tbuckley/cabot-search huggingface dataset:
Abstract 2943: MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Authors: Srividya Swaminathan, Adriane Mosley, Crista Horton, Daniel F. Liefwalker, Anja Deutzmann, Renumathy Dhanasekaran, Arvin Gouw, Andrew Gentles, Martin Eilers, Holden T. Maecker, Dean W. Felsher
Journal: Cancer Research (2017)

Abstract The MYC oncogene drives the pathogenesis of many hematopoietic malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). These malignancies are often “oncogene-addicted” to MYC. Using mass cytometry (CyTOF), we demonstrate that MYC-addicted T-ALL excludes specific immune subsets from the tumor microenvironment implicated in immune surveillance, including natural killer (NK) cells. MYC inhibition clears malignant lymphocytes from the spleen and restores the normal splenic NK composition. Concordantly, peripheral blood of T-ALL patients have reduced percentages of activated NK cells as compared to healthy individuals. We show that MYC excludes activated NK cells from sites of lymphomagenesis by suppressing ERK1/2-STAT1/2-Type I IFN signaling, in both murine and human lymphomas. Furthermore, MYC-associated BL patients with higher than median expression of STAT1/2, and cytotoxic NK cell genes, PRF1 and Granzymes, have favorable clinical outcomes. Hence, oncogenic MYC appears to causally and reversibly suppress NK-mediated immune surveillance during lymphomagenesis. Citation Format: Srividya Swaminathan, Adriane Mosley, Crista Horton, Daniel F. Liefwalker, Anja Deutzmann, Renumathy Dhanasekaran, Arvin Gouw, Andrew Gentles, Martin Eilers, Holden T. Maecker, Dean W. Felsher. MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies [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 2943. doi:10.1158/1538-7445.AM2017-2943
Abstract 4903: Cationic polymer inhibits pancreatic cancer invasionin vitroand metastasisin vivo
Authors: Ibtehaj A. Naqvi, Ruwan Gunaratne, Jessica McDade, Douglas Rouse, Jen Jen Yeh, David Pisetsky, Jaewoo Lee, Rebekah White, Bruce Sullenger
Journal: Cancer Research (2017)

Abstract Pancreatic cancer has the poorest prognosis of all major cancers with a 5-year survival of less than 5%. Cell-free DNA (cfDNA) has been well-validated as a biomarker that correlates with tumor burden. More recently, a role for cfDNA in facilitating tumor progression has also been identified. The latter occurs through activation of nucleic acid sensing receptors such as toll-like receptors (TLRs) in both tumor cells and the host environment, which can upregulate pro-metastatic signaling pathways. In addition, tumor-derived extracellular vesicles such as microparticles and exosomes have also been implicated in promoting metastasis by activating pro-invasive pathways in tumor cells and pre-conditioning secondary sites for metastatic establishment. Our laboratory has previously shown that cationic polymers can scavenge negatively charged nucleic acids like cfDNA and abrogate aberrant inflammation in disease models of autoimmunity and infection. Herein, we investigated the ability of the cationic polymer, PAMAM-G3, to bind and inhibit cfDNA as well as anionic tumor-derived extracellular vesicles using in vitro models of pancreatic cancer cell line invasion. We also evaluated the effect of PAMAM-G3 treatment in a bioluminescent syngeneic murine model of pancreatic cancer metastasis. PAMAM-G3 significantly inhibited in vitro invasion of pancreatic cancer cell lines in response to both cfDNA and tumor-derived extracellular vesicles. Moreover, biweekly intraperitoneal treatment with PAMAM-G3 (20 mg/kg) starting 48 hours after pancreatic tumor cell implantation led to a significant reduction in liver metastasis without affecting primary tumor growth. Thus, cationic polymers such as PAMAM-G3 may represent a novel class of therapeutics to combat pancreatic cancer metastasis. Citation Format: Ibtehaj A. Naqvi, Ruwan Gunaratne, Jessica McDade, Douglas Rouse, Jen Jen Yeh, David Pisetsky, Jaewoo Lee, Rebekah White, Bruce Sullenger. Cationic polymer inhibits pancreatic cancer invasion in vitro and metastasis in vivo [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 4903. doi:10.1158/1538-7445.AM2017-4903
Abstract 91: Molecular insight into drug resistance in acute myeloid leukemia: Anin-silicoandin-vitroapproach
Authors: Urja Desai, Sheefa Mirza, Sonia Parikh, Rakesh Rawal
Journal: Cancer Research (2017)

