doi:10.1158/1538-7445.AM2013-2258
Abstract 229: Pterostilbene suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via modulating NF-κB/microRNA448 circuit.
Authors: Yeh Chi-Tai , Chiou Jeng-Fong , Wu Chih-Hsiung , Wu Alexander TH 
Published: August 2014

Abstract
Tumor microenvironment plays a key role in promoting epithelial-to-mesenchymal transition (EMT), a cellular step for cancer cells to gain metastatic ability and is also associated to the generation of cancer stem cells (CSCs). Agents capable of modulating the tumor microenvironment could be more efficient in managing tumor progression. Pterostilbene, a natural stilbene isolated from blueberries have been suggested for its anti-cancer effects. Here, we explored the potential microenvironment modulating effects of pterostilbene in a M2-polarized macrophages (M2 TAMs) and breast cancer cell co-culture system. We first demonstrated that co-culturing with M2 TAMs increased the percentage of CD44+/CD24- CSC population and migratory/invasive abilities. We then showed that pterostilbene treatment dose-dependently overcame M2 TAM-induced enrichment of CSCs and metastatic potential of breast cancer cells. Mechanistically, pterostilbene suppressed NFκB, Twist1, Vimentin and increased E-cadherin expression. Importantly, pterostilbene-mediated NFκB downregulation was correlated to an increased amount of microRNA448. Finally, using non-invasive bioluminescence technique we demonstrated that pterostilbene treatment significantly suppressed M2 TAM co-cultured MDA-MB-231 tumorigenesis and metastasis. Thus, pterostilbene could be a potential anti-CSC agent for clinical development.
Citation Format: Chi-Tai Yeh, Jeng-Fong Chiou, Chih-Hsiung Wu, Alexander TH Wu. Pterostilbene suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via modulating NF-κB/microRNA448 circuit. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 229. doi:10.1158/1538-7445.AM2013-229
Abstract 230: Connectivity-map analyses identify FDA-approved drugs targeting breast cancer stem cells.
Authors: Bhat-Nakshatri Poornima , Goswami Chirayu , Badve Sunil , Sledge George W. , Nakshatri Harikrishna 
Published: August 2014

Abstract
Recently developed genomics-based tools are allowing repositioning of established drugs as cancer treatments. This approach has not been employed extensively to identify drugs that may target cancer stem cells (CSCs) of solid tumors. CD44+/CD24- cancer cells are the first described CSCs for breast cancer, which are enriched in mesenchymal stem-like (MSL) and mesenchymal-like (ML) subtypes of triple negative (TNBCs) and in anti-estrogen resistant breast cancers. We subjected gene expression array datasets containing list of genes differentially expressed in CD44+/CD24- CSCs compared to non-CSCs as well as in cells enriched for other markers of CSCs including CD271 and GD3S (six datasets in total) to connectivity map (CMAP) to identify drugs that may reverse gene expression patterns unique to CSCs. All trans retinoic acid (ATRA) was negatively connected with gene expression in CD44+/CD24-, CD271+, and GD3S+ CSCs as well as in ML and MSL subtypes of TNBCs. Independently, ATRA was found to modulate the expression of several genes in the recently described CSC-enriched Yes-Associated Protein (YAP) signature. ATRA-inducible genes of the YAP signature were associated with good prognosis, whereas ATRA-repressible genes were associated with poor prognosis, depending on the subtype of breast cancer. ATRA reduced mammosphere forming ability of breast cancer cells including acquired anti-estrogen resistant cells, which correlated with ATRA-mediated reduction of the critical stemness-associated gene SOX2 and induction of SOX21, which functions as a differentiation factor depending on the cell type. CD44+/CD24- breast cancer cell line with K-ras mutation was resistant to ATRA, which was reversed by MAP kinase inhibitors. From these results, we propose ATRA as a potential therapy for specific subtypes of breast cancers enriched for CSCs. A biomarker-driven patient selection may help to identify patients who may benefit from ATRA therapy.
Citation Format: Poornima Bhat-Nakshatri, Chirayu Goswami, Sunil Badve, George W. Sledge, Harikrishna Nakshatri. Connectivity-map analyses identify FDA-approved drugs targeting breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 230. doi:10.1158/1538-7445.AM2013-230
Abstract 2306: MicroRNA 199a*: a potent suppressor of tumor metastasis and angiogenesis.
Authors: Ghosh Alip , Ghosh Amit , Dasgupta Debanjali , Roychowdhury Shrabasti , Roychowdhury Shrabasti , Datta Simanti , Chowdhury Abhijit , Banerjee Soma 
Published: August 2014

