tbuckley/cabot-search huggingface dataset:
Abstract 2312: TEM8/ANTXR1 specific T cells co-target tumor stem cells and tumor vasculature in triple-negative breast cancer
Authors: Tiara Byrd, Kristen Fousek, Antonella Pignata, Christopher Szot, Kevin Bielamowicz, Steven Seaman, Daniel Landi, Nino Rainusso, Poul Sorensen, Joachim Koch, Winfried Wels, Bradley Fletcher, Meenakshi Hegde, Brad St Croix, Nabil Ahmed
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no approved targeted therapies. Tumor endothelial marker 8 (TEM8), initially identified as a marker of tumor endothelial cells in colorectal cancer and other solid tumors has recently been shown to be upregulated in TNBC and breast cancer stem cells (BCSCs). We investigated whether TEM8 specific chimeric antigen receptor (CAR) T cells recognize and kill both tumor endothelial cells as well as TNBC tumor cells. TEM8 specific CAR molecules were generated using single chain variable fragment derived from the monoclonal antibody, L2. L2 CAR T cells selectively recognized TEM8, secreted immunostimulatory cytokines and effectively killed both TEM8 positive TNBC and tumor endothelial cell lines. Moreover, L2 CAR T cells targeted breast cancer stem cells significantly reducing the number of mammospheres relative to non-transduced T cells. In vivo, adoptive transfer of L2 CAR T cells induced regression of established vascularized TNBC xenografts. Hence, TEM8 may serve as an attractive target for immunotherapy of TNBC. Citation Format: Tiara Byrd, Kristen Fousek, Antonella Pignata, Christopher Szot, Kevin Bielamowicz, Steven Seaman, Daniel Landi, Nino Rainusso, Poul Sorensen, Joachim Koch, Winfried Wels, Bradley Fletcher, Meenakshi Hegde, Brad St Croix, Nabil Ahmed. TEM8/ANTXR1 specific T cells co-target tumor stem cells and tumor vasculature in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2312.
Flu vaccination reduces hospital admissions for cardiovascular disease in people with diabetes, study shows
Authors: Jacqui Wise
Journal: BMJ (2016)

Patients with type 2 diabetes who receive the influenza vaccine are less likely to be admitted to hospital for myocardial infarction, stroke, and heart failure, a large retrospective study has shown.1

The retrospective cohort study included 124 503 adults with type 2 diabetes, registered with 300 general practices in England, who were followed up across a seven year study period from 2003-04 …
Abstract 3039: Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II
Authors: Gema Santamaria-Nunez, Carlos M. Genes-Robles, Juan F. Martínez-Leal, Carlos M. Galmarini, Jean Marc Egly
Journal: Cancer Research (2016)

Abstract Cancer cells are characterized for their avid demand for active transcription, which reaches the level of a real addiction in solid tumors as small cell lung cancer (SCLC) or triple-negative breast cancer. Pharmacological modulation of transcription may thus provide a therapeutic approach to treat tumor types that depend on deregulated transcription for the maintenance of their oncogenic state. Lurbinectedin, currently under evaluation in a Phase III clinical trial for platinum-resistant ovarian cancer patients, and with very promising activity in combination with doxorubicin in SCLC, inhibits active transcription. Here we demonstrate that, after binding to specific DNA triplets highly represented in the CG-rich region surrounding the promoter of genes, this drug induces a rapid degradation of RNA Polymerase II (Pol II). Our results show that the hyperphosphorylated form of Pol II, already engaged in transcription elongation and likely blocked during this process by the lurbinectedin-DNA adduct, is then specifically submitted to the ubiquitin/proteasome degradation process, which finally removes the majority of the Pol II protein pool in treated cells. Disappearance of Pol II is followed by the formation of DNA breaks, process in which the nucleotide excision repair (NER) machinery, specifically the endonuclease XPF, has an important role. Pol II degradation and subsequent DNA damage were not only abrogated by inhibitors of CDK7 and CDK9 cyclin dependent kinases (DRB and flavopyridol), ubiquitin ligation (PYR-41), or proteasome activity (MG132), but also correlated with the antiproliferative activity of lurbinectedin in different cancer cell line models. In summary, lurbinectedin exemplifies a prototype drug for targeting transcriptional dependency in tumor cells and, thus, it could represent a new therapeutic alternative for solid tumors with this addiction. Citation Format: Gema Santamaria-Nunez, Carlos M. Genes-Robles, Juan F. Martínez-Leal, Carlos M. Galmarini, Jean Marc Egly. Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3039.