Abstract INTRODUCTION: Drug resistance of leukemic stem cells is a surmountable obstacle to effective chemotherapy in acute myeloid leukemia (AML). P-glycoprotein (Pgp) and FLT3 undoubtedly contribute to worse prognosis and mechanisms of these proteins lead to shorter survival and chemotherapy resistance. Due to heterogeneity of stem cells in AML, outcome of patients with a normal karyotype is highly challenging and changes in drug resistance genes likely to be identified which will contribute to a better understanding of the disease biology, eventually leading to the development of alternative therapeutic approaches regarding drug resistance in AML. METHODOLOGY: Blood and Bone-marrow samples were collected from newly diagnosed adult AML patients with normal karyotype. Gene expression analysis of MDR genes like Pgp, MRP1, BCRP and LRP was done by qRT-PCR in FLT3-ITD+/- and CD34+/- subgroups. Higher expression of Pgp amongst all MDR genes instigated to undertake in-silico analysis of Pgp with natural compound library using YASARA. MTT assay was used to find out IC50 value of natural compounds shortlisted from in-silico analysis and used alone or with cytarabine on THP-1 cell line and in primary AML stem cells. Pgp inhibitory activity of natural compounds was assessed by fluorimetric MDR assay. RESULTS: A significant upregulation of Pgp expression was observed in FLT3-ITD+, CD34+ group after cytarabine exposure during their induction (7+3) therapy. Docking analysis revealed curcumin, hesperidin and silymarin having better binding affinity with Pgp as compared to its known inhibitor Verapamil. Furthermore, these selected compounds were used in-vitro, and results of MTT assay suggested 6.1µM, 40.73µM, 63.09µM and 54.95µM IC50 values of cytarabine, curcumin, hesperidin and silymarin respectively in THP-1 cell line. Combination index (CI) analysis revealed that curcumin (25µM), hesperidin (30µM) and silymarin (35µM) having synergistic effect with cytarabine and decreased IC50 value of cytarabine (1µM). In addition to this, Silymarin at 250nM and 500nM concentration showed equivalent inhibition of Pgp as compared to control Verapamil. CONCLUSION: A combination of in-silico and in-vitro screening revealed Curcumin, Hesperidin and Silibinin can be used as MDR modulators as well as chemosensitizer to reduce the cytotoxicity profile and drug resistance in AML. Citation Format: Urja Desai, Sheefa Mirza, Sonia Parikh, Rakesh Rawal. Molecular insight into drug resistance in acute myeloid leukemia: An in-silico and in-vitro approach [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 91. doi:10.1158/1538-7445.AM2017-91
Abstract LB-022: PTP1B directed therapeutics for HER2 positive breast cancer
Authors: Nava Krishnan
Journal: Cancer Research (2017)

Abstract PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. Currently, we are testing MSI-1436 in a Phase 1 clinical trial in HER2-positive breast cancer patients, in collaboration with the Monter Cancer Center at Northwell Health formerly NS-LIJ. Note: This abstract was not presented at the meeting. Citation Format: Nava Krishnan. PTP1B directed therapeutics for HER2 positive 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 LB-022. doi:10.1158/1538-7445.AM2017-LB-022
Selective amplification of one allele and mutations of the EGFR gene in lung cancers
Authors: Masaharu Nomura, Hisayuki Shigematsu, Li Lin, Mani Yegappan, Mark Siegelman, Pila Estess, Takao Takahashi, Makoto Suzuki, Ziding Feng, John D. Minna, Adi F. Gazdar
Journal: Cancer Research (2005)

2789   Abstract  Purpose : We examined the relationship between allele specific amplification of a polymorphic dinucleotide repeat (CA-SSR I) in intron one of the EGFR gene and mutations in its tyrosine kinase (TK) domain of the gene in Orientals and other ethnicities.  Background : Mutations in the TK domain of EGFR occur in distinct subpopulations of lung cancers and have been reported to predict, imprecisely, for response to TK inhibitors (TKIs). Gene amplifcation has also been reported in similar subpopulations of lung cancers. Over expression of the gene is frequent in lung cancers but does not correspond to mutational status. Selective amplification of the shorter allele of the CA-SSRI polymorphic locus has been linked to over expression of EGFR in breast cancers. These findings suggest that factors other than mutation such as allele specific amplification of CA-SSR I may modulate the response to TKIs.  Methods : We examined 517 resected lung cancers including 308 (60%) from Orientals and 209 (40%) from other ethnicities and corresponding non malignant lung tissues. We sequenced the four exons (18 - 21) of the TK domain known to harbor activating mutations. The status of the CA-SSR I alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) was determined by a standardized semiautomated method of microsatellite analysis.  Results : In Orientals, the modal number of the two alleles was 20/20 compared to 16/20 for other ethnicities (p
Abstract 4724: Combined clinical and biological risk stratification in pediatric hepatoblastoma
Authors: Stefano Cairo, Carolina Armengol, Beate Häberle, Marina Simon-Coma, Catherine Guettier, Ivo Leuschner, Marie-Annick Buendia, Dietrich von Schweinitz, Roland Kappler
Journal: Cancer Research (2017)

