tbuckley/cabot-search huggingface dataset:
Abstract 1263: Andrographolide inhibits prostate cancer by suppressing cytokine involved in promoting epithelial to mesenchymal transition
Authors: Hina Mir, Neeraj Kapur, Guru Sonpavde, Shailesh Singh
Journal: Cancer Research (2017)

Abstract Mesenchymal phenotypes are responsible for cancer progression and poor therapeutic response. Hence, approaches targeting mesenchymal phenotype or inhibiting epithelial to mesenchymal transition will significantly prevent cancer progression or improve therapeutic outcome. Using in vitro models and molecular approaches we have shown that Andrographolide (AG), a compound isolated from Andrographis paniculata, shows promising effect on mesenchymal cells. It disposes PCa cells towards epithelial phenotype by modulating E-cadherin, ZEB-1, SNAIL and TWIST. In addition to these, significant inhibition in IL-6, which is known to be a poor prognostic maker, was observed in PCa cells treated with AG compared to untreated cells. This reduction in IL-6 could be due to AG induced suppression of SOCS (Suppressor of cytokine signaling) molecules. Therefore, our data underscores the ability of AG to impede cancer growth by impacting EMT and rationalizes its application as a potent therapeutic agent. Citation Format: Hina Mir, Neeraj Kapur, Guru Sonpavde, Shailesh Singh. Andrographolide inhibits prostate cancer by suppressing cytokine involved in promoting epithelial to mesenchymal transition [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 1263. doi:10.1158/1538-7445.AM2017-1263
The Role of Screening and Treatment in National Progress Toward Hepatitis C Elimination — Georgia, 2015–2016
Authors: Muazzam Nasrullah, David Sergeenko, Lia Gvinjilia, Amiran Gamkrelidze, Tengiz Tsertsvadze, Maia Butsashvili, David Metreveli, Lali Sharvadze, Maia Alkhazashvili, Shaun Shadaker, John W. Ward, Juliette Morgan, Francisco Averhoff
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Georgia, a country in the Caucasus region of Eurasia, has a high prevalence of hepatitis C virus (HCV) infection. In April 2015, with technical assistance from CDC, Georgia embarked on the world's first program to eliminate hepatitis C, defined as a 90% reduction in HCV prevalence by 2020 (1,2). The country committed to identifying infected persons and linking them to care and curative antiviral therapy, which was provided free of charge through a partnership with Gilead Sciences (1,2). From April 2015 through December 2016, a total of 27,595 persons initiated treatment for HCV infection, among whom 19,778 (71.7%) completed treatment. Among 6,366 persons tested for HCV RNA ≥12 weeks after completing treatment, 5,356 (84.1%) had no detectable virus in their blood, indicative of a sustained virologic response (SVR) and cure of HCV infection. The number of persons initiating treatment peaked in September 2016 at 4,595 and declined during October-December. Broader implementation of interventions that increase access to HCV testing, care, and treatment for persons living with HCV are needed for Georgia to reach national targets for the elimination of HCV.
Abstract 5237: Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule inhibitors
Authors: Richard Barrios, Jared Hammill, Jaeki Min, Kip Guy
Journal: Cancer Research (2017)

