tbuckley/cabot-search huggingface dataset:
Abstract 949: Resistin potentiates stemness and chemoresistance of breast cancer cells through STAT3 activation: implications in breast cancer health disparity
Authors: Sachin Kumar Deshmukh, Arun Bhardwaj, Sanjeev K. Srivastava, Nikhil Tyagi, Ahmed Al-Ghadhban, Ajay P. Singh, Donna L. Dyess, James E. Carter, Seema Singh
Journal: Cancer Research (2017)

Abstract Breast cancer (BC) is most frequently diagnosed cancer and remains the second leading cause of cancer-related deaths in women in the United States. African American (AA) women bear an additional burden of BC with early onset of disease, poorer prognosis, higher risk of recurrence, and worst clinical outcome as compared to Caucasian American (CA) women. Emerging evidence strongly argue the role of tumor-microenvironment (TME) in BC of AA and CA racial backgrounds. On the similar line, our earlier findings suggested that serum levels of resistin; an inflammatory cytokine are significantly elevated in AA BC patients compared to their CA counterparts. Furthermore, we demonstrated that resistin promoted growth and aggressiveness of BC cells. In the present study, we investigated the role of resistin in stemness and chemoresistance of BC cells. For this, two BC cells of CA (MDA-MB-231) and AA (MDA-MB-468) origin were treated with resistin and sphere-forming ability, a key characteristic of cancer stem cells, was determined. Data demonstrate that number of spheres is significantly enhanced in both the BC cells upon resistin stimulation. Immunoblot analyses reveal that resistin-induced sphere-forming ability is associated with enhanced levels of stemness-associated transcription factors (Nanog and KLF4) in BC cells. We next examined if resistin conferred chemoresistance to BC cells. Our data suggest that resistin-treated MDA-MB-231 and MDA-MB-468 BC cells develop greater resistance against doxorubicin-induced cytotoxicity. Notably, the effects conferred by resistin were more prominent in AA BC cells comparing to CA BC cells. Our mechanistic studies unveiled an important role of STAT3 activation in the resistin-induced stemness and chemoresistance of BC cells. Taken together, our findings provide novel insight into the role of resistin in BC biology and further strengthen its role in racially disparate clinical outcomes. Citation Format: Sachin Kumar Deshmukh, Arun Bhardwaj, Sanjeev K. Srivastava, Nikhil Tyagi, Ahmed Al-Ghadhban, Ajay P. Singh, Donna L. Dyess, James E. Carter, Seema Singh. Resistin potentiates stemness and chemoresistance of breast cancer cells through STAT3 activation: implications in breast cancer health disparity [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 949. doi:10.1158/1538-7445.AM2017-949
Abstract 2235: Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese and diabetic mice
Authors: Yohei Shirakami, Koki Obara, Masaya Ohnishi, Takayasu Ideta, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima
Journal: Cancer Research (2017)

Abstract Obesity, diabetes mellitus, and their related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Sodium glucose cotransporter (SGLT)-2 inhibitors, recently approved anti-diabetic agents, are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of the SGLT2 inhibitor tofogliflozin on the development of NAFLD-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The direct effects of tofogliflozin on human HCC cell proliferation were also evaluated. Male db/db mice were administered diethylnitrosamine-containing water for two weeks and were treated with tofogliflozin throughout the experiment. Tofogliflozin was kindly provided by Kowa Co., Ltd. and the chemical structure will be disclosed at the time of presentation at the meeting. In mice treated with tofogliflozin, the development of hepatic pre-neoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the NAFLD activity score, in comparison to those in the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of SGLT2 protein-expressing HCC cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and NAFLD-related liver carcinogenesis by attenuating chronic inflammation and steatosis in the liver, while the agent had no significant direct effect on the proliferation of HCC cells. Therefore, SGLT2 inhibitors may have a chemopreventive effect on obesity-related HCC. Citation Format: Yohei Shirakami, Koki Obara, Masaya Ohnishi, Takayasu Ideta, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese and diabetic mice [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 2235. doi:10.1158/1538-7445.AM2017-2235
Abstract 5848: Fucoidan adminstration attenuates radiation pneumonitis and fibrosis through reducing inflammatory cytokine expression in lung tissue
Authors: Szu-Yuan Wu
Journal: Cancer Research (2017)

