tbuckley/cabot-search huggingface dataset:
Abstract 4486: Redox regulation of the biosynthesis of mitronic tsmiR miR6855 in the basal like breast cancer cells
Authors: Smita Misra, Gautam Chaudhuri
Journal: Cancer Research (2017)

Abstract Radiation and chemotherapeutic agents eradicate tumors by inducing irreparable DNA damage. However, cancer cells often develop resistance to therapy by manipulating the DNA repair machinery. Conversely, a dividing cell constantly exposed to environmental and endogenous DNA damaging agents can transform into a tumor due to incorrect repair. Therefore the expression level of DNA repair proteins is critical both for cancer therapy and tumorigenesis. Our preliminary studies implied a unique mechanism involving an miRNA miR-6855-3p that promotes the biosynthesis of the transcriptional regulator protein SPRDX5 which enhances the expression of the tumor suppressor protein BRCA2 leading to the genotoxin and radiation-resistance of aggressive SLUG-high basal-like breast cancer (BLBC) cells. The miRNA miR-6855-3p thus acts as a tumor suppressor miRNA (tsmiR). Interestingly, the gene for the miRNA miR-6855-3p is mitronic and is nested within the intron#13 of the USP20 gene which is a deubiquitinase. Thus, the transcription of miR-6855-3p gene is regulated through the USP20 gene promoter. We present evidence here that USP20 and miR-6855 gene transcriptions are up regulated by oxidative stress. Tert-butylhydroperoxide was used for oxidative stress. Under the oxidative stress conditions tested, NRF2 level and the levels of several NRF2-regulated proteins are increased, indicating activation of NRF2 in the stressed BLBC cells. Under the stress conditions the levels of USP20 and miR-6855-3p are increased significantly. Knockdown of NRF2 prevented stress-induced elevation of USP20 and miR-6855-3p RNA level in the BLBC cells indicating the involvement of NRF2 in this process. The binding of NRF2 to the USP20 gene promoter and its function were characterized by ChIP analysis, site-directed mutagenesis and using the promoter-luciferase reporter constructs. We conclude that the biosynthesis of the tsmiR miR-6855-3p in the BLBC cells is regulated by oxidative stress and involves NRF2. Since oxidative stress is a hallmark in the etiology and progression of metastatic breast cancer, understanding the redox regulation of a tsmiR that positively influences BRCA2 gene expression in the BLBC cells could be clinically significant. Supported in part by DOD-CDMRP IDEA Expansion Grant# BC103645 and NIH/NCI grant 1R21CA181920-01 to GC and 1U54RR026140 to SM. Citation Format: Smita Misra, Gautam Chaudhuri. Redox regulation of the biosynthesis of mitronic tsmiR miR6855 in the basal like 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 4486. doi:10.1158/1538-7445.AM2017-4486
Abstract 3112: Roles of asialoglycoprotein receptor 2 in gastric cancer progression
Authors: Haruyoshi Tanaka
Journal: Cancer Research (2017)

Abstract Background Hepatic metastasis and relapse contribute to the high incidence of gastric cancer (GC)-related fatalities, and represent a frequent and crucial problem for oncologists. Knowledge of the unique molecular attributes to hepatic metastasis will improve our understanding of the biology of metastatic GC and facilitate development of specific biomarkers and appropriate targeted therapies, leading to efficacious personalized treatment. Methods Transcriptome and bioinformatics analyses were conduct to identify a candidate molecule that specifically mediate hepatic recurrences of GC. Small interfering RNA (siRNA) experiments to determine the effect of knockdown on phenotype. Expression levels of the candidate molecule was determined in the gastric tissues of 200 patients with GC. Results Asialoglycoprotein receptor 2 (ASGR2), a membrane trafficking protein, was identified as a candidate biomarker specific to hepatic metastasis. Transcription levels of ASGR2 were differential among GC cell lines and increased compared to a control nontumorigenic epithelial cell line. Inhibiting ASGR2 expression decreased the invasion and migration abilities of GC cells. Increased expression of ASGR2 mRNA in GC tissues was significantly associated with lymphatic involvement, vessel invasion, advanced stage and hepatic metastasis. In patient subgroup of stage II GC, those with increased ASGR2 expression had significantly shorter overall and disease-free survival than those without. Conclusions ASGR2 may represent a biomarker for hepatic metastasis of GC and as a target for therapy. Citation Format: Haruyoshi Tanaka. Roles of asialoglycoprotein receptor 2 in gastric cancer progression [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 3112. doi:10.1158/1538-7445.AM2017-3112
Abstract LB-023: STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin
Authors: Taiki Kida, Harry A. Rogoff, Chiang J. Li
Journal: Cancer Research (2017)