Abstract Due to the anti-neoplastic properties and clinical successes of the proteasome inhibitors Bortezomib and Carfilzomib, the ubiquitin-proteasome system (UPS) has become a new target of interest in oncology research. The clinical toxicity induced by these inhibitors, likely caused by complete inhibition of the UPS, has resulted in a need for the development of more selective UPS regulators. A more in depth understanding of the intrinsic molecular mechanisms that are associated with the UPS has unmasked the potential for improved therapies via more specific targets such as the process of neddylation, which is thought to control 15 - 20% of the UPS (5). During neddylation, an enzyme known as DCN1 for “defective in cullin neddylation 1” functions as a co-E3 to help steer a ubiquitin-like protein (UBL), NEDD8, from an E2 enzyme, UBC12, to a cullin (CUL) neddylation site (6 - 7, 9 - 11). Because DCN1 has been found to be amplified in certain squamous cell carcinomas (9) (SCCs; e.g. lung, esophagus, and head and neck), this in vitro, pre-clinical study demonstrates the potential of the DCN1-UBC12 interaction as a therapeutic site in lung SCCs through the use of novel small-molecule inhibitors from the St. Jude (SJ) library. After optimizing dosing regimens, it has been determined that re-administering the SJ compounds (i.e. SJ690, SJ447, SJ446, and SJ323) every 24-hours to address the issue of protein turn-over, produces more efficacious treatment. The most biochemically-potent antagonists in the compound series were also shown in these primary cell lines to potentiate other therapeutic agents such as Cisplatin; however, these compounds alone do not induce DNA damage, nor do they elicit caspase 3/7 activity. Nonetheless, combination treatment of the SJ compounds with Staurosporine in SCC cell lines, potentiated caspase 3/7 activity at varying degrees. Collectively, this data enhances our understanding of the mechanism by which the inhibition of DCN1 affects cancer cells, informing pre-clinical development of the SJ DCN1 antagonists. Citation Format: Richard Barrios, Jared Hammill, Jaeki Min, Kip Guy. Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule 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 5237. doi:10.1158/1538-7445.AM2017-5237
Abstract 5925: Mapping the molecular communication within the tumor microenvironment of pancreatic cancer as well as between tumor and peritumoral tissue
Authors: Mohamed S. Alhamdani, Andrea S. Bauer, Jörg D. Hoheisel
Journal: Cancer Research (2017)

Abstract We are analyzing in detail the molecular communication between the different cell types in the microenvironment of pancreatic ductal adenocarcinomas (PDAC). Also, its regulation is being investigated, looking at aspects such as the kind and mixture of molecules needed for triggering a particular regulative function, and unraveling the inter- and intracellular processes utilized to transmit a molecular message. Although a rare tumor entity, adding up to only about 3% of all cancer cases in the Western world, PDAC is the fourth most frequent cause of cancer-related death; mortality is nearly identical to incidence. There is no real remedy apart from surgery, which can be applied to only 10 to 20% of patients. Even then, basically all patients will experience tumor recurrence. Our study is based on a large basic set of data at the levels of DNA, RNA and protein that was generated from some 1000 pancreatic tumor samples [1], supplemented with information from studies that aim at an elucidation of functional molecules and comparative analyses in other tumors. This has already led to the creation of basic functional knowledge about metastasis [e.g., 2], the establishment of means for diagnosis [3, 4], an accurate disease prognosis [1], the characterization of communication processes [5] and the identification of new therapeutic avenues [6]. At the conference, we will report about the status of mapping particularly the protein-mediated communication between the different cell types in the tumor microenvironment. Also, we will show results about the effect that PDAC tissue has on the wider peritumoral environment and vice versa. The peritumoral tissue is exhibiting a field defect that does not seem to be dependent on DNA-methylation. A comparison of PDAC and cystic pancreatic tumors revealed that differences in communicating with the peritumoral tissue could actually be more important to the known pathological difference between the two cancer entities than the molecular variations in the tumor cells. 1. Bauer et al. (2017), work submitted for publication 2. Botla et al. (2016) Cancer Res. 76, 4149-4159 3. Keller et al. (2014) BMC Med. 12, 224 4. Moskalev et al. (2015) Oncotarget 6, 4418-4427 5. Dror et al. (2016) Nature Cell Biol. 18, 1006-1017 6. Jandaghi et al. (2016) Gastroenterology, in press (doi: 10.1053/j.gastro.2016.08.040) www.dkfz.de/funct_genome/ Note: This abstract was not presented at the meeting. Citation Format: Mohamed S. Alhamdani, Andrea S. Bauer, Jörg D. Hoheisel. Mapping the molecular communication within the tumor microenvironment of pancreatic cancer as well as between tumor and peritumoral tissue [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 5925. doi:10.1158/1538-7445.AM2017-5925
Abstract 2232: Dietary flavonoids, CYP1A1 genetic variants, and the risk of colorectal cancer
Authors: Jeongseon Kim, Young Ae Cho, Jeonghee Lee, Jae Hwan Oh, Dae Kyung Sohn, Hee Jin Chang
Journal: Cancer Research (2017)