Abstract Purpose: There is no well-known compound to prevent radiation pneumonitis (RP) or prophylactically use to attenuate the toxicity of RP. RP is one of major complications in chest part irradiation and limitations of radiation dose. Fucoidan is a sulfated polysaccharide found mainly in various species of brown algae and brown seaweed. Recent studies have demonstrated its anti-inflammation effect. Since RP is an radiation induced inflammatory and fibrosis related complication, we investigated the effect of fucoidan adminstration on radiation pneumonitis and fibrosis. Materials and Methods: In this study, we compared the pneumonitis and fibrosis in lung tissue specimen between the lungs irradiated (10Gy/one shot) C57BL/6 mice with or without Fucoidan adminstration (200mg/kg /day, oral gavage for 14 days). Results: The results demonstrated that fucoidan adminstration attenuates pneumonitis and fibrosis in lung tissue. We found the accumulation of neutrophils in irradiated lung tissue was decreased, and the radiation induced Masson trichrome staining fibrosis was decreased. We also investigate the inflammatory -cytokine profiles in the irradiated lung tissue by protein array. The results revealed that fucoidan adminstration changes the inflammatory -cytokine expression pattern in in the irradiated lung tissue. Conclusions: This study demonstrated that inflammatory -cytokine expression after whole lung irradiation is correlated with neutrophil accumulation and radiation induced fibrosis. Interestingly, Fucoidan adminstration changes the inflammatory -cytokine expression pattern which may lead to attenuates radiation pneumonitis and fibrosis. It is potential to be a therapeutic molecular to attenuate or prevent radiation pneumonitis. Note: This abstract was not presented at the meeting. Citation Format: Szu-Yuan Wu. Fucoidan adminstration attenuates radiation pneumonitis and fibrosis through reducing inflammatory cytokine expression in lung 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 5848. doi:10.1158/1538-7445.AM2017-5848
Carcinogenic Potency of Stilbestrol and Estrone in Strain C&lt;sub&gt;3&lt;/sub&gt;H Mice
Authors: Michael B. Shimkin, Hugh G. Grady
Journal: JNCI Journal of the National Cancer Institute (1940)

Carcinogenic Potency of Stilbestrol and Estrone in Strain C3H Mice Get access Michael B. Shimkin, Michael B. Shimkin assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Hugh G. Grady Hugh G. Grady research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 1, 1940-1941, Pages 119–128, https://doi.org/10.1093/jnci/1.1.119 Published: 01 August 1940
Abstract 1718: RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell carcinoma
Authors: Martha Zavridou, Areti Strati, George Koutsodontis, Amanda Psyrri, Evi Lianidou
Journal: Cancer Research (2017)