Abstract Cancer stem cells (CSCs) are considered to play an important role in cancer therapy resistance, metastasis, and recurrence. Wnt/β-catenin is one of key signaling pathways that confer cancer stemness properties to a portion of the heterogeneous cancer cell population. Dysregulation of the Wnt/β-catenin pathway may lead to accumulation of β-catenin and aberrant activation of its target gene transcription. However, it has been proven difficult to design a therapeutic targeting β-catenin. Identification of a drugguble target for the β-catenin pathway is highly desirable given the importance of β-catenin in promoting cancer stemness. Here, we demonstrate that Serine Threonine Kinase 17A (STK17A), a novel member of the death-associated protein family of serine/threonine kinases, promotes cancer stemness phenotypes via β-catenin. Over-expression of STK17A resulted in increased anchorage-independent spherogenesis and invasive phenotype of cancer cells, whereas STK17A gene silencing reduced these malignant phenotypes. Overexpression of STK17A led to increased transcriptional activity of β-catenin and upregulation of its target genes. These changes were accompanied by increased phosphorylation of β-catenin at ser675. Cell-free in vitro kinase assay revealed that STK17A directly phosphorylates β-catenin at ser675 in an ATP-dependent manner. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness kinase inhibitor, was found to potently inhibit STK17A, leading to inhibition of β-catenin phosphorylation at ser675. These results suggest that inhibition of STK17A is a promising approach for targeting cancer stemness. Citation Format: Taiki Kida, Harry A. Rogoff, Chiang J. Li. STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin [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 LB-023. doi:10.1158/1538-7445.AM2017-LB-023
Abstract 3731: A novel multidimensional cfDNA assay for real time analysis of chemotherapy response
Authors: Pavan P. Shah, Katherin Patsch, Naim Matasci, Anjana Soudararajan, Patricia Diaz, David B. Agus, Daniel Ruderman, Mitchell E. Gross
Journal: Cancer Research (2017)

