bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 504: Acarbose enhances intratumoral CD8 T cell responses in a pre-clinical model of kidney cancer
Authors: Orlandella Rachael M. , Smith Daniel L. , Norian Lyse A. 
Published: August 2019

Abstract
Metastatic renal cell carcinoma (RCC) exhibits high mortality rates and chemotherapeutic resistance. Treatment options include immune-stimulatory therapies, such as high-dose IL-2 and anti-PD-1; however, these agents only generate responses in 20-50% of patients. This illustrates the need to find ways to improve patient response rates. Long-term caloric restriction (CR) extends longevity and reduces cancer risk in animal studies. Caloric restriction mimetics (CRMs), which replicate the benefits of CR without reductions in calorie intake, were recently found to enhance chemotherapeutic efficacy by improving CD8 T cell mediated anti-tumor immunity. Here we examined acarbose, an FDA-approved anti-diabetic agent with CRM properties, in a preclinical model of kidney cancer. BALB/c mice were orthotopically tumor challenged with syngeneic luciferase-expressing Renca renal carcinoma cells, which spontaneously metastasize to the lungs. Mice were then randomized to either an acarbose-supplemented or control diet. Compared to mice on control diet, acarbose did not alter renal tumor progression at Day 28. Importantly, acarbose did not exacerbate weight loss associated with renal tumor growth. Flow cytometric analysis at Day 28 revealed increased frequencies of activated (CD44+CD62L-) intra-tumoral CD8 T cells in mice on acarbose (p=0.012). Additionally, renal tumors from mice on acarbose displayed increased frequencies of early effector (CD127-KLRG1-) CD8 T cells, in addition to heightened frequencies of PD-1+ CD8s. These findings suggest that acarbose exhibits immune-modulatory properties which could promote anti-tumor immunity. Future experiments will focus on elucidating mechanisms contributing to alterations in anti-tumor immunity. Importantly, these studies warrant investigating acarbose in combination with currently available treatments as a potentially novel therapeutic adjuvant.
Citation Format: Rachael M. Orlandella, Daniel L. Smith, Lyse A. Norian. Acarbose enhances intratumoral CD8 T cell responses in a pre-clinical model of kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 504.
Abstract 5052: Immune profiles in the San Francisco Adult Glioma Study using Immunomethylomics
Authors: Wiencke John K. , Molinaro Annette , Gayathri Warrier , Clarke Jennifer , Taylor Jennie , Koestler Devin , Wiemels Joe , Hanson Helen , Sean Lee , Rice Terri , McCoy Lucie , Salas Lucas , Margaret Wrensch , Christensen Brock , Kelsey Karl T. 
Published: August 2019

Abstract
Glioma patients demonstrate abnormalities in peripheral blood leukocytes that have been associated with survival time. Here we assessed immune cell profiles in archival blood samples obtained 5-25 years ago using a novel epigenetic approach called immunomethylomics. We first validated the approach to measure the proportions of CD4 T, CD8 T cells, B cells, NK cells, neutrophils, and monocytes in archival blood using the new 850,000 feature EPIC Illumina methylation bead array. The immunomethylomic assay was shown to match the performance of multiparametric flow cytometry and thus is a highly accurate method for immune profiling. We next measured cell profiles in blood from 312 molecularly defined AGS subjects. In this cohort we enriched for patients with triple negative tumor subtypes (IDH wildtype, 1p19q negative, TERT non-mutant). Elevations in the neutrophil lymphocyte ratio (NLR) significantly increased with grade, whereas the proportions of T and B cells decreased with increasing grade. Using an established cut point of &gt; 4.0 for the NLR revealed that this immune parameter was associated with shorter survival times in glioblastoma (median overall survival (mOS) 12.6 vs. 16.9 months) and non-glioblastoma (mOS 16.7 vs. 36 months) patients. Ongoing analyses of the cohort will be presented to evaluate the effects of age, gender, surgery, chemoradiation and tumor grade on the survival results. Because DNA based immune cell profiles do not require intact cells nor preserved proteins, they provide a powerful tool to glean potentially important immunologic information from historic stored samples that would otherwise be useless using current cytometry-based approaches.
Citation Format: John K. Wiencke, Annette Molinaro, Warrier Gayathri, Jennifer Clarke, Jennie Taylor, Devin Koestler, Joe Wiemels, Helen Hanson, Lee Sean, Terri Rice, Lucie McCoy, Lucas Salas, Wrensch Margaret, Brock Christensen, Karl T. Kelsey. Immune profiles in the San Francisco Adult Glioma Study using Immunomethylomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5052.
Abstract 5054: Are co-occurring structural birth defects associated with risk of acute lymphoblastic leukemia among children with Down syndrome
Authors: Schraw Jeremy M. , Chambers Tiffany M. , Woodhouse John P. , Langlois Peter H. , Canfield Mark A. , Scheuerle Angela E. , Scheurer Michael E. , Plon Sharon E. , Rabin Karen R. , Lupo Philip J. 
Published: August 2019