Abstract 3087: Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis <i>in vivo</i>
Authors: Jessica Wagner, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Abstract ONC201 is a first-in-class small molecule anti-tumor agent (Allen et al., 2013; Wagner et al., 2014; Prabhu et al., 2015; Kline et al., 2015) that upregulates endogenous TRAIL and activates the integrated stress response leading to increased DR5 expression, among other anti-tumor effects. ONC201 recently completed a phase I clinical trial in advanced solid tumors and is currently in multiple phase I/II clinical trials in select advanced cancers (NCT02250781, NCT02324621, NCT02420795, NCT02392572, NCT02609230, NCT02525692, NCT02038699). Colorectal cancer (CRC) remains one of the leading causes of death from cancer worldwide; predominantly due to its metastatic nature. Increasing clinical evidence including randomized clinical trials has demonstrated that there is an increased efficacy from certain cytotoxic chemotherapeutic agents when placed in combination with molecular agents that target the vascular endothelial growth factor (VEGF) pathway. Bevacizumab (Avastin), a monoclonal antibody that targets VEGF, has become an important therapeutic option for patients with advanced metastatic CRC. The single agent activity of ONC201 in preclinical models of colorectal cancer have been well documented, however a combinatorial regimen for this investigational agent has not been prioritized for this indication. We investigated the efficacy of ONC201 in combination with bevacizumab in preclinical models of colorectal cancer based on the previously reported cooperative efficacy with this combination in preclinical GBM models. While each agent showed efficacy as a single agent, the combination of ONC201 with bevacizumab appeared synergistic in the suppression of CRC xenograft growth including a significant impact on tumor regression and occasional complete tumor regressions. The ONC201 combination with bevacizumab also suppressed metastasis from xenografted human colorectal cancer cells. Mechanistic studies and angiogenesis imaging studies are ongoing to demonstrate the importance of this combination on both tumor growth, migration, and invasion. Our results demonstrate that combining anti-angiogenic bevacizumab with ONC201 enhances anti-tumor efficacy in preclinical models of colorectal cancer and suggest that further testing of the combination is warranted in the clinic. Citation Format: Jessica Wagner, Wafik S. El-Deiry. Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3087.
Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study
Authors: N Saman Wijesooriya, Roger W Rochat, Mary L Kamb, Prasad Turlapati, Marleen Temmerman, Nathalie Broutet, Lori M Newman
Journal: The Lancet Global Health (2016)

In 2007, WHO launched a global initiative for the elimination of mother-to-child transmission of syphilis (congenital syphilis). An important aspect of the initiative is strengthening surveillance to monitor progress towards elimination. In 2008, using a health systems model with country data inputs, WHO estimated that 1·4 million maternal syphilis infections caused 520 000 adverse pregnancy outcomes. To assess progress, we updated the 2008 estimates and estimated the 2012 global prevalence and cases of maternal and congenital syphilis.We used a health systems model approved by the Child Health Epidemiology Reference Group. WHO and UN databases provided inputs on livebirths, antenatal care coverage, and syphilis testing, seropositivity, and treatment in antenatal care. For 2012 estimates, we used data collected between 2009 and 2012. We updated the 2008 estimates using data collected between 2000 and 2008, compared these with 2012 estimates using data collected between 2009 and 2012, and performed subanalyses to validate results.In 2012, an estimated 930 000 maternal syphilis infections caused 350 000 adverse pregnancy outcomes including 143 000 early fetal deaths and stillbirths, 62 000 neonatal deaths, 44 000 preterm or low weight births, and 102 000 infected infants worldwide. Nearly 80% of adverse outcomes (274 000) occurred in women who received antenatal care at least once. Comparing the updated 2008 estimates with the 2012 estimates, maternal syphilis decreased by 38% (from 1 488 394 cases in 2008 to 927 936 cases in 2012) and congenital syphilis decreased by 39% (from 576 784 to 350 915). India represented 65% of the decrease. Analysis excluding India still showed an 18% decrease in maternal and congenital cases of syphilis worldwide.Maternal and congenital syphilis decreased worldwide from 2008 to 2012, which suggests progress towards the elimination of mother-to-child transmission of syphilis. Nonetheless, maternal syphilis caused substantial adverse pregnancy outcomes, even in women receiving antenatal care. Improved access to quality antenatal care, including syphilis testing and treatment, and robust data are all important for achieving the elimination of mother-to-child transmission of syphilis.The UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction in WHO, and the US Centers for Disease Control and Prevention.