Abstract Due to its non-invasive nature and transient lifespan (~30 mins), circulating cell free DNA (cfDNA) may provide novel insights into cancer evolution and response to therapy. Here, we have developed a multidimensional cfDNA assay to measure patients’ responses to chemotherapy on a time scale that would be impossible using traditional biopsy methodologies. We extracted cfDNA from plasma collected immediately before and after infusion of cytotoxic chemotherapy, and 24 hours after treatment. We developed assays to (1) quantify cfDNA via qPCR of a 288 base pair amplicon of Long Interspersed Nuclear Elements (LINE1), (2) determine the DNA Integrity Index based on additional analysis of 115bp and 516bp LINE1 amplicons, and (3) analyze androgen receptor exon 8 via targeted deep sequencing. We analyzed cfDNA extracted from 17 patients with metastatic castration-resistant prostate cancer through sequential application of these 3 assays. Median PSA levels were 69 (0-2223) ng/dl, Hgb 12 (8.2-15) g/L, Alk Phos 117 (35-879) IU/mL. Deep sequencing of AR exon 8 revealed 6 of the 17 patients presented with 1-2 SNVs (H874Y, T877A, D890H or D879Y) at ≥1% frequency. Considering LINE1 quantification alone, the average change pre/post chemotherapy was 38.78 pg/mL (0.5-292.0 pg/mL). A variety of responses was noted including: 8 of the patients expressed elevated LINE1 levels post-treatment when compared to baseline, and 5 expressed depressed levels. Importantly, therapy did not affect tumor subclones equally, as demonstrated by sequencing and quantitation of mutant AR exon 8 species. Additional data on changes in DNA Integrity Index will be presented. We conclude that cytotoxic chemotherapy produces immediately observable effects on cfDNA. The effect of docetaxel chemotherapy on distinct clones within the tumor can be measured within hours. Now that a short-time dynamics response has been demonstrated, follow up studies will be performed involving more patients to determine the prognostic value. Citation Format: Pavan P. Shah, Katherin Patsch, Naim Matasci, Anjana Soudararajan, Patricia Diaz, David B. Agus, Daniel Ruderman, Mitchell E. Gross. A novel multidimensional cfDNA assay for real time analysis of chemotherapy response [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 3731. doi:10.1158/1538-7445.AM2017-3731
Abstract 320: Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects
Authors: Xi Qiao
Journal: Cancer Research (2017)

Abstract Transcription factor MYC is a driver of many human cancers due to its widespread effects on gene expression. An understanding of the mechanisms determining MYC’s transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage-induced proliferation. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells or general well-being of the mice. Meanwhile, in breast cancer cells, CIP2A depletion was shown to inhibit the MYC serine 62 phosphorylation, MYC-mediated gene expression, and anchorage-independent growth. Furthermore, CIP2A supports MDA-MB-231 xenograft growth in nude mice. Therefore, results of these studies collectively suggest for a novel opportunity to target MYC’s function in MYC- driven cancers via CIP2A, and without detrimental physiological effects. Citation Format: Xi Qiao. Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects [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 320. doi:10.1158/1538-7445.AM2017-320
“Save or Create”: The Practical Asymmetry of Judgment Training in Decision Making in Neonatology–When Basic Desires Clash With Preparation to Act
Authors: Michael R. Gomez
Journal: The American Journal of Bioethics (2017)

Humans have a basic desire to procreate and use a complex social structure to encourage protection and nurturing of their offspring to be fruitful and successful, creating an incentive to repeat th...
Abstract 5541: Identification of sod and sod2 as potential prognostic biomarkers for patients with non-small cell lung cancer
Authors: Chen Yin, Ren Wang, Xiao-xing Li, Yang Yang, Mei-yin Zhang, Hui-Yun Wang, Steven X. Zheng
Journal: Cancer Research (2017)

Abstract Backgrounds: Reactive oxygen species (ROS) is accumulated in cancer cells related to increased metabolism, which is characteristic of cancer progression. With the rapid advance of cancer research, redox regulation has drawn more and more attentions. The superoxide dismutases SOD1 and SOD2 are essential enzymes for eliminating ROS. To date, SOD1 or SOD2 have not been well characterized in non-small cell lung cancer(NSCLC). Here we compared the expression of SOD proteins between normal and cancer tissues and investigated its prognostic significance in NSCLC patients. Method: we detected the expression of SOD1 and SOD2 in 178 NSCLC samples by immunohistochemistry and their clinical significances were analyzed. Western blotting is used to confirm the protein level of SOD1 and SOD2 in the normal and cancer tissues of NSCLC patients. Results: The expression of SOD1 and SOD2 is significantly higher in both adenocarcinoma or squamous cell carcinoma (p&amp;lt;0.0001), compared to matched adjacent normal tissues. Correlation analysis indicates that SOD1 expression is reversely associated with TNM stage, and SOD2 is negatively correlated with tumor size, tumor number and TNM stage remarkably (all p &amp;lt;0.05). Moreover, higher expression of SOD1 and SOD2 is correlated with better prognosis of NSCLC patients. Finally, Univariate and multivariate Cox regression modes further indicate that SOD1 and SOD2 can be used as independent prognostic factors in NSCLC patients. Conclusion: Higher expressions of SOD1 and SOD2 in NSCLC tissues are observed compared to adjacent tissues and indicate better prognosis, suggesting that SOD proteins are potentially useful biomarkers for prognostic evaluation of patients with NSCLC. Key Words: Reactive oxygen species; Non-small cell lung cancer; Superoxide dismutase 1/2; Prognosis. Citation Format: Chen Yin, Ren Wang, Xiao-xing Li, Yang Yang, Mei-yin Zhang, Hui-Yun Wang, Steven X. Zheng. Identification of sod and sod2 as potential prognostic biomarkers for patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2017-5541
Abstract 603: Evaluation of CD19 targeted T cells in relapsed or refractory ALL patients unable to afford allogenic bone marrow transplant in India
Authors: Alka Dwivedi, Sushant Kumar, Terry Fry, Gaurav Narula, Rahul Purwar
Journal: Cancer Research (2017)

