tbuckley/cabot-search huggingface dataset:
Abstract 3937: Diversity index as a novel predictor of tumor progression in breast cancer
Authors: Yul Ri Chung, Hyun Jeong Kim, Young A Kim, Mee Soo Chang, Ki-Tae Hwang, So Yeon Park
Journal: Cancer Research (2017)

Abstract Intratumoral genetic heterogeneity leads to tumor progression and therapeutic resistance. However, due to the difficulty associated with its assessment, application of intratumoral genetic heterogeneity as a prognostic or predictive marker is limited. We investigated the significance of Shannon diversity index as a tool for measuring genetic heterogeneity by performing fluorescence in situ hybridization of c-Myc gene in invasive breast cancers, and correlated the Shannon diversity index for c-Myc copy number variation with clinicopathologic features of tumor including patient survival. Shannon index for c-Myc copy number variation strongly correlated with average c-Myc copy number and was significantly higher in tumors with c-Myc genetic or regional heterogeneity than in those without c-Myc amplification. High Shannon index was associated with high histologic grade, lymphovascular invasion, p53 overexpression, high Ki-67 proliferation index, hormone receptor negativity, and HER2 amplification. In survival analyses, c-Myc amplification or c-Myc copy number gain was not associated with patient survival. However, a high level of Shannon index was associated with poor disease-free survival. In subgroup analyses, it was found to be an adverse prognostic factor in hormone receptor-positive group, but not in hormone receptor-negative group. In a validation set, high Shannon diversity index for c-Myc copy number variation was also found to be associated with poor survival of the patients. We further investigated the correlation with clinicopathologic features and predictive power of Shannon index using another gene, fibroblast growth factor receptor 1 (FGFR1) and observed that high Shannon index for FGFR1 gene copy number variation was an independent prognostic factor for poor clinical outcome in a whole group and in hormone receptor-positive subgroup. In conclusion, this study demonstrated that higher diversity index was associated with adverse pathologic parameters of breast cancer and poor clinical outcome suggesting that Shannon diversity index, which represents intratumoral genetic heterogeneity, can be used as a potential biomarker for tumor progression and prognostication in patients with breast cancer. Citation Format: Yul Ri Chung, Hyun Jeong Kim, Young A Kim, Mee Soo Chang, Ki-Tae Hwang, So Yeon Park. Diversity index as a novel predictor of tumor progression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3937. doi:10.1158/1538-7445.AM2017-3937
Abstract 2131: Tanshinone IIA can decrease growth factor receptors expression and dural-block both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways to inhibit human breast cancer BT-20 cells
Authors: Chin Cheng Su
Journal: Cancer Research (2017)

Abstract Background : Tanshinone IIA (Tan-IIA, C19H18O3) with anti-inflammatory activities and antioxidant properties, is one of the diterpine quinones extracted from Salviae miltiorrhizae radix (Danshen). Tan-IIA can inhibit many human cancer cell lines through different molecular mechanisms. The phosphoinositide-3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Transmembrane tyrosine kinase has been strongly implicated in the proliferation, survival, and metastasis of human tumors. Both pathways represent important signal transduction mechanisms that facilitate the proliferation and survival of cancers driven by growth factor receptors, such as vascular endothelial growth factor receptor (VEGFR), insulin-like growth factor-I receptor (IGF-IR), or epidermal growth factor receptor (EGFR). Targeting both the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR Pathways for suppressing inhibitor resistant cells is necessary because the individual downstream components of these signaling cascades either through epigenetic modification or somatic mutation are also known to be frequently altered in cancer, thus contributing to resistance to anticancer therapies and tumorigenesis. Material and methods: In the present study, the human breast cancer BT-20 cells were treated with Tan-IIA in vitro. The cytotoxicity of Tan-IIA was evaluated by MTT assay. The effects of Tan-IIA on the protein expressions of EGFR, IGF-IR, VEGFR, PI3K, AKT, mTOR, Ras, Raf, MEK and ERK and β-actin in the BT-20 cells were examined by western blot analysis. Results: The results showed that Tan-IIA can induce the proliferation inhibition with time and dose dependent and inhibit the activity of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. In addition, it was showed that Tan-IIA treatment inhibited the protein expression levels of EGFR, VEGFR and IGF-IR significantly. Conclusions: These findings indicated that one of the molecular mechanisms for Tan-IIA to inhibit BT-20 cells maybe through inhibiting the protein expression levels of EGFR, VEGFR, IGF-IR and both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. The use of Tan-IIA for breast cancer may become a feasible novel therapy option. Further studies are warranted to elucidate its mechanisms fully. Citation Format: Chin Cheng Su. Tanshinone IIA can decrease growth factor receptors expression and dural-block both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways to inhibit human breast cancer BT-20 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 2131. doi:10.1158/1538-7445.AM2017-2131
Abstract 4389:TSC1/2mutations define a molecular subset of HCC with aggressive behavior and treatment implication
Authors: Daniel Wai Ho, Lo Kong Chan, Yung Tuen Chiu, Iris Ming Xu, Ronnie Poon, Tan To Cheung, Chung Ngai Tang, Victor Tang, Irene Lo, Polly Lam, Derek Yau, Miao Xin Li, Chun Ming Wong, Irene O. L. Ng
Journal: Cancer Research (2017)