Abstract 4893: Molecular detection of ALL in the peripheral blood is more sensitive than flow cytometric analysis of the bone marrow in patients with treatment-related hypocellularity
Authors: Hannah Smithers, Olivia Finney, Ilan Kirsch, Beryl Crossley, Michael Jensen, Rebecca Gardner
Journal: Cancer Research (2016)

Abstract Measurable residual disease detection (MRD) is an important tool for early detection and monitoring relapse. Traditionally, bone marrow is collected and analyzed by flow cytometry (FC) to evaluate MRD status in acute lymphoblastic leukemia patients (ALL). More recently, highly sensitive molecular methods such as deep sequencing allow for higher sensitivity detection of MRD. Although the bone marrow is considered to be more representative of tumor burden than sampling the blood, bone marrow collection is more invasive, disruptive, and resource intensive than peripheral blood draws. ALL patients enrolled in the Seattle Children's Pediatric Leukemia Adoptive Therapy (PLAT-02) trial undergo MRD assessment pre and post CD19 CAR T cell infusion using FC analysis of a bone marrow sample. We have used high throughput sequencing (HTS) in paired blood and bone marrow samples from these patients to evaluate the complete B cell repertoire and assess MRD up to 63 days post-infusion. To-date, we have obtained 38 paired samples. Using HTS alone we have observed a significant correlation in both the frequency of total reads and the number of malignant cells per million in paired peripheral blood and bone marrow samples. 26/38 of the bone marrow samples were determined either aparticulate or hypocellular. Importantly, 8/14 of patients that were MRD negative in the bone marrow by FC were MRD positive in the blood by HTS. These data suggest, that, in cases where the bone marrow is hypocellular or aparticulate, peripheral blood samples evaluated by HTS are more sensitive than traditional flow cytometric analysis in the bone marrow for detection of MRD. The impact of B cell aplasia may be important in increasing the sensitivity of HTS in the detection of MRD. The ability to detect an ALL B cell clone in the blood through HTS has many clinical implications; blood can be sampled more often, is less of a burden to patients, and can provide earlier prediction of relapse. Citation Format: Hannah Smithers, Olivia Finney, Ilan Kirsch, Beryl Crossley, Michael Jensen, Rebecca Gardner. Molecular detection of ALL in the peripheral blood is more sensitive than flow cytometric analysis of the bone marrow in patients with treatment-related hypocellularity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4893.
