tbuckley/cabot-search huggingface dataset:
Abstract 3248: Identification and optimization of a highly active, cross reactive Complex-1 inhibitor
Authors: Jeffrey Mowat, Sven Christian, Carolyn Sperl, Alexander Ehrmann, Stephan Menz, Judith Guenther, Roman Hillig, Marcus Bauser, Andrea Haegebarth, Wolfgang Schwede
Journal: Cancer Research (2017)

Abstract Mitochondria are key regulators of both energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, potentially providing an opportunity for selectively targeting tumor cells. Based on a high throughput screen (HTS), we identified new, albeit moderately active, lead structures with cross reactivity between mouse and human Complex 1. SAR elaboration of the lead structure allowed for optimization of the potency, although compounds still suffered from low metabolic stability. Further improvement of the in vitro and in vivo PK properties finally permitted in vivo animal studies. Herein, we report for the first time the preclinical profile and structure of a highly active, optimized, human/mouse cross-reactive Complex I inhibitor that allowed for the further investigation into the therapeutic potential of Complex I inhibition in cancer. Citation Format: Jeffrey Mowat, Sven Christian, Carolyn Sperl, Alexander Ehrmann, Stephan Menz, Judith Guenther, Roman Hillig, Marcus Bauser, Andrea Haegebarth, Wolfgang Schwede. Identification and optimization of a highly active, cross reactive Complex-1 inhibitor [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 3248. doi:10.1158/1538-7445.AM2017-3248
Abstract 4636: p53 governs the tumoricidal activity of M1 macrophages in lung cancer
Authors: Yi-Jing Hsiao, Hsuan-Yu Chen, Kang-Yi Su, Bing-Ching Ho, Jeremy J.W. Chen, Pan-Chyr Yang, Sung-Liang Yu
Journal: Cancer Research (2017)

Abstract Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. M1 macrophage is associated with favorable clinical outcome of lung cancer patients, but the detail molecular mechanism is not thoroughly understood. Herein, we elucidate the anti-tumor mechanism of M1 macrophages by in vitro and in vivo assays. M1 conditioned media (CM) significantly reduced the tumor size in the xenograft mouse model via intratumoral administration. The M1-altered differential expression was profiled by microarray and the pathway analysis indicated that p53 was a critical regulator. Lung cancer cells harboring wild-type p53 (wt-p53) went apoptosis after M1 CM culture, but cells with mutant p53 did not. Additionally, M1 CM enhanced wt-p53 accumulation through reducing p53 ubiquitination and increasing protein stability. Moreover, we identified a p53 interacting protein STAT1 involved in M1-induced apoptosis and p53 accumulation. The M1 CM not only enhanced the interaction between STAT1 and p53 but also up-regulated and activated STAT1. We found that STAT1-Y701 phosphorylation is required for the p53 stability. The interaction of STAT1-Y701F and p53 was reduced compared to wild-type STAT1. To reveal the upstream signaling, we found that knockdown of IFNAR2, JAK1 and TYK2 attenuates M1-induced apoptosis. Taken together, STAT1 signaling is essential for M1 CM-induced apoptosis and p53 accumulation. Our findings imply that p53 and M1 macrophages play important roles in the immune surveillance in lung cancers. Citation Format: Yi-Jing Hsiao, Hsuan-Yu Chen, Kang-Yi Su, Bing-Ching Ho, Jeremy J.W. Chen, Pan-Chyr Yang, Sung-Liang Yu. p53 governs the tumoricidal activity of M1 macrophages in 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 4636. doi:10.1158/1538-7445.AM2017-4636
Abstract 1367: The dynamic mechanism of SARAH domain in RASSF5 activation by K-Ras4B
Authors: Tsung-Jen Liao, Hyunbum Jang, Chung-Jung Tsai, David Fushman, Ruth Nussinov
Journal: Cancer Research (2017)