Abstract CAR-T cell therapy has demonstrated remarkable success in long-term remission of relapsed or refractory B-ALL. Unlike western countries, most of the relapsed/refractory B-ALL patients in India are unable to afford allogeneic stem cell transplant (allo-SCT), and simply choose palliation. To assess the potential use of CAR-T cells as a first line therapy, it is critical to evaluate CAR-T cell efficacy in patients unable to undergo allo-SCT. As a first step, a novel anti-CD19 CAR was designed and CD19-vector was produced using lentiviral mediated gene delivery system. To generate CD19+CAR T cells, T cells from healthy subjects were transduced and expanded either with rIL-2 or rIL-15. Almost 20-50% transduced T cells express CD19-CAR on their surface as analysed by flow cytometry. Next, efficacy of CD19-CAR-T cells was examined by cytotoxicity assay using CD19+ malignant B cell lines (Raji cells) and autologous B cells. CAR-T cells were able to kill majority of CD19+B cells effectively (100% killing). In addition, CAR-T cells secreted high levels of IFNΓ and IL-2. The CAR-T cells expanded in presence of rIL-15 showed fewer Treg compared to CAR-T cells expanded using rIL-2, however, there were no differences in numbers of T stem cells (TSC) and central memory T cells (TCM). In addition to data on healthy volunteers reflected above, results of above tests in relapsed/ refractory B-ALL patients is ongoing and being collated for inclusion in the final analysis. In conclusion, our data demonstrate the successful development of an indigenous CAR-T cell platform for subsequent use in clinical trials of CD19+B cell malignancies. Citation Format: Alka Dwivedi, Sushant Kumar, Terry Fry, Gaurav Narula, Rahul Purwar. Evaluation of CD19 targeted T cells in relapsed or refractory ALL patients unable to afford allogenic bone marrow transplant in India [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 603. doi:10.1158/1538-7445.AM2017-603
Abstract 4554A: Simple, efficient, and quantitative approach for determination of synergism, additive effect, and antagonism of drugs <i>in vivo</i> using combination index method: a proposition for clinical protocol design and regulatory synergy claims
Authors: Jianing Fu, Ting-Chao Chou
Journal: Cancer Research (2017)