Abstract
Background: Children with Down syndrome (DS) have a 15- to 20-fold increased risk of developing acute leukemia (ALL). While children with DS typically also present with multiple co-occurring major and minor structural birth defects, very little is known about whether the number and type of these co-occurring birth defects in children with DS are associated with risk of ALL.
Methods: The Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study included linking data from population-based birth defects and cancer registries in Texas for the years 1999-2013. We performed a case-control analysis of ALL risk in participants diagnosed with DS. We evaluated the risk of ALL according to the presence of major birth defects in eight organ systems, as well as by the number of birth defects.
Results: We identified 7,684 children with DS (controls) and 81 children with DS-ALL (cases) from among 5.7 million live births. There was a high burden of co-occurring birth defects in both the DS and DS-ALL groups, with 97% compared to 98% being diagnosed with at least one co-occurring birth defect (p = 0.39), respectively, and 68% compared to 71% being diagnosed with at least one major birth defect (p = 0.33). Similar to what has been reported among the general population of ALL patients, children with DS and ALL had a significantly higher mean birthweight (3088 vs 2891 g, p &lt;0.001) than children with DS overall, and were born to older parents (mean maternal age 33.7 vs. 31.7 yrs, p = 0.01; mean paternal age 36.6 vs. 33.8 yrs, p = 0.02). Although there were trends towards increased prevalences of major birth defects overall and in most organ systems among the DS-ALL group, none reached statistical significance. Similarly, we identified a non-significantly greater mean number of total birth defects in the DS-ALL group (p = 0.2). Neither number of total birth defects nor number of major birth defects were associated with ALL in multivariable Cox regression models.
Conclusions: In this population-based assessment, we did not find strong evidence that co-occurring structural birth defects were related to ALL risk among children with DS. However, the small numbers of children with DS-ALL make it difficult to draw definitive conclusions.
Citation Format: Jeremy M. Schraw, Tiffany M. Chambers, John P. Woodhouse, Peter H. Langlois, Mark A. Canfield, Angela E. Scheuerle, Michael E. Scheurer, Sharon E. Plon, Karen R. Rabin, Philip J. Lupo. Are co-occurring structural birth defects associated with risk of acute lymphoblastic leukemia among children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5054.
Abstract 511: An assessment of pre-conditioning regimens for optimal hCD34+ hematopoietic stem cell humanization of NSGTMmice
Authors: Parello Caitlin S. , Cuiffo Benjamin G. , Kury Alexandria , Reardon Kasey , Dam Brett Van , Vu Sallyann , Costa Catarina , Ritchie Veronica , Gagnon Gavin , Bateson Timothy , Rogers Samantha , Lyng Gregory D. , Sonis Stephen T. 
Published: August 2019