Abstract RASSF5 is a tumor suppressor, which acts as an adaptor linking Ras and the Hippo pathways. RASSF5 activates MST1/2, a key upstream protein of the Hippo pathway, through SARAH domain heterodimerization, resulting in Hippo signaling. Signaling stimulates YAP1 phosphorylation, leading to its degradation and thereby cell apoptosis. Association with K-Ras4B promotes RASSF5 to release its SARAH which heterodimerizes with MST1/2. We aim to reveal how K-Ras4B regulates the Hippo pathway through RASSF5 by resolving the structure and conformational dynamics of RASSF5 complexes. Our modeling and simulations help elucidate the intrinsic dynamic interactions of RASSF5 RA (Ras binding) and SARAH domains. Surprisingly, we found that the residue E388 on RASSF5 SARAH plays a significant role in the dynamic mechanism of SARAH homo-/hetero- dimerization and the RA-SARAH association. The mutants E388A and E388K dramatically decrease the strength of RASSF5 homo-SARAH and RASSF5-MST2 hetero-SARAH, suggesting that the E388 mutation may be oncogenic. Simulations of selected RASSF5 configurations with GTP-bound K-Ras4B indicate that the interactions between RA and SARAH are reduced. We conclude that Ras binding weakens the RA-SARAH association, increasing the SARAH dynamic fluctuation. The released RASSF5 SARAH has high propensity to dimerize with MST1/2 SARAH, activating Hippo signaling thus cancer suppression. Funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH under contract HHSN261200800001E. Citation Format: Tsung-Jen Liao, Hyunbum Jang, Chung-Jung Tsai, David Fushman, Ruth Nussinov. The dynamic mechanism of SARAH domain in RASSF5 activation by K-Ras4B [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 1367. doi:10.1158/1538-7445.AM2017-1367
Adjuvant chemotherapy in stage II non-small cell lung cancer: A population-based analysis utilizing NCDB.
Authors: Gaurav Goyal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2014)

e18511 Background: Many prospective trials show that addition of chemotherapy after operable non-small cell lung carcinoma improves survival. Studies determining the effects of patient characteristics and insurance status on the use of adjuvant chemotherapy are lacking. Our aim was to examine the practice patterns for adjuvant chemotherapy in surgically resectable stage II non-small cell lung carcinoma using the National Cancer Database (NCDB). NCDB is a nationwide oncology outcomes database for ~70% of newly diagnosed cases from more than 1,500 accredited cancer programs in the United States and Puerto Rico. Methods: It is a retrospective study of patients diagnosed with non-small cell lung cancer stage II between the years 2000 and 2011 from the NCDB (n=102617). We focused on the patients who received adjuvant chemotherapy to see if there is any difference based on demographic and insurance characteristics. Chi-square test was used as the test of significance. Results: Between the years 2000 to 2011, the percentage of patients receiving adjuvant chemotherapy increased from 9.1% to 18.4% from the year 2003 to 2004 and was greater than 18% after that. Females, private/managed insurance, age 30-69, White/Hispanic race, higher income groups, higher education status are all seen to have more number of people undergoing adjuvant chemotherapy. P-value for all<.0001. Conclusions: This is the largest study involving the patients with stage II non- small cell lung cancer. There has been an increase in the use of adjuvant chemotherapy over the last decade, especially from the year 2003 to 2004 when most of the trials indicating its benefit were published. Factors that determine the use of adjuvant chemotherapy are age, insurance status, race, socioeconomic status, educational status and sex of the patient. Variables Included Percentage of patients receiving adjuvant chemotherapy Age <30 7 30-69 23 >69 5 Insurance status Private/managed 24 Medicaid 18 Medicare 14 Uninsured 13 Sex Male 16 Female 18 Annual Household Income (USD) <33,000 15 33,000-48,999 17 >49,000 20 Educational status (% patients without HS degree) >31% 14 18-30.9% 17 <18% 19 Race White 17 Black 16 Hispanic 18 P-value significant for all comparison at < 0.0001.
Abstract 4534: Theory and methodology for the design and analysis of PDX mouse clinical trials
Authors: Sheng Guo, Binchen Mao, Henry Q. Li
Journal: Cancer Research (2017)