Abstract The role of dietary flavonoid intake in colorectal carcinogenesis might differ according to flavonoid subclasses and individual genetic variants related to carcinogen metabolism. Therefore, we examined whether greater habitual dietary intake of flavonoid subclasses was associated with a lower risk of colorectal cancer and whether CYP1A1 genetic variants altered this association. A semi-quantitative food frequency questionnaire was used to assess the dietary intake of six flavonoid subclasses (flavonols, flavonones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones) in 923 patients with colorectal cancer and 1,846 controls; furthermore, CYP1A1 genetic variants (rs4646903 and rs1048943) were genotyped. A logistic regression was used to investigate dietary flavonoid intake, CYP1A1 genetic variants, and their interaction in relation to colorectal cancer risk. Among the subclasses of flavonoids, flavonols (OR [95% CI] = 0.10 [0.06, 0.16], highest vs. lowest quartile) and flavan-3-ols (OR [95% CI] = 0.54 [0.41, 0.71], highest vs. lowest quartile) were significantly associated with colorectal cancer risk after adjusting for confounders. Homozygous variants of CYP1A1 rs4646903 showed a protective effect on the risk of rectal cancer (OR [95% CI] = 0.60 [0.37, 0.96], CC vs. TT/TC). Carriers of the CC homozygous variant with high flavonol intake showed a greater decrease in colorectal cancer risk compared with T allele carriers with low flavonol intake (P for interaction = 0.02), particularly regarding rectal cancer (P for interaction = 0.005). In conclusion, the effect of dietary flavonoid intake on colorectal cancer risk differs by flavonoid subclasses and CYP1A1 genetic variants. Citation Format: Jeongseon Kim, Young Ae Cho, Jeonghee Lee, Jae Hwan Oh, Dae Kyung Sohn, Hee Jin Chang. Dietary flavonoids, CYP1A1 genetic variants, and the risk of colorectal 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 2232. doi:10.1158/1538-7445.AM2017-2232
Abstract 3421: Pharmacological inhibition of histone methylation attenuates TGFβ induced EMT characteristics in pancreatic cancer
Authors: Hardik R. Mody, Rajgopal Govindarajan
Journal: Cancer Research (2017)

Abstract Epithelial-to-Mesenchymal Transition (EMT) is a tumor cell remodeling process that drives progression of several epithelial solid tumors including pancreatic tumors. Transforming growth factor (TGF) β signaling is a key promoter of EMT pathway and remains an attractive target for curtailing tumor progression. Here we present a strategy for investigating inhibitors of TGFβ signaling in pancreatic cancer via reprograming of miRNAs. We find a carbocyclic adenosine analog and histone methyl transferase inhibitor, 3-deazaneplanocin A (DZNep) to significantly attenuate the TGFβ signaling induced EMT characteristics in pancreatic ductal adenocarcinoma (PDAC). Specifically, we find DZNep treatment to restore expression of selective epigenetically silenced miRNAs (mir-663a, miR-4787-5p, and miR-202) that inhibit endogenous TGFβ1 ligand and receptor expression via RNA interference. Consequently, DZNep significantly attenuated both exogenous and endogenous TGFβ-induced EMT response. Lentiviral overexpression of mir-663a, miR-4787-5p or miR-202 reduced tumor cellular proliferation and EMT phenotypic characteristics similar to DZNep in cultured pancreatic cancer cells, whereas locked nucleic acids inhibition of miRNAs abrogated such effects. In an orthotopic pancreatic cancer mouse model, DZNep and all three miRs reduced overall tumor burden in pancreas and metastatic load in liver, lungs and spleen. Together, these findings suggest epigenetic reprograming of miRNAs by synthetic histone methylation reversal agents as a potentially viable approach for attenuating TGFβ signaling pathway involved in pancreatic cancer progression. Citation Format: Hardik R. Mody, Rajgopal Govindarajan. Pharmacological inhibition of histone methylation attenuates TGFβ induced EMT characteristics in pancreatic 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 3421. doi:10.1158/1538-7445.AM2017-3421
Abstract 4546: Structural evaluation of mutations identified on Cue domain of FANCD2
Authors: Mohd Quadir Siddiqui, Ashok K. Varma
Journal: Cancer Research (2017)