Abstract 3132: Genome-wide scan for genetic markers modifying survival of pancreatic cancer patients
Authors: Hongwei Tang
Journal: Cancer Research (2016)

Abstract Background: Genetic factors that are associated with pancreatic cancer survival have previously been examined in Genome-Wide Association Studies (GWAS), but the results are inconsistent due to limited sample size. Method: We performed a two-stage study on pancreatic cancer survival. The discovery phase took advantage of the existing GWAS data of 868 patients with European descendent from a case-control study conducted at MD Anderson. The validation study on ten top hits was conducted in another 820 white patients with Taqman. The missing genotypes were imputed using IMPUTE2 based on 1000 Genomes Project. Cox regression model was fitted to calculate allele-specific hazard ratios (HR) and 95% confidence intervals (95% CI) with adjustment for demographics, tumor stage, resection, and chemotherapy. Results: After imputation, 7,738,399 SNPs with a Quality Score &amp;gt;0.03, minor allele frequency &amp;gt;0.01, and Hardy-Weinberg equilibrium were obtained for analysis. Three loci in complete LD at chromosome 2 were associated with overall survival (OS) at genome-wide significance (P = 1 ×): rs113988120 in PAIP2B (poly(A) binding protein interacting protein 2B), rs112493246 and rs138529893 in DYSF (dysferlin). The variant allele was associated with 3.02 fold higher risk of dying (95% CI: 2.07-4.40). SNP rs113988120 and nine others were examined in the validation study and rs113988120 remained nominally significant (P = 2.85 ×; HR: 1.45, 95% CI: 1.04-2.03). In the combined datasets of 1688 patients, this SNP was significantly associated with OS (P = 1.46 × and HR = 1.80 (95% CI: 1.42-2.30). Conclusion: These observations support our hypothesis that genetic variations to a certain degree influence patient survival in pancreatic cancer. Key words: Pancreatic cancer, GWAS, Survival Citation Format: Hongwei Tang. Genome-wide scan for genetic markers modifying survival of pancreatic cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3132.
Abstract 63: A transposon-based forward genetic screen for steatosis-associated liver cancer drivers
Authors: Barbara R. Tschida, N. Alpay Temiz, Ju D. Yang, Vincent W. Keng, David A. Largaespada
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC), or liver cancer, is the second leading cause of death from cancer worldwide (Ferlay et al, Lyon, France: International Agency for Research on Cancer, 2013). HCC is linked with hepatic steatosis, or fatty liver disease, the most common chronic liver disease in the US. Both hepatic steatosis and HCC are increasing in prevalence in the US. However, the molecular mechanisms that cause HCC in a steatotic liver are not entirely understood. To uncover mutations promoting cancer in fatty livers and elucidate the role of steatosis in HCC, we performed a forward genetic screen using the conditional Sleeping Beauty (SB) transposon insertional mutagenesis system in mice treated with ethanol and a choline deficient diet to induce steatosis. Mice developed hepatic steatosis and liver cancer without sex bias, modeling the pattern seen in humans in whom HCC's with steatosis as a preceding condition are represented by a nearly equal number of males and females. We found that hepatic steatosis caused a downregulation of liver Foxa1 expression and increased Foxa2 inactivating phosphorylation, thus providing a molecular explanation for the loss of gender bias in our mouse model. Transposon insertion sites were mapped from the mouse HCC tumors, and genes near or in which more insertions were observed than expected by chance were identified as common insertion sites (CIS), which we consider putative steatosis-associated liver cancer genes. Wnt/b-catenin signaling, which defines a subclass of HCC and can induce tumors in mice without sex bias, was one of the top CIS associated pathways identified. Interestingly, alpha-adrenergic and dopamine signaling were also among the top steatosis-specific CIS associated pathways, suggesting a role for the sympathetic nervous system and cAMP signaling in fatty liver-associated cancer. Further studies are underway to test the roles of the pathways and individual genes identified in this study in driving HCC. Our studies implicate Wnt/beta-catenin and sympathetic nervous system signaling in steatosis-associated HCC and suggest methods for treatment or prevention in such cases. Citation Format: Barbara R. Tschida, N. Alpay Temiz, Ju D. Yang, Vincent W. Keng, David A. Largaespada. A transposon-based forward genetic screen for steatosis-associated liver cancer drivers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 63.