Abstract Introduction Advances in chemotherapy and surgery have greatly improved overall survival rates of children with hepatoblastoma (HB). However, prognosis still remains quite poor for HB patients with high risk characteristics such as portal/hepatic venous macrovascular involvement, extrahepatic growth, high extent of the disease, and metastasis, as shown by studies of the International Childhood Liver Tumours Strategy Group (SIOPEL). The aim of our trinational study was to validate recently identified genetic and transcriptional characteristics of HB as prognostic biomarkers to aid development of a new risk stratification system based on clinical and biological factors. Experimental procedures Tumor tissue of a cohort of 171 hepatoblastoma patients from Germany, France and Spain was analyzed for mutations in CTNNB1, NFE2L2 and TERT (Eichenmüller et al., J Hepatol 2014; 61:1312-1320) by Sanger sequencing and the 16-gene signature (Cairo et al., Cancer Cell 2008; 14:471-84) by real-time PCR. Kaplan-Meier estimates of specific survival time in the various groups were compared using the log-rank Mantel-Cox test. Results Mutations of CTNNB1, NFE2L2, and TERT were found in 133 (78%), 10 (6%), and 10 (6%) patients, respectively. The adverse C2 subtype of the 16-gene signature was detected in 60 (35%) patients. Kaplan-Meier analyses depicted a significant association of the 16-gene signature (P&amp;lt;0.0001) and NFE2L2 mutations (P&amp;lt;0.0166) with poor outcome. Stratifying the patients of our cohort into a standard and high risk group based on the commonly used clinical SIOPEL criteria (Zsiros et al., J Clin Oncol 2010; 28:2584-2590) also revealed a strong association (P&amp;lt;0.0001) of the high risk group with poor outcome. When added to the SIOPEL risk groups, presence of at least one biomarker could discriminate the SIOPEL high risk patients into an intermediate and a very high risk group (P&amp;lt;0.0001), whereas biomarker positive and negative standard risk patients showed no difference in outcome. Conclusions We have validated the 16-gene signature and NFE2L2 mutations as highly prognostic biomarkers in HB and propose a new stratification system that is based on the combination of clinical and biological factors, which might facilitate more tailored and risk-adapted therapies and thus better outcome of high risk patients in the future. Citation Format: Stefano Cairo, Carolina Armengol, Beate Häberle, Marina Simon-Coma, Catherine Guettier, Ivo Leuschner, Marie-Annick Buendia, Dietrich von Schweinitz, Roland Kappler. Combined clinical and biological risk stratification in pediatric hepatoblastoma [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 4724. doi:10.1158/1538-7445.AM2017-4724
Abstract 5875: Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents
Authors: Junko Murai, Yves Pommier
Journal: Cancer Research (2017)

Abstract The putative DNA/RNA helicase, Schlafen 11 (SLFN11), is a recently discovered determinant of sensitivity to DNA damaging agents such as platinums, topoisomerase I and II inhibitors (camptothecins, etoposide, doxorubicin), cisplatin, gemcitabine (1-3) and PARP inhibitors (olaparib, talazoparib) (4). Because SLFN11 expression is suppressed in ~45% cancer cell lines, SLFN11 inactivation is potentially one of the most prevalent mechanisms of resistance to DNA damaging agents. However, the molecular mechanisms of SLFN11 action in the DNA damage response have not been solved. Using isogenic cell lines of SLFN11-knockout and SLFN11-overexpression, we will show that SLFN11 binds to chromatin in response to camptothecin within 2 hours. ChIP-seq analysis reveals that SLFN11 preferentially binds to replication origins under camptothecin treatment. We identify two helicases DHX9 and MCM3, which are involved in replication and origin firing, as binding partners of SLFN11 by IP-MS analysis. Cell cycle analyses revealed that SLFN11 inhibits replication in response to camptothecin, which irreversibly lasts until apoptosis is exerted. Notably, the S-phase arrest by SLFN11 is independent of ATR-mediated S-phase checkpoint. Unscheduled origin firing by ATR inhibition under camptothecin treatment is suppressed in the presence of SLFN11. Hence, SLFN11 enforces irreversible S-phase arrest in damaged cells possibly by inhibiting dormant origin firing and inactivating the MCM helicase in conjunction with DXH9. We conclude that the irreversible S-phase arrest by SLFN11 leads to cell death in response to DNA damaging agents, which is a novel mechanism of how cancer cells are killed by DNA damaging agents. 1. Sousa FG, Matuo R, Tang SW, Rajapakse VN, Luna A, Sander C, et al. Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. DNA Repair (Amst) 2015;28:107-15. 2. Zoppoli G, Regairaz M, Leo E, Reinhold WC, Varma S, Ballestrero A, et al. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc Natl Acad Sci U S A 2012;109(37):15030-5. 3. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012;483(7391):603-307. 4. Murai J, Feng Y, Yu GK, Ru Y, Tang SW, Shen Y, et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 2016. Citation Format: Junko Murai, Yves Pommier. Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents [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 5875. doi:10.1158/1538-7445.AM2017-5875
Abstract 1674: Quantifying tumor-infiltrating leukocytes in hematoxylin stained NSCLC tissue samples using morphometric features
Authors: Elliott Ergon, Allison S. Harney, Nathan Martin, Will Paces, Famke Aeffner, Kristin Wilson, Janet Patterson-Kane, Karen Ryall, Daniel G. Rudmann, Brooke Hirsch, Joseph Krueger
Journal: Cancer Research (2017)