Abstract Patient-derived xenograft (PDX) is a well-accepted experimental cancer model mimicking original patients in histo- &amp; molecular pathology, as well as drug response. Mouse clinical trials (MCT) using PDX becomes increasingly prevalent in oncology research, yet the theory and methodology for trial design and analysis is underdeveloped. By analyzing tumor growths of 34081 PDX mice, we showed that majority of them can be satisfactorily modeled by exponential growth kinetics, based on which we derived a new drug response readout called the AUC ratio that is superior to the tumor growth inhibition (TGI) and its variants. We outlined a bootstrap algorithm to calculate its confidence interval, and showed that a 4:4 (4 mice in both treatment groups) or up design sharply increases measurement accuracy over the lesser design. Next, we introduce three approaches for drug evaluation and biomarker discovery in MCTs. In the end-point based analysis, we used a cohort of gastric PDXs to show a positive correlation between EGFR mRNA expression and cetuximab efficacy, in agreement with clinical trial results. We then used linear mixed models (LMMs) to describe MCTs as clustered longitudinal studies that capture the growth and drug response heterogeneities across PDXs and among mice within a PDX. Further, LMMs can separate prognostic and predictive biomarker effects, quantify response difference to a drug for multiple cancers, or efficacy difference of multiple drugs to a cohort of PDXs. Thirdly, we used additive frailty models to perform survival analysis on MCTs. We defined survival endpoints of PFS and OS in PDXs, and showed that hazard ratios can be more accurately estimated. We revealed an inherent connection between frailty and growth rate for PDXs. We performed computational simulations for the last two methods to show that statistical power improves tremendously with a 3:3 or up design. This work lays the foundation for rational design and analysis of PDX mouse clinical trials. Citation Format: Sheng Guo, Binchen Mao, Henry Q. Li. Theory and methodology for the design and analysis of PDX mouse clinical trials [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 4534. doi:10.1158/1538-7445.AM2017-4534
Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia
Authors: H-A Hou, J-W Lu, T-Y Lin, C-H Tsai, W-C Chou, C-C Lin, Y-Y Kuo, C-Y Liu, M-H Tseng, Y-C Chiang, Y-L Peng, J-L Tang, Z Gong, L-I Lin, H-F Tien
Journal: Blood Cancer Journal (2017)

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.
Prevalence and mortality of colorectal cancer with iron deficiency anemia in the South.
Authors: Stuthi Perimbeti, Kevin Ye Hou, William May Lee, Erika Correa, Kathleen Degen, Shaun Bryan Hanson, Luiz Antonio Liarte Marconcini, Seema Niphadkar, Kristine Marie Ward, Maneesh Rajiv Jain, Neilanjan Nandi, Michael Styler
Journal: Journal of Clinical Oncology (2017)

e15141 Background: The Centers for Disease Control and Prevention has published data on incidence rates of colorectal cancer (CRC) referenced from the U.S. Cancer Statistics Working Group. Using data on admissions from the National Inpatient Sample (NIS) from 1999-2014. Iron deficiency anemia (IDA) is a commonly encountered comorbidity of CRC, particularly in late stage disease and is associated with higher rates of complications. Methods: Adult admissions with a primary diagnosis of CRC and secondary diagnosis of IDA were extracted from the NIS database using ICD-9 codes from 1999-2014 (N = 5,130, weighted N = 25,594). The sample was weighted to approximate the full inpatient population of the U.S. to analyze differences in regional distribution (Northeast, Midwest, South, and West) we assumed a normal distribution of 25% per region and then performed a chi squared analysis. Results: There were more cases of CRC with IDA in the South (38.32%) compared to the Midwest (22.76%), West (20.45%) and Northeast (18.46%) (p = 0.001). In addition, there were higher rates of mortality from CRC with IDA in the South (29.32%) compared to the Midwest (22.87%), West (21.43%) and Northeast (16.37%) (p &lt; 0.0001). Conclusions: Our data demonstrates a correspondence between the prevalence of IDA associated CRC with a greater prevalence and increased risk of mortality in the South relative to other regions in the U.S.Regional differences in prevalence also corresponded to regional differences in mortality. Future research should investigate the factors that explain these regional disparities.
Abstract 654: The epigenetic landscape of T cell exhaustion
Authors: Debattama Sen
Journal: Cancer Research (2017)