Abstract
The growth of a solid tumor depends on diffusion of nutrients from the tumor microenvironment through vascular system. Angiogenesis, the new blood vessels formation is the primary route by which tumor cells get nutrients as well as exit from primary site and enter into the blood circulation. The proliferation and migration of vascular endothelial cells are triggered by angiogenic growth factors secreted by tumor cells, such as VEGF, TGF-β etc. Recent evidences showed HGF also plays an important role in angiogenesis by enhancing the proliferative activity and intracellular signaling. HGF/its receptor, c-MET and VEGF/VEGFR1 are two independent pathways for angiogenesis and metastasis. Thus detection of a molecule that hits both pathways could be a potent therapeutic agent that could facilitate the inhibition of improved barrier function. Recently mir199a* has been shown to target both CD44 and cMET molecule to block the metastasis in cancer. The present study aim to show that mir199a* also target HGF, the key modulator of the HGF/c-Met signaling cascade in epithelial cells to shut off the mesenchymal transition and VEGFR1 to prevent angiogenesis more effectively.
Luciferase 3’ UTR assay was performed to investigate HGF as a target of mir-199a*. HGF mRNA and protein expression was determined by real time RT-PCR, Western blot analysis in liver stellate cell line LX2 transfected with mir-199a* and HGF shRNA. The cultured media of mir-199a* transfected LX2 cells was used to verify the effect of mir-199a* on HGF induced migration and invasion ability on metastatic cell lines using Boyden chamber assay with or without matrigel coated membrane and angiogenesis by tube formation assay.
The mir-199a* binding site was detected by pictar, target scan analysis of the 3’UTR of HGF and VEGFRs. The binding of mir-199a* to the 3′UTR of HGF and VEGFR1 were confirmed by luciferase assay, mutagenesis and western blotting. Down regulation of HGF protein expression in HGF producing hepatic stellate cell, LX2 was observed by mir-199a*. Addition of LX2 conditioned media transfected with mir199a* to metastatic cell reduces the migration and invasion and also block angiogenesis in endothelial cells.
As Mir-199a* could target HGF/cMET, CD44-cMET and VEGF/VEGFR1 signaling cascade, it could be used as a potential therapeutic target of HCC.
Citation Format: Alip Ghosh, Amit Ghosh, Debanjali Dasgupta, Shrabasti Roychowdhury, Shrabasti Roychowdhury, Simanti Datta, Abhijit Chowdhury, Soma Banerjee. MicroRNA 199a*: a potent suppressor of tumor metastasis and angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2306. doi:10.1158/1538-7445.AM2013-2306
Abstract 232: Cancer stem cells and cisplatin.
Authors: Modur Vishnu 
Published: August 2014