Abstract Quantification of tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancers (NSCLC) is valuable for understanding patient prognosis and survival. TILs comprise a subset of tumor-infiltrating leukocytes that modulate immune evasion and response to therapy. Understanding the composition of TIL subsets, especially relative to the total tumor leukocyte population, may provide additional context for understanding NSCLC pathogenesis and patient response to treatment. However, availability of tissues and use of chromogenic assays can limit the number of TIL and leukocyte subset markers assayed in a tissue section. Therefore, this study evaluated the identification of total leukocyte component in NSCLC using morphometric parameters and routine TIL marker monoplex immunohistochemistry (IHC) assays to further identify the composition of TIL subsets. Computational Tissue Analysis (cTA™) tools were used to determine the morphometric parameters which could identify immune cells in the absence of biomarker stain. The morphometric features which characterized immune infiltrates were used to quantify the total immune cell population frequency in the tumor nests and surrounding stroma in hematoxylin-stained tissues. The leukocyte population identified with morphometric parameters was correlated with CD45+ cell frequencies identified by cTA based on biomarker staining in CD45-stained serial sections. This morphometric ruleset was then applied to CD3- and CD8-stained tissues to evaluate the frequency of CD3+ and CD8+ TILs in the context of total infiltrating leukocytes. The relative populations of CD3+ and CD8+ TILs were consistent with available literature demonstrating that the morphometric ruleset could be utilized to enable evaluation of TIL sub-types relative to total leukocyte population without the need for additional IHC stains. The approach could, therefore, provide an added dimension of analysis for tissues stained by IHC for identifying the total immune cell infiltrating component without requiring additional biomarker staining. Citation Format: Elliott Ergon, Allison S. Harney, Nathan Martin, Will Paces, Famke Aeffner, Kristin Wilson, Janet Patterson-Kane, Karen Ryall, Daniel G. Rudmann, Brooke Hirsch, Joseph Krueger. Quantifying tumor-infiltrating leukocytes in hematoxylin stained NSCLC tissue samples using morphometric features [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 1674. doi:10.1158/1538-7445.AM2017-1674
Multiplexed Optogenetic Stimulation of Neurons with Spectrum‐Selective Upconversion Nanoparticles
Authors: Xudong Lin, Ying Wang, Xian Chen, Runhuai Yang, Zixun Wang, Jingyu Feng, Haitao Wang, King W. C. Lai, Jufang He, Feng Wang, Peng Shi
Journal: Advanced Healthcare Materials (2017)

Optical modulation of nervous system becomes increasingly popular as the wide adoption of optogenetics. For these applications, upconversion materials hold great promise as novel photonic elements. This study describes an upconversion based strategy for combinatorial neural stimulation both in vitro and in vivo by using spectrum-selective upconversion nanoparticles (UCNPs). NaYF4 based UCNPs are used to absorb near-infrared (NIR) energy and to emit visible light for stimulating neurons expressing different channelrhodopsin (ChR) proteins. The emission spectrum of the UCNPs is selectively tuned by different doping strategy (Tm3+ or Er3+ ) to match the responsive wavelength of ChR2 or C1V1. When the UCNPs are packaged into a glass microoptrode, and placed close to or in direct contact with neurons expressing ChR2 or C1V1, the cells can be reliably activated by NIR illumination at single cell level as well as network level, which is characterized by patch-clamping and multielectrode-array recording in culture primary neurons. Furthermore, the UCNP-based optrode is implanted into the brain of live rodents to achieve all-optical remote activation of brain tissues in mammalian animals. It is believed that this proof-of-concept study opens up completely new applications of upconversion materials for regulating physiological functions, especially in neuroscience research.
Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing
Authors: Mirza Ali Mofazzal Jahromi, Parham Sahandi Zangabad, Seyed Masoud Moosavi Basri, Keyvan Sahandi Zangabad, Ameneh Ghamarypour, Amir R. Aref, Mahdi Karimi, Michael R. Hamblin
Journal: Advanced Drug Delivery Reviews (2017)