Abstract Background: Molecular characterization of circulating tumor cells (CTCs) is very challenging since these cells are rare, and the amount of available sample for their analysis is very limited. Moreover, CTC are highly heterogeneous and enrichment technologies based on EpCAM expression present the risk of missing EpCAM-negative CTCs. The Parsortix system (ANGLE plc, UK), is a novel microfluidic technology platform designed for marker-independent capture of CTCs. In this study we used for the first time the Parsortix system to isolate CTCs from patients with Head and Neck Squamous Cell carcinoma (HNSCC), and proceeded to downstream molecular characterization through RT-qPCR gene expression analysis. Methods: Peripheral blood samples (10 mL) from head and neck squamous cell carcinoma (HNSCC) patients (n=19) and healthy donors used as a control group (n=10) were used for the isolation of CTCs using the Parsortix device. Enriched CTCs were harvested in Trizol reagent, followed by extraction of total RNA and cDNA synthesis. RT-qPCR was performed in the LightCycler (Roche) for the following gene targets: PD-L1, VIM, TWIST, EGFR, and B2M (used as a reference gene). The expression levels of PD-L1, VIM, TWIST and EGFR were normalized using the 2-ΔΔCt approach in respect to the expression of B2M. Results: All samples analyzed were of excellent RNA quality as this was evaluated by B2M expression. According to our results, PD-L1 overexpression was detected in 5/19(26.3%) samples, VIM was overexpressed in 3/19 (15.7%) and TWIST-1 in 1/19 (5.3%) sample, while EGFR expression was not detected in any patient (0/19, 0%). These are preliminary results and these percentages may change, since the number of samples that we are analyzing is continuously increasing. Conclusions: This preliminary study is showing for the first time that RT-qPCR can be successfully used for the molecular characterization of CTCs isolated by the label-free Parsortix microfluidic device in HNSCC. Overexpression of individualized immunotherapy important biomarkers such as PD-L1 in CTCs of HNSCC patients could be of significant clinical importance for the selection and follow up of these patients. Citation Format: Martha Zavridou, Areti Strati, George Koutsodontis, Amanda Psyrri, Evi Lianidou. RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell carcinoma [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 1718. doi:10.1158/1538-7445.AM2017-1718
Abstract 2743: Comparison of enhanced Tagged-Amplicon Sequencing and digital PCR for circulating tumor DNA analysis in advanced breast cancer
Authors: Isaac Garcia-Murillas, Matthew Beanney, Michael Epstein, Karen Howarth, Andrew Lawson, Sarah Hrebien, Emma Green, Nitzan Rosenfeld, Nick Turner
Journal: Cancer Research (2017)

Abstract Background Circulating tumor DNA (ctDNA) analysis allows non-invasive detection of tumor mutations and amplifications in advanced breast cancer. Multiple technologies have been developed to analyse ctDNA and here we compared two leading ctDNA detection technologies, enhanced Tagged-Amplicon Sequencing™ (eTAm-Seq™) and digital PCR (dPCR) assays, in advanced breast cancer. Methods We recruited a cohort of 35 women with advanced breast cancer, of whom 23 had two separate blood samples taken in a standard EDTA tube processed immediately or in preservative Streck tubes processed up to 120 hours after venipuncture. Digital PCR was conducted with assays for hotspot actionable mutations in 3 known drivers in breast cancer: PIK3CA exon 9 and 20, ESR1 ligand binding domain and AKT1 (c.49G&amp;gt;A; p.E17K), and ctDNA sequencing was conducted with eTAm-Seq method using a 35-gene panel including cancer hotspots, entire coding regions and copy number variants (CNVs). Results Across both assays, 37 mutations were detected in 35 patients, with PIK3CA mutation in 13 patients (37%), ESR1 mutations in 10 patients (29%), and no AKT1 mutations. ESR1 mutations were polyclonal in 8 patients, with ctDNA eTAm-Seq method revealing substantially more diversity in mutations, with up to 8 individual mutations detected in a patient. There was 96.15% agreement for PIK3CA mutation detection between assays (Kappa 0.89, 95% CI 0.743 to 1.000), 100% agreement for ESR1 mutations (Kappa 1.00, 95% CI 1.000 to 1.000). There was very high correlation in mutation allele frequency between eTAm-Seq and dPCR (r=0.93, 95%CI 0.86 to 0.96, p&amp;lt;0.0001). The sensitivity and specificity for HER2 amplification detection by eTAm-Seq was 100% compared to tumor HER2 status. Comparison of immediate processing and Streck tubes revealed 97.92% agreement (Kappa 0.95, 95% CI 0.868 to 1.000) for mutation calling. Conclusions This study demonstrates that ctDNA analysis using eTAmSeq and dPCR have very high agreement in mutation detection in patients with advanced breast cancer patients. Streck tubes present a robust alternative to immediate processing of samples. eTAm-Seq and digital PCR have high clinical validity in mutation detection. Citation Format: Isaac Garcia-Murillas, Matthew Beanney, Michael Epstein, Karen Howarth, Andrew Lawson, Sarah Hrebien, Emma Green, Nitzan Rosenfeld, Nick Turner. Comparison of enhanced Tagged-Amplicon Sequencing and digital PCR for circulating tumor DNA analysis in advanced 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 2743. doi:10.1158/1538-7445.AM2017-2743
Abstract 4311: Targeting specific regulatory subunits of protein phosphatase 1 phenocopies estrogen-induced apoptosis
Authors: Catherine Sevigny, Surojeet Sengupta, Kerrie B. Bouker, Robert Clarke
Journal: Cancer Research (2017)