Abstract Exhausted T cells in cancer and chronic viral infection have distinctive patterns of gene expression, including sustained expression of the inhibitory receptor PD-1, but the regulation of gene expression in exhausted T cells is poorly understood. Here we define the accessible chromatin landscape in mouse and human exhausted CD8+ T cells and show that it is profoundly different from functional memory CD8+ T cells. Exhausted CD8+ T cells in a mouse model of chronic viral infection acquire an extensive, state-specific pattern of enhancers, which are organized into functional modules. One enhancer, -23.8kb from the Pdcd1 locus, is found only in exhausted T cells and other lymphocytes with sustained PD-1 expression. Genome editing shows it to be required for high PD-1 expression. Cas9-mediated in situ saturation mutagenesis of the enhancer pinpoints critical minimal sequences that correspond to bound transcription factor motifs for RAR, T-bet and Sox3 in exhausted CD8+ T cells. State-specific enhancer profiles identified in mouse exhausted CD8+ T cells are conserved in human exhausted antigen-specific CD8+ T cells responding to HIV and HCV infection. Detailed functional enhancer maps of T cell exhaustion reveal state-specific regulatory sequences and offer targets for genome editing that could alter gene expression preferentially in exhausted CD8+ T cells. Citation Format: Debattama Sen. The epigenetic landscape of T cell exhaustion [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 654. doi:10.1158/1538-7445.AM2017-654
Abstract 1819: Reprogramming the tumor microenvironment by targeting endothelial DNA repair
Authors: Cristina Espinosa-Diez, RaeAnna Wilson, Rebecca Ruhl, Nathan Kanner, Namita Chatterjee, Clay Hudson, Sudarshan Anand, Shushan Rana
Journal: Cancer Research (2017)

Abstract The tumor microenvironment (TME) plays a critical role in orchestrating immune infiltration, tumor progression and response to therapeutics. Therefore, strategies to manipulate the TME including cytokine gene therapy, antibodies to reverse macrophage polarization etc are under active investigation. We have identified an alternative approach to target the TME by disrupting DNA repair in the tumor endothelial cells (ECs). We discovered a seven-microRNA (miR) signature induced in ECs in in vitro and in vivo by oxidative stress and DNA damage. The top miR candidate in this signature, miR-103 altered the TME by inducing DNA damage in ECs, eliciting type I interferons, upregulating immune costimulatory receptors and decreasing PD-L1 expressing tumor associated macrophages and granulocytes. Moreover, miR-103 treatment had a paracrine effect on the tumors and upregulated Fas and TRAIL receptors. Mechanistically, these functions of miR-103 were largely due to its downregulation of the three prime exonuclease TREX1. Local, systemic or vascular targeted delivery of miR-103 decreased both angiogenesis and tumor burden in multiple mouse tumor models. Complementary to the role of miR-103, two additional miRs in the miR signature, miRs 494 and 99b each induced senescence in the vasculature by downregulating the Mre11a-Rad50-NBN (MRN) complex. Ectopic expression of miRs 494 or 99b decreased telomerase activity, increase p21 levels with a concomitant decrease in pRb levels. Vascular targeted delivery of miR-494 decreased angiogenesis in vivo whereas systemic delivery decreased tumor growth. Interestingly, both miR mimics and the MRN knockdowns induced the transcription of a number of senescence associated genes including CD44. Taken together these data suggest that miRs 494 and 99b targeting of the MRN complex induces senescence. The MRN complex interacts with the ATM kinase, histone H2AX and TREX1 suggesting that the miRs we identified disrupt critical nodes of a DNA Damage Response (DDR) network. Our findings reveal a complex, miR mediated cross talk between EC DNA damage pathways, the TME and tumor cells. These interactions can be exploited for designing therapies that synergize with tumor cell killing to enhance host anti-tumor responses. Citation Format: Cristina Espinosa-Diez, RaeAnna Wilson, Rebecca Ruhl, Nathan Kanner, Namita Chatterjee, Clay Hudson, Sudarshan Anand, Shushan Rana. Reprogramming the tumor microenvironment by targeting endothelial DNA repair [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 1819. doi:10.1158/1538-7445.AM2017-1819
Prognostic Factors in Syphilitic Uveitis
Authors: Florence Hoogewoud, Laure Frumholtz, Paul Loubet, Caroline Charlier, Philippe Blanche, David Lebeaux, Nadjet Benhaddou, Neila Sedira, Laetitia Coutte, Clelia Vanhaecke, Odile Launay, Claire Le Jeunne, Emmanuel Héron, Dominique Monnet, Olivier Lortholary, José-Alain Sahel, Nicolas Dupin, Antoine Brézin, Marie-Hélène Errera, Sawsen Salah, Matthieu Groh
Journal: Ophthalmology (2017)
Abstract 930: Role of DLK1 in sarcoma stem cells
Authors: Ilkyu Han, Sun Hee Ahn, Han-Soo Kim
Journal: Cancer Research (2017)