Abstract We investigated the mutational landscape of mTOR signaling cascade in hepatocellular carcinomas (HCCs) with chronic hepatitis B (HBV) background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyper-activation in hepatocarcinogenesis. We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of TSC1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony formation assay in HCC cell lines and the treatment was further tested using our patient derived tumor xenograft (PDTX) models. Results: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n = 18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leading to more aggressive tumor behavior. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony forming ability upon Rapamycin treatment. With the use of the biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hyper-sensitivity towards Rapamycin treatment. Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyper-activation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signaling, with potential significance of effective specific drug therapy. Citation Format: Daniel Wai Ho, Lo Kong Chan, Yung Tuen Chiu, Iris Ming Xu, Ronnie Poon, Tan To Cheung, Chung Ngai Tang, Victor Tang, Irene Lo, Polly Lam, Derek Yau, Miao Xin Li, Chun Ming Wong, Irene O. L. Ng. TSC1/2 mutations define a molecular subset of HCC with aggressive behavior and treatment implication [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 4389. doi:10.1158/1538-7445.AM2017-4389
Abstract 4229: Metabolically active macrophages: A novel link between obesity and TNBC
Authors: Payal Tiwari, Kelly Schoenfelt, Ariane Blank, Chang Cui, Marsha Rich Rosner, Lev Becker
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) patients have an extremely poor prognosis due to their high metastatic potential and lack of targeted drug therapies. Emerging epidemiological data suggest that obesity is strongly linked to the incidence and severity of TNBC. However, mechanisms by which obesity potentiates TNBC progression are unclear. Adipose tissue macrophages (ATMs) are an attractive mechanistic link between obesity and TNBC because they are the predominant type of macrophage in the breast during early tumorigenesis and obesity causes accumulation of ATMs. However, during obesity, the macrophage phenotype was reported to switch from an apparent pro-tumorigenic M2-like phenotype to an apparent anti-tumorigenic M1-like phenotype. This result raises a paradox: how does obesity promote tumor progression if it activates an anti-tumorigenic macrophage phenotype? Here we show that metabolic dysfunction promotes a mechanistically distinct pro-inflammatory phenotype (metabolic activation; MMe) in breast adipose tissue macrophages isolated from obese women. These ATMs express cell surface markers of MMe (CD36, ABCA1) but not M1 (CD38, CD319, CD274) macrophages. We further demonstrate that pretreating TNBC cells with conditioned media derived from MMe but not M1 macrophages promotes mammosphere formation as well as invasion in vitro, and intravasation of cancer cells into the blood in vivo. Moreover, pre-treated cancer cells showed a two-fold increase in the expression of stem-like cell markers (OCT4, SOX2 and NANOG). Remarkably, we saw the same effect on ‘stemness’ of tumor cells in a spontaneous TNBC mouse model when fed a 60% high fat diet and a significant increase in tumor incidence in obese mice compared to lean mice in a syngeneic mouse model. We further show that blocking inflammatory cytokines expression in MMe(s) using genetic knockouts inhibits the ability of MMe(s) to promote both mammosphere formation and invasion. These findings suggest that obesity-induced changes to mammary adipose tissue reprogram macrophages to an MMe phenotype that potentiates TNBC initiation and metastasis via inflammatory cytokines. A comprehensive understanding of the signaling mechanism(s) involved in metabolic activation of mammary ATMs would enable development of directed therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact. Citation Format: Payal Tiwari, Kelly Schoenfelt, Ariane Blank, Chang Cui, Marsha Rich Rosner, Lev Becker. Metabolically active macrophages: A novel link between obesity and TNBC [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 4229. doi:10.1158/1538-7445.AM2017-4229
Abstract 5075: Phenotypic human tumor cell line profiling and predictive biomarker analysis for epigenetic inhibitors
Authors: Usha Warrior, Jesse J. Parry, Samantha C. Burkart, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Steven M. Garner, Timothy J. Sindelar, Charles R. Wageman, Alastair J. King
Journal: Cancer Research (2017)