Abstract The growth of estrogen receptor positive (ER+) breast cancers is considered to be dependent on estrogen and its actions can be blocked by selective estrogen receptor modulators (SERMS), like tamoxifen, or by inhibiting the synthesis of estrogen, by aromatase inhibitors (AIs). Both of these classes of drug are used to treat ER+ breast cancers in the clinic. Paradoxically, before the discovery of SERMs and AIs, high dose estrogen was the choice of endocrine therapy to treat post-menopausal breast cancers. Recent clinical trials have confirmed a 30% clinical benefit rate with high, as well as low, doses of estrogen therapy in AI- resistant breast cancers. However, the underlying mechanism by which estrogen triggers the tumor regression remains unknown. Using an in vitro cell model MCF7:5C cells, that undergo estrogen-induced apoptosis, we demonstrate that sustained phosphorylation of eukaryotic initiation factor 2-alpha (eIF2-α), a downstream target of PERK activation, is crucial in estrogen-induced apoptosis. Growth arrest and DNA damage inducible-34 (GADD34) and constitutive repressor of eIF2α phosphorylation (CReP) are two regulatory subunits of protein phosphatase 1 (PP1) complex, that provides substrate specificity towards eIF2α, and are responsible for its de-phosphorylation. Our results show that pharmacological inhibition of GADD34 and CReP, or their genetic depletion, can enhance the phospho-eIF2α (p-eIF2α) levels and promote apoptosis. Elevated levels of p-eIF2α attenuated global translation but preferentially allowed high expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) that are involved in apoptosis. Both estrogen and inhibition of GADD34 and CReP promote apoptosis by an identical mechanism. Importantly, inhibition of GADD34 and CReP induced apoptosis in another estrogen-independent breast cancer cell line, LCC9, which is resistant to both tamoxifen and fulvestrant but does not undergo estrogen mediated apoptosis. Overall, our study provides crucial evidence that inhibiting specific regulatory subunits (GADD34 and CReP) of PP1 complex, can mimic estrogen-induced apoptosis in breast cancer cells that are not susceptible to estrogen mediated apoptosis. Therefore, GADD34 and CReP can be targeted for potential therapeutic intervention in endocrine therapy resistant breast cancers. Citation Format: Catherine Sevigny, Surojeet Sengupta, Kerrie B. Bouker, Robert Clarke. Targeting specific regulatory subunits of protein phosphatase 1 phenocopies estrogen-induced apoptosis [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 4311. doi:10.1158/1538-7445.AM2017-4311
Abstract 559: Estimation of immune cell content in bulk tumour tissue using reference profiles from single-cell RNA-seq data
Authors: Max Schelker, Jinyan Du, Sonia Feau, Edda Klipp, Birgit Schoeberl, Gavin MacBeath, Andreas Raue
Journal: Cancer Research (2017)