Abstract Fanconi anemia complementation group D2 (FANCD2) protein plays pivotal role in DNA interstrand crosslink (ICL) repair and genome stability. FANCD2 comprises conserved CUE domain at N terminus, which is important for DNA ICL repair and protein stability. However, molecular mechanism associated to genetic alteration has not well characterized. Here, we have carried out multimodal approaches to explore folding pattern of FANCD2 Cue domain and functionally relevant mutations. Dynamic Light Scattering and Mass Spectrometry data of purified proteins could revealed that wild- type protein is predominantly monomeric, but mutated counterparts are exhibiting oligomeric properties. Secondary, tertiary structure assessment and their thermal stability of wild- type, mutants were studied by Circular Dichroism (CD) and Fluorescence spectroscopy. Furthermore, binding affinity and kinetics of Cue domain and mutants with monoubiquitin was evaluated by surface plasmon resonance (SPR). Molecular modelling, simulation, normal mode analysis, principal component analysis and docking studies were carried out to understand in-depth conformational dynamics and interactions. References:- 1. Regulation of the Fanconi anemia pathway by a CUE ubiquitin-binding domain in the FANCD2 protein. Rego, M. A. et al, Blood 120: 2109-2117,(2012). 2. Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Kalb et al, Am J Hum Genet 80: 895-910, (2007) Citation Format: Mohd Quadir Siddiqui, Ashok K. Varma. Structural evaluation of mutations identified on Cue domain of FANCD2 [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 4546. doi:10.1158/1538-7445.AM2017-4546
Abstract 5937: Obesity-induced destabilization of p16INK4Apromotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin
Authors: Huda H. Alkhalaf, Abdelilah Aboussekhra
Journal: Cancer Research (2017)

Abstract Obesity, a disease linked to increased number of adipocytes in various tissues, is increasingly recognized as a risk factor for the development of breast cancer. However, the molecular basis of adipocyte-related breast carcinogenesis remains elusive. In this study, we established and characterized normal stromal adipocytes from post-plastic surgery of breast tissues from obese and lean women. We have shown that adipocytes from obese women express low level of the tumor suppressor p16 protein, have higher secretion of various adipokines and higher invasion and migration capabilities as compared to adipocytes from lean women. In addition, down-regulation of p16INK4A by shRNA in adipocytes from lean women increased the expression/secretion levels of various adipokines including leptin, activated breast adipocytes and enhanced their migration/invasion abilities. Consequently, media conditioned with p16-deficient adipocytes or adipocytes from obese women promote epithelial-to-mesenchymal-transition in normal breast luminal cells in a leptin-dependent manner and induced tumor growth in vivo. Indeed, p16INK4A suppresses Leptin at the mRNA level through miR-141 and miR-146b-5p, which inhibits Leptin expression through a specific sequence at the Leptin 3’UTR. These results show the existence of active adipocytes in the mammary gland of obese women in absence of breast cancer cells and provide the first indication that p16INK4A through targeting miR-141 and miR-146b-5p suppresses Leptin and its procarcinogenic effects. This indicates that p16 pathway has non-cell-autonomous tumor suppressor function in breast stromal adipocytes. Note: This abstract was not presented at the meeting. Citation Format: Huda H. Alkhalaf, Abdelilah Aboussekhra. Obesity-induced destabilization of p16INK4A promotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin [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 5937. doi:10.1158/1538-7445.AM2017-5937
Abstract 1579: Bicalutamide-induced expression of T-type Ca2+channels in prostate cancer cells undergoing neuroendocrine differentiationin vitro
Authors: Miguel Martin-Caraballo, Megan Hall, Bryan Todd, Yoon Jung Kwon, Vu Nguyen, Jennifer L. Hearne
Journal: Cancer Research (2017)