Abstract
Humanized immune system (HIS) mice - immunocompromised Nod.Cg-Prkdcscid Il2rgtm1Wjl/SzJ animals in which the immune system has been humanized by the engraftment of CD34+ hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), or other human cells/tissues - represent an important tool in pre-clinical oncology research. Here we investigated several pre-conditioning regimens (Busulfan pre-treatment or total body irradiation (TBI)) to determine which would yield maximum human leukocyte engraftment and lineage diversity. Animals were pre-treated either one or two doses of Busulfan (25 mg/kg) or varying doses of TBI (1.75, 2.0, or 2.5 Gy). One to two days later, animals received an adoptive transfer of native hCD34+ HSCs. Engraftment was monitored by flow cytometry assessment of peripheral blood four weeks after adoptive-transfer, and every four weeks thereafter through experiment termination at Week 16. Upon termination, spleen and bone-marrow were assessed for various leukocyte populations by flow cytometry. Animals undergoing pre-conditioning displayed increased human CD45+ cell engraftment at all timepoints as compared to animals without pre-conditioning, with animals treated with two doses of Busulfan demonstrating the greatest human CD45+ engraftment at all timepoints and reaching statistical significance at endpoint (vs no pre-conditioning; p&lt;0.05). Diversity of leukocyte cell types (B cells, T cells, NK cells, and other hCD45+) in the bone-marrow was similar across pre-treatment paradigms, however for some lineages, representation in the bone-marrow was significantly altered between pre-conditioning type. The absolute number of T or B cells were increased in TBI and Busulfan treated groups, respectively, whereas NK cells as a percentage of singlets were increased in TBI treated groups. The diversity of leukocyte cell types in the spleen was likewise similar across groups, with B cells dominating. These data provide important insights into the utility of various pre-conditioning regimens for the humanization of NSG mice for pre-clinical oncology research, and demonstrate that the optimum pre-conditioning regimens should be selected based on treatment target.
Citation Format: Caitlin S. Parello, Benjamin G. Cuiffo, Alexandria Kury, Kasey Reardon, Brett Van Dam, Sallyann Vu, Catarina Costa, Veronica Ritchie, Gavin Gagnon, Timothy Bateson, Samantha Rogers, Gregory D. Lyng, Stephen T. Sonis. An assessment of pre-conditioning regimens for optimal hCD34+ hematopoietic stem cell humanization of NSGTMmice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 511.
Abstract 5110: An online tool for summarizing and searching human cancer-genomic publications
Authors: Williams Kevin , Zhang Myron , Ramos Anayancy , Johnson Andrew , Stravoravdis Stefanos , Heenehan Megan , Dancik Garrett M. 
Published: August 2019

Abstract
PubMed catalogs over 33,000 articles published with the keywords “cancer” and “gene” in the past year alone. The large volume of cancer genomic publications necessitates the development of text-mining tools to help cancer researchers navigate and summarize articles efficiently. Here we present a Cancer Publication Portal (CPP) that allows a researcher to search and summarize cancer genomic literature based on a gene of interest. CPP integrates data from several sources, including PubTator, which uses robust text-mining tools to identify associations between articles and biological concepts; the Medical Subject Headings (MeSH) database; the HUGO Gene Nomenclature Committee human gene name database; PubMed, a database of biomedical literature citations; and the National Cancer Institute (NCI) Thesaurus. To begin a search, a user selects a gene of interest. CPP then summarizes the relevant cancer-related publications mentioning this gene through tabular and graphical summaries showing the frequency of articles stratified by references to any (1) cancer type, (2) pharmacological agent, (3) genomic mutation, and (4) additional human gene. Additionally, CPP catalogs and summarizes articles based on mentions of &gt;30 additional cancer-related terms, based on an analysis of terms that are significantly more likely to occur in cancer-related abstracts. CPP allows users to quickly obtain statistics, e.g., to find the frequency of articles mentioning EGFR and Erlotinib across cancer types. Interactive summaries allow users to narrow in on a topic of interest by applying additional filters, in which case the summaries are updated and the process can be repeated. At any point, the user can browse through the current set of article abstracts and citation information to get more information about an article. Finally, we introduce a Citation Analysis module for helping users identify “important” articles. This module identifies articles which cite articles in a provided list. The module then generates an edge list that can be imported into network analysis tools such as Gephi for visualization and analysis. CPP currently includes information for ~1.1 million cancer-related publications associated with &gt;19,000 human genes. The underlying data is stored in an MySQL database while R/Shiny is used to implement the web interface. CPP is available from the following link: https://gdancik.github.io/bioinformatics/CPP/
Citation Format: Kevin Williams, Myron Zhang, Anayancy Ramos, Andrew Johnson, Stefanos Stravoravdis, Megan Heenehan, Garrett M. Dancik. An online tool for summarizing and searching human cancer-genomic publications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5110.
Abstract 5128: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York
Authors: Froeling Fieke E. , Robine Nicolas , Hubert Benjamin , Zody Michael , Oschwald Dayna , Varmus Harold E. , Sawyers Charles L. , Tuveson David A. ,   On behalf of the NYGC P1000 Consortium
Published: August 2019

Abstract
Background and aims