Abstract Although therapeutics that modulate the immune system provide remarkable benefit for many cancer patients, predicting who will respond remains an unsolved problem. As interactions between the immune system and cancer are governed by a complex network of cell-cell interactions, knowing the specific immune cell composition of a solid tumour may be essential in predicting response to immunotherapy. Here, we describe how to derive the cellular composition of a solid tumour from bulk gene expression data by mathematical deconvolution, using consensus cell type-specific gene expression profiles from recently published tumour-derived single-cell RNA sequencing data. Notably, successful deconvolution depends on these new data, as previously-available profiles from peripheral blood are insufficient. The presented method makes the problem of obtaining a patient’s tumour immune cell composition from existing databases like The Cancer Genome Atlas as well as in the clinical setting computationally tractable. Citation Format: Max Schelker, Jinyan Du, Sonia Feau, Edda Klipp, Birgit Schoeberl, Gavin MacBeath, Andreas Raue. Estimation of immune cell content in bulk tumour tissue using reference profiles from single-cell RNA-seq data [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 559. doi:10.1158/1538-7445.AM2017-559
Abstract 2352: Effect of inhibition of cell cycle versus transcription cyclin-dependent kinases (CDKs) in ovarian cancer cells
Authors: Rosaria Chilà, Nicolò Panini, Eugenio Erba, Giovanna Damia, Massimo Broggini
Journal: Cancer Research (2017)

Abstract Background. Cell cycle is regulated by cyclin-dependent kinases (CDKs) activity, whose deregulation can lead to uncontrolled proliferation and cancer. Other CDKs are engaged in the regulation of transcription and post-transcriptional mRNA processing through the phosphorylation of the C-terminal domain of RNA polymerase II, such as CDK9 and CDK12. Inhibitors of cell cycle CDKs have been developed as anticancer agents and some of them are under clinical validation (e.g. palbociclib). While recent data would suggest that inhibition of CDK9 is feasible and has antitumor effect, the data on the therapeutic role of CDK12 inhibition are very scanty. Methods. Ovarian cancer cell lines were maintained in RPMI medium supplemented with 5% glutamine and 10% FBS. Cells were treated with different drug concentrations and after 72 hours cell survival was evaluated by MTS assay (Promega). IC50 values were calculated by interpolation method. Cell cycle analysis and apoptosis were performed with standard flow cytometric methods. A2780 and SKOV3 ovarian cancer cell lines knocked out for CDK12 were generated with CRISPR/CAS9 genome editing tool. Results. The cytotoxicity of palbociclib (a CDK4/6 inhibitor) and LDC000067 (a CDK9 inhibitor) was tested in a panel of ovarian cancer cell lines (A2780, SKOV3, OVCAR3, OVCAR5, OVCAR8, OVCA432, OVCA433, IGROV1, EFO27). Sensitivity of cells was similar for palbociclib and LDC000067, ranging from 10 to 33 and from 8 to 60 μM, respectively. A preferential G1 block was observed with palbociclib, while LDC000067 caused a S-G2 block. A higher induction of apoptosis was observed after LDC000067 than after palbociclib treatment in both A2780 and SKOV3. The palbociclib-induced G1 block was associated with decreased Rb phosphorylation, while no modulation of the Ser2 in the carboxyterminal domain of RNA polymerase II was observed after LDC000067 treatment. We generated CDK12 knocked out cells transfecting CRISPR/CAS9 engineered plasmid in both A2780 and SKOV3 ovarian cancer lines. The biological and pharmacological characterization of these clones is under study. Conclusions. Palbociclib and LDC000067 showed a dose dependent cytotoxic effect in the panel of ovarian cancer cell lines tested and were active in the μM range. Preliminary data of treatment induced cell cycle perturbation and apoptosis suggest that the two drugs behave in a different manner and have distinct molecular effects on cells. Citation Format: Rosaria Chilà, Nicolò Panini, Eugenio Erba, Giovanna Damia, Massimo Broggini. Effect of inhibition of cell cycle versus transcription cyclin-dependent kinases (CDKs) in ovarian 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 2352. doi:10.1158/1538-7445.AM2017-2352