Abstract 1344: Novel targeting all-in-one nanoporphyrin platform against bladder cancer
Authors: Yuanpei Li, Tzu-yin Lin, Chongxian Pan, Kit S. Lam
Journal: Cancer Research (2016)

Abstract We have developed an extremely versatile and highly innovative theranostic nanoporphyrin (NP) platform for the integration of a broad range of clinical relevant imaging and therapeutic functions, including magnetic resonance imaging (MRI), positron emission tomography, fluorescence optical tomography, photodynamic therapy, photothermal therapy and targeted drug delivery. NPs exhibit architecture-dependent fluorescence- and magnetic resonance- properties, which could significantly increase the sensitivity of optical imaging and MRI for tumor detection. We recently integrated the NP platform into our previously reported bladder cancer targeted nanoparticles that were coated with a bladder cancer-specific ligand named PLZ4, resulting in a novel bladder cancer targeting and multifunctional PLZ4-nanoporphyrin (PNP) platform. PNP selectively delivered photosensitizer and chemotherapy into bladder cancer cells 30-50 times more than to adjacent normal urothelial cells, compared to only 2-3 times with reported photosensitizer, 5-aminolevulinic acid (ALA). Photodynamic therapy with PNP generated reactive oxygen species was over 100 times more potent than 5-ALA in vitro. PNP-mediated intravesical photo-therapy completely eliminated orthotopic patient-derived bladder cancer xenografts (PDXs). Image-guided photodynamic and photothermal therapies synergized with targeted chemotherapy of doxorubicin and significantly prolonged overall survival of mice carrying PDXs. This uniquely engineered targeting PNP platform has tremendous potential to improve the management of bladder cancer in clinic. Citation Format: Yuanpei Li, Tzu-yin Lin, Chongxian Pan, Kit S. Lam. Novel targeting all-in-one nanoporphyrin platform against bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1344.
Abstract 3614: Comparison and evaluation of somatic mutation using PGM and proton platform in cell free DNA of non-small cell lung cancer patients
Authors: Jae Sook Sung, Jong Won Lee, Boyeon Kim, Saet Byeol Lee, Nak-Jung Kwon, Won-Chul Lee, Hae Mi Kim, Won Jin Jang, Yun Ji Choi, Kyung Hwa Park, Yeul Hong Kim
Journal: Cancer Research (2016)

Abstract Non-small cell lung cancers (NSCLC) are characterized by a unique pattern of genetic driver mutations, and some of mutations may be used to predict prognosis and targeted treatment such as EGFR TKIs. Cell free (cfDNA) present in the blood stream shows much potential as a useful cancer maker for early diagnosis and cancer progression monitoring. Especially, analyzing the cfDNA with Next Generation Sequencing (NGS) technology allows high through put examination of various genes concurrently at a low cost. However, there are still no standardized methods to identify mutations in cfDNA. In this study, we examined the viability of PGM and Proton platforms. Ion AmpliSeq Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze cfDNA of 125 serum samples from NSCLC patients. The on target was 88% and mean depth was 643x using PGM platform. And, the on target was 92% and mean depth was 22,868x in Proton platform. To validate the results of two NGS platforms, we analyzed EGFR status by sanger sequencing in available 100 tumor tissues. EGFR mutations were identified in 34 (34%) by sanger sequencing. EGFR mutations were identified in 32 (25.6%) and 28 (22.4%) by PGM and Proton platform. Interestingly, out of 34 mutations of tumor tissue, EGFR mutations were matched to 11 and 26 in PGM and Proton platform, respectively. These results showed concordance of 76.5% between the tDNA (sanger sequencing) and cfDNA (Proton). In addition, KRAS (codon 12 and 13) mutations were 4 (3.2%) and 18 (14.4%), respectively. In our study, we demonstrated that Proton platform of high depth is a useful assay to identify somatic mutations of cfDNA in NSCLCs. [This research was supported by the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HI14C0066)] Citation Format: Jae Sook Sung, Jong Won Lee, Boyeon Kim, Saet Byeol Lee, Nak-Jung Kwon, Won-Chul Lee, Hae Mi Kim, Won Jin Jang, Yun Ji Choi, Kyung Hwa Park, Yeul Hong Kim. Comparison and evaluation of somatic mutation using PGM and proton platform in cell free DNA of non-small cell lung cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3614.