Abstract Sarcoma is a rare form of cancer that comprises about 1% of all malignancies. A large proportion of deaths by sarcomas are caused by tumor metastasis, of which the biological basis remains obscure. A significant body of evidence suggests that only a small population of sarcoma cells possess the ability to initiate and maintain tumors. These tumor-initiating cells have the ability to self-renew, recapitulating the cellular heterogeneity of the original cancer, and thus are often referred as cancer stem like cells (CSLCs).Delta-like factor 1 (DLK1) was cloned in the preadipocyte cells 3T3-L1 cDNA library. Previous studies reported on the role of DLK1 in mesenchymal stem cell differentiation, adipogenesis, myogenesis, and osteoblastogenesis. It was reported that DLK1+ liver cancer cells have characteristics similar to those of CSLCs and that DLK1 could be a potential therapeutic target against the liver CSLCs. However, little is known about role of DLK1 in CSLCs of sarcoma. The mRNA (real time PCR) and protein (Western blot) expression of DLK1 from 13 sarcoma cell lines was examined. CSLCs from sarcoma cell lines were isolated using FACS with CD133 and sphere forming assay. The effect of DLK1 on sarcoma tumorigenesis was examined using cell proliferation and cell invasion assays by DLK1 siRNA treatment.Real-time PCR showed the increased expression of DLK1 mRNA in sarcoma cell lines. In particular, DLK1 mRNA was highly expressed in U2OS (osteosarcoma), SW872 (liposarcoma), A204 (rhabdomyosarcoma), and HS-SYII (synovial sarcoma) cells. We observed a reduction in cell proliferation and invasion in U2OS, A204, and sw872 cells treated with DLK1 siRNA. CSLCs were isolated from U2OS, A204, and sw872 by the FACS sorting method using the CD133, a CSLC marker in sarcoma. The number of active sarcoshperes in CD 133+ cells were significantly higher than that in CD133- cells by sphere forming assay. Soft agar assays revealed the presence of many more colonies in CD133+ cells than in CD133- or wild type cells. To investigate the effect of DLK1 on sarcoma CSLCs, sw872 cells were categorized into four groups: wild type, CD133-, CD133+ and spheres. Real-time PCR and western blot were used to detect the DLK1 gene in all four groups. We observed that DLK1 expression in sw872 CSLCs (CD133+ and spheres) were relatively low. We found that suppression of DLK1 by siRNA inhibited the invasiveness of CSLCs although it inhibited more effectively to activation of invasive cells as well as cell proliferation in sw872 non-CSLCs.These results suggest that DLK1 may play a role in tumorigenesis of CSLCs and cancer cells in various sarcomas. Citation Format: Ilkyu Han, Sun Hee Ahn, Han-Soo Kim. Role of DLK1 in sarcoma stem 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 930. doi:10.1158/1538-7445.AM2017-930