Abstract In recent years, epigenetic target inhibitors have emerged as viable therapeutics for treating various types of cancers. Testing of the epigenetic inhibitors in cell proliferation assays revealed that inhibition of many epigenetic targets resulted in a significantly delayed drug response that is not revealed by conventional, 72-hour cell growth assays. OncoPanel LT™ from Eurofins Pharma Discovery Services is developed specifically for evaluation of compounds with a protracted mechanism of action, and consists of a large collection of cell lines with broad cancer type and subtype representation, and extensive genomic characterization. We have tested decitabine, a DNA methyltransferase inhibitor, panobinostat, a histone deacteylase inhibitor, GSK-343, an EZH2 inhibitor, GSK-J4, a JMJD3/UTX inhibitor, and JQ1, a BRD2/3/4 inhibitor in OncoPanel LT™. These epigenetic inhibitors were incubated for 10 days with more than 200 human tumor cell lines and the inhibition data were analyzed to determine IC50, EC50, and GI50 values. These inhibition data, as well as the genomic features of the cell lines, were utilized to perform univariate genomic analysis to identify predictive biomarkers of response. We will discuss the activity of compounds against this cell line panel, as well as statistically significant biomarkers of response, based on the univariate genomic analysis. Citation Format: Usha Warrior, Jesse J. Parry, Samantha C. Burkart, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Steven M. Garner, Timothy J. Sindelar, Charles R. Wageman, Alastair J. King. Phenotypic human tumor cell line profiling and predictive biomarker analysis for epigenetic 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 5075. doi:10.1158/1538-7445.AM2017-5075
Too few people have access to tests and treatment for hepatitis, says WHO
Authors: Sophie Cousins
Journal: BMJ (2017)

Although an increasing number of countries are invested in eliminating hepatitis, too few are taking action to test and treat people, the World Health Organization has said.

More than 70% of the 28 countries surveyed by WHO—which make up almost three quarters of the world’s hepatitis burden—have begun to develop plans to enable access to prevention, diagnosis, treatment, and services, new data have shown.

But while almost 90% of the countries surveyed—including Egypt, India, and South Africa—have set national hepatitis elimination targets, fewer than half are aiming for elimination by providing universal access to treatment.

The introduction of a short course of highly effective direct acting antivirals, such as sofosbuvir and velpatasvir, in 2014 transformed the treatment of …
Abstract 3473: Functional analysis of the KIF22 in human prostate cancer cells
Authors: Rina Sakamaki, Shungo Saito, Tatsuya Kitano, Tadashi Nittami, Jieun Seo, Akimitsu Takagi, Hitoshi Ishiguro, Hiroji Uemura, Masatoshi Watanabe
Journal: Cancer Research (2017)