Abstract Based on the systematic dynamic rate derivations with the mass-action principle and mathematical induction-deduction, the median-effect equation of Chou, and the combination index (CI) equation and their algorithm allow quantitative determination of synergism (CI&amp;lt;1), additive effect (CI=1) and antagonism (CI&amp;gt;1) (Pharmacol Rev 58:621-681, 2006). Based on Google Scholar Citations, the CI simulation has been cited 7,712 times in &amp;gt;800 bio-medical journals as of 10.19.2016. However, most citing papers were with experiments in vitro, relative few in vivo and rarely in clinical trials. This is despite the fact that the CI method equation, algorithm, and the CompuSyn software are the same for in vitro and in vivo, although the practical aspects such as sample size, time and cost, the readiness of the end-point measurement, and the ethical considerations are different. Our recent publication (in Fu J et al. Synergy 3: 15-30, 2016) of two-drug combination (docetaxel and T-607 compound, 1:2) against HCT-116 colon carcinoma xenograft in nude mice has demonstrated very desirable synergy. We now illustrate the experimental and data-analytical details of the experimental planning and design, execution, measurements, for docetaxel and T-Compound combination against MX-1 mammary carcinoma xenograft in nude mice. Treatment Q3Dx4 i.v. starting Day 7, and the tumor sizes and bodyweight changes measured on Days 16, 19, and 22. A total of 50 nude mice were used (each drug and combinations, 3 doses each (n=5) plus a control group of 5). Full spectrum of synergism (CI=0.79 to 0.93) were observed on Days 19 and 22. Automated simulation were carried out for dose-effect curve, ME plot, Fa-CI plot, isobologram, and Fa-DRI (Dose-Reduction Index) plot with CompuSyn software (Free download available upon registration via www.combosyn.com). This simple, efficient, “econo-green” bio-research paves the way for drug combination clinical trial design and regulatory synergy claims. Citation Format: Jianing Fu, Ting-Chao Chou. Simple, efficient, and quantitative approach for determination of synergism, additive effect, and antagonism of drugs in vivo using combination index method: a proposition for clinical protocol design and regulatory synergy claims [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 4554A. doi:10.1158/1538-7445.AM2017-4554A
Abstract 1505: Breast cancer cells treated with mitochondria targeted redox active agents induce mitophagy
Authors: Thomas Biel, Ashutosh Rao
Journal: Cancer Research (2017)

Abstract Triphenylphosphonium (TPP) conjugated agents induce mitochondrial dysfunction in cancer cells. However, the onset of mitophagy to remove the dysfunctional mitochondria is unknown. Here, a series of mitochondria targeted redox active agents (MTA) that contain TPP were used to investigate mitochondrial dysfunction and mitophagy in MDA-MB-231 cells as compared to MCF-12A cells. Three different MTAs were identified to induced mitochondrial depolarization and enhanced autophagic flux selectively in MDA-MB-231 cells. Mitochondrial reactive oxygen species generation and respiration indicated that MDA-MB-231 cells had a heighten sensitivity to MTA treatments. Using stably expressing mt-mKeima MDA-MB-231 and MCF-12A cell lines, a non-cell type selective decline in mitochondrial alkalinity and altered mitochondrial morphology was detected. Furthermore, FACS analysis of mt-mKeima revealed MTAs induced lysosomal dependent mitochondrial degradation in the presence of Bafilomycin, a lysosomal inhibitor. To confirm MTAs induced mitochondrial autophagy in MDA-MB-231 cells, MitoTracker Red preloaded GFP-LC3 expressing MDA-MB-231 cells were used to identify autophagosomes containing mitochondria using confocal microscopy, in addition to coimmunoprecipitation for the detection of an endogenous autophagy-related protein complex, and immunoblot to for mitochondrial PINK1 accumulation. To translate these in vitro studies to an in vivo rat SST-2 xenograph breast cancer model, tumor mitochondrial extracts from rats treated with MitoQ demonstrated an accumulation of mitochondrial PINK1. Collectively, these data suggest that mitochondrial agents selectively caused mitochondrial depolarization, PINK1 accumulation and mitophagy in MDA-MB-231 cancer cells as compared to MCF-12A healthy cells. Citation Format: Thomas Biel, Ashutosh Rao. Breast cancer cells treated with mitochondria targeted redox active agents induce mitophagy [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 1505. doi:10.1158/1538-7445.AM2017-1505