Abstract
Introduction:
Cisplatin is an important chemotherapeutic agent, which has resulted in higher overall response rates when combined with 5-FU or taxane combinations in treating squamous cellular carcinoma of the head and neck. However, HNSCC tumor response rates to cisplatin range from 20-30%, a major clinical hurdle today. To address this issue thoroughly, we investigated the resistance to cisplatin in HNSCC under the purview of the cancer stem cell hypothesis, using the widely studied CSC marker combinations of, CD44+ 24- and ALDH-Hi. In order to get a broader perspective on this issue, we worked on multiple HNSCC tumor cell lines with varying degrees of cisplatin resistance, arising from tumors of the pharynx, larynx, tongue, tonsils, alveolus, hypopharynx and supraglottis.
Methods:
Seven HNSCC cell lines were analyzed for their CSC percentage through FACS, utilizing CD44+ 24- and ALDH-Hi marker systems. Cisplatin IC-50 for each of these seven cell lines was then determined by plotting percent viability vs. drug concentration curves. The remaining viable cells after cisplatin treatment were then analyzed through FACS for their CD44+ 24- and ALDH-Hi percentages in order to compare with the CSC percentage in the untreated HNSCC lines.
Results:
There was a wide variation in the percentages of CD44+24- and ALDH-Hi cells across these seven HNSCC lines. An inverse correlation between the initial percentages of CD44+24- and ALDH-Hi cells and the corresponding cisplatin IC-50 values was seen. HNSCC cell lines that had lower IC-50 values for cisplatin displayed greater cell viability at higher concentrations of cisplatin. This was evident by a long tail in the sigmoidal dose response curve. The number of viable cells at the end of cisplatin treatment had a linear relationship with the overall percentage of CSCs in the control untreated cell lines.
Conclusion:
Our results suggest that the resistance offered by the CD44+24- and ALDH1-Hi cells is apparent only once the initial 50% loss of cells occurs. This in vitro biphasic decline in percent viable cells clearly indicates that HNSCC cisplatin resistance is a twofold problem. The bulk of non-cancer stem cells within a tumor can acquire resistance to cisplatin via multiple molecular pathways, but this is only a front line cover of resistance to the resistance offered by the cancer stem cells.
Citation Format: Vishnu Modur. Cancer stem cells and cisplatin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2013-232
Abstract 2328: Loss of 14-3-3zeta impairs oncogene-induced mammary tumorigenesis and metastasis.
Authors: Joshi Sonali , Yang Jun , Wang Qingfei , Li Ping , Wang Hai , Pickering Brian , Xiong Yan , Parker-Thornburg Jan , Behringer Richard , Yu Dihua 
Published: August 2014

Abstract
The 14-3-3 family proteins are highly conserved in eukaryotes and can interact with signaling proteins by binding phosphorylated Ser/Thr motifs. Studies in our laboratory have demonstrated that 14-3-3zeta is overexpressed in greater than 40% of breast cancer patients and is a strong indicator of poor patient prognosis, however the role of 14-3-3zeta in an in vivo context, especially its role in cancer, remains to be examined. We generated a 14-3-3zeta knockout mouse model to characterize the role of 14-3-3zeta in breast cancer progression. Loss of 14-3-3zeta resulted in neonatal lethality in the C57Bl/6 genetic background due to respiratory failure. Outbreeding to CD-1 or backcrossing to FVB/N background rescued the neonatal lethality. Crossing 14-3-3zeta knockout mice with MMTV-PyMT and MMTV-neu transgenic mice revealed that loss of 14-3-3zeta prolonged tumor latency and reduced lung metastasis as compared to MMTV-PyMT and MMTV-neu mice. Mechanistically, loss of 14-3-3zeta suppressed tumor proliferation and angiogenesis and promoted apoptosis. Reverse phase protein array analysis suggested that loss of 14-3-3zeta suppressed the Akt and Erk pathway and upregulated the expression of the tumor suppressor p53. Our results demonstrate an important role for 14-3-3zeta in normal development and cancer. Additionally our 14-3-3zeta knockout mouse model will also enable future studies on the role of 14-3-3zeta in other physiological and pathological processes.
Citation Format: Sonali Joshi, Jun Yang, Qingfei Wang, Ping Li, Hai Wang, Brian Pickering, Yan Xiong, Jan Parker-Thornburg, Richard Behringer, Dihua Yu. Loss of 14-3-3zeta impairs oncogene-induced mammary tumorigenesis and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2328. doi:10.1158/1538-7445.AM2013-2328