Abstract In the previous study, we identified genes that were differentially expressed between monolayers and spheroids in prostate cancer cell lines. The KIF22 gene was extracted as one of candidate genes related with spheroid formation and multicellular resistance. KIF22 is one of the kinesin superfamily proteins that are microtubule-dependent molecular motor proteins with DNA-binding capacity. KIF22 plays an important role in eukaryotic cell mitosis and macromolecule transportation. Alteration of KIF22 expression and function may lead to cancer development and progression. In this study, we explored the function of the KIF22 in prostate cancer cell lines, DU145 and LNCaP using the KIF22 siRNA. The KIF22 mRNA levels in LNCaP and DU-145 monolayers were detected, and time-dependently increased in both spheroids. The inhibition of KIF22 mRNA using siRNA affected cell proliferation in DU145 and LNCaP spheroids as well as monolayers. In addition, this suppression caused G2/M arrest and apoptosis in both cell lines. In clinical samples, its mRNA expression was significantly higher in tumor portions than in non-cancerous portions. However, the inhibition of KIF22 mRNA did not affect cell migration and invasion in DU145 and LNCaP cells. These findings suggest that KIF22 may play an important role in prostate cancer proliferation, especially spheroid formation, and have the potential to be targeted for prostate cancer treatments such as combination therapy with docetaxel. Citation Format: Rina Sakamaki, Shungo Saito, Tatsuya Kitano, Tadashi Nittami, Jieun Seo, Akimitsu Takagi, Hitoshi Ishiguro, Hiroji Uemura, Masatoshi Watanabe. Functional analysis of the KIF22 in human prostate 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 3473. doi:10.1158/1538-7445.AM2017-3473
The IL-1R/TLR signaling pathway is essential for efficient CD8+ T-cell responses against hepatitis B virus in the hydrodynamic injection mouse model
Authors: Zhiyong Ma, Jia Liu, Weimin Wu, Ejuan Zhang, Xiaoyong Zhang, Qian Li, Gennadiy Zelinskyy, Jan Buer, Ulf Dittmer, Carsten J Kirschning, Mengji Lu
Journal: Cellular and Molecular Immunology (2017)

The outcome of hepatitis B viral (HBV) infection is determined by the complex interactions between replicating HBV and the immune system. While the role of the adaptive immune system in the resolution of HBV infection has been studied extensively, the contribution of innate immune mechanisms remains to be defined. Here we examined the role of the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling pathway in adaptive immune responses and viral clearance by exploring the HBV mouse model. Hydrodynamic injection with a replication-competent HBV genome was performed in wild-type mice (WT) and a panel of mouse strains lacking specific innate immunity component expression. We found higher levels of HBV protein production and replication in Tlr2−/−, Tlr23479−/−, 3d/Tlr24−/−, Myd88/Trif−/− and Irak4−/− mice, which was associated with reduced HBV-specific CD8+ T-cell responses in these mice. Importantly, HBV clearance was delayed for more than 2 weeks in 3d/Tlr24−/−, Myd88/Trif−/− and Irak4−/− mice compared to WT mice. HBV-specific CD8+ T-cell responses were functionally impaired for producing the cytokines IFN-γ, TNF-α and IL-2 in TLR signaling-deficient mice compared to WT mice. In conclusion, the IL-1R/TLR signaling pathway might contribute to controlling HBV infection by augmenting HBV-specific CD8+ T-cell responses.
Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit
Authors: M. L. North, M. J. Jones, J. L. MacIsaac, A. M. Morin, L. M. Steacy, A. Gregor, M. S. Kobor, A. K. Ellis
Journal: Allergy (2017)