Abstract The growth of prostate cancer cells depends on the activation of androgen receptors. Anti-androgen therapies that inhibit androgen synthesis or receptor activation are effective in limiting tumor growth. However, prolonged treatment with anti-androgen therapies result in the transition of prostate cancers into an androgen refractory state. Neuroendocrine differentiation (NED) has been associated with the progression of prostate cancers to an androgen resistant phenotype. In this work we investigated the effect of the androgen receptor blocker bicalutamide in promoting NED of LNCaP cells and whether it is accompanied by increased T-type Ca2+ channel expression. The ability of bicalutamide to evoke morphological and biochemical changes associated with NED was assessed by PCR, western blot and immuno-histochemical analysis. Changes in the Cav3.2 T-type Ca2+ channel subunit expression was studied using PCR analysis, western blot and whole cell recordings. The role of T-type Ca2+ channels in promoting the differentiation of LNCaP cells was assessed by a cell viability assay and changes in cell morphology, specifically the development of neurite-like processes. PCR analysis of bicalutamide-stimulated cells indicates no significant changes in Cav3.2 mRNA, yet results in Cav3.2 protein expression and functional channels. Western blot and immuno-histochemical analysis of LNCaP cells simulated with bicalutamide for 4-10 day reveals biochemical changes consistent with NED including the expression of tubulin IIIbeta and neuron-specific enolase. Pharmacological inhibition of T-type Ca2+ channel function with nickel ions and NNC 33-0936 disrupts the morphological differentiation and cell viability of LNCaP cells treated with bicalutamide. These results suggest that bicalutamide treatment of LNCaP cells evokes significant morphological and biochemical changes associated with NED and results in increased expression of T-type Ca2+ channels, which can significantly alter Ca2+ homeostasis. Citation Format: Miguel Martin-Caraballo, Megan Hall, Bryan Todd, Yoon Jung Kwon, Vu Nguyen, Jennifer L. Hearne. Bicalutamide-induced expression of T-type Ca2+ channels in prostate cancer cells undergoing neuroendocrine differentiation in vitro [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 1579. doi:10.1158/1538-7445.AM2017-1579
Post-Transplant Treatment with Ponatinib for Patients with High-Risk Philadelphia Chromosome Positive Leukemia
Authors: Maria Teresa Lupo-Stanghellini, Francesca Lunghi, Andrea Angelo Assanelli, Elena Guggiari, Raffaella Greco, Mara Morelli, Tommaso Perini, Serena Camilla Dalto, Elisa Sala, Francesca Lorentino, Simona Piemontese, Francesca Pavesi, Sara Mastaglio, Daniele Mannina, Carlo Messina, Luca Vago, Sarah Marktel, Matteo Giovanni Carrabba, Magda Marcatti, Massimo Bernardi, Consuelo Corti, Chiara Bonini, Jacopo Peccatori, Fabio Ciceri, Fabio Giglio
Journal: Blood (2016)
Abstract 2985: Interaction between the malignant melanoma cell of the primary lesion and the metastatic lesion
Authors: Takaharu Hatano, HIsashi Motomura, Heishiro Fujikawa, Masakazu Yashiro, Kishu Kitayama
Journal: Cancer Research (2017)

Abstract Introduction: The prognosis of patients with malignant melanoma is extremely poor because of the frequent metastasis. We have occasionally experienced the clinical cases that malignant melanoma patients rapidly developed distant metastases after the surgical resection of primary cancer lesion. These cases suggested that a primary tumor may control a metastatic tumor. We hypothesized that primary melanoma cells might produce a factor(s) which regulate the progression of metastatic melanoma cells. Then we investigated the growth and invasion interaction between primary malignant melanoma cells and high metastatic melanoma cells. Materials and methods: We used two malignant melanoma cell lines, B16 as a parent primary melanoma cell line and a selected daughter cell line B16/BL6 with high metastatic ability. We investigated the invasive interaction between the parent B16 cells and daughter B16/BL6 cells in vitro. The conditioned medium from B16 cells and B16/BL6 cells was added to B16 cells or B16/BL6 cells. Then we examined the effect of these conditioned medium on the motility and proliferation of melanoma cells by MTT assay or invasion assay at 24 hours and 72 hours after the addiction of the conditioned medium. Results:The conditioned medium from B16 cells significantly (p=0.02) suppressed the invasion ability of B16/BL6 cells at 24 hours after the addiction of the conditioned medium. In contrast, the invasion ability of B16 cells were not affected by the conditioned medium from B16/BL6 cells at 24 hours. Each conditioned medium did not affect on the proliferation of both melanoma cell lines. On the other hand, at 72 hours after the addiction of the conditioned medium from B16 cells significantly (p=0.000003) suppressed the growth of B16/BL6 cells. Conclusion: Primary melanoma cells might down-regulate the progression of metastatic melanoma cells by a soluble factor(s). Citation Format: Takaharu Hatano, HIsashi Motomura, Heishiro Fujikawa, Masakazu Yashiro, Kishu Kitayama. Interaction between the malignant melanoma cell of the primary lesion and the metastatic lesion [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 2985. doi:10.1158/1538-7445.AM2017-2985