Abstract Background Epigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis ( AR ). Our aim was to examine genome‐wide epigenetic changes induced by controlled pollen exposure in the environmental exposure unit ( EEU ). Methods 38 AR sufferers and eight nonallergic controls were exposed to grass pollen for 3 hours on two consecutive days. We interrogated DNA methylation at baseline and 3 hours in peripheral blood mononuclear cells ( PBMC s) using the Infinium Methylation 450K array. We corrected for demographics, cell composition, and multiple testing (Benjamini‐Hochberg) and verified hits using bisulfite PCR pyrosequencing and qPCR . To extend these findings to a clinically relevant tissue, we investigated DNA methylation and gene expression of mucin 4 ( MUC 4 ), in nasal brushings from a separate validation cohort exposed to birch pollen. Results In PBMC s of allergic rhinitis participants, 42 sites showed significant DNA methylation changes of 2% or greater. DNA methylation changes in tryptase gamma 1 ( TPSG 1 ), schlafen 12 ( SLFN 12 ), and MUC 4 in response to exposure were validated by pyrosequencing. SLFN 12 DNA methylation significantly correlated with symptoms ( P &lt; 0.05), and baseline DNA methylation pattern was found to be predictive of symptom severity upon grass allergen exposure ( P = 0.029). Changes in MUC 4 DNA methylation in nasal brushings in the validation cohort correlated with drop in peak nasal inspiratory flow (Spearman's r = 0.314, P = 0.034), and MUC 4 gene expression was significantly increased ( P &lt; 0.0001). Conclusion This study revealed novel and rapid epigenetic changes upon exposure in a controlled allergen challenge facility, and identified baseline epigenetic status as a predictor of symptom severity.
Abstract 358: LTB and LTBR mediates alternative Nf-kB activation through NIk and RELB/NF-kB2 to promote cell migration of HNSCC
Authors: Rita Das, Jamie Coupar, Anthony saleh, Paul E. Clavijo, Zhong Chen, Carter VanWaes
Journal: Cancer Research (2017)

Abstract Nuclear factor-κB (NF-κB) includes a family of NF-κB/REL transcription factors that regulate key inflammatory and cancer genes, and which are aberrantly activated in head and neck squamous cell carcinomas (HNSCC). Lymphotoxin beta/Lymphotoxin beta receptor (LTβ/LTβR) can mediate activation of the “alternative” NF-κB pathway that includes NF-κB-inducing kinase (NIK), Inhibitor-κB kinase α (IKKα), and transcription factors RELB/NF-κB2. While LTβ is expressed in lymph nodes where HNSCC spread, the role of this pathway in pathogenesis of HNSCC is not well studied. Analysis of The Cancer Genome Atlas (TCGA) data reveals that LTβR is amplified or overexpressed in larynx or oral cavity HNSCC, while LTα/β, NIK, (MAP3K14) and RELB are overexpressed in oropharynx and tonsil cancers. Similarly, we observed overexpression of LTβR, NIK, and RELB proteins in subsets of HNSCC cell lines. In UM-SCC46, LTβ enhanced nuclear translocation of RELB/NF-κB2 (p52) subunit proteins, while LTβR siRNA knockdown decreased the expression of its target kinase NIK and RELB/NF-κB2 (p52). NIK knockdown also decreased RELB/NF-κB2 (p52) protein expression, whereas LTβ treatment stabilized NIK, and RELB/NF-κB2 (p52). Functional LTβ-mediated NF-κB activation was examined using a stably transfected NF-κB reporter cell line for β-lactamase/Fret activity. Knockdown of LTβR and NIK decreased NF-κB activity, whereas treatment with LTβ partially restored it. Treatment with a NIK inhibitor (1, 3[2H, 4H]-Iso-Quinoline Dione) reduced the protein expression of NIK, IKKα, and RELB/NF-κB2 (p52) in the cytoplasm and/or in the nucleus, and blocked LTβ induced translocation of RELB to nucleus. NIK and RELB knockdown by siRNA or using NIK inhibitor slowed HNSCC migration. Knockdown of NIK inhibited the LTβ-induced expression of MET, and SERPINE1 genes involved in migration, and knockdown of MET by siRNA inhibited the migration of HNSCC cell lines. Our findings show that LTβ/LTβ receptor promotes activation of the alternative NIK-IKKa-RELB/NF-κB2 pathway, to enhance MET-mediated cell migration in HNSCC. This may help explain why HNSCC exhibit migration and metastasis to local lymph nodes, where LTβ is expressed. The constitutive and LTβ induced activation of NIK and downstream NF-κB alternate pathway proteins, RELB and NF-κB2/p52 could be therapeutic targets in HNSCC. (Supported by NIDCD intramural projects ZIA-DC-000016, 74) Citation Format: Rita Das, Jamie Coupar, Anthony saleh, Paul E. Clavijo, Zhong Chen, Carter VanWaes. LTB and LTBR mediates alternative Nf-kB activation through NIk and RELB/NF-kB2 to promote cell migration of HNSCC [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 358. doi:10.1158/1538-7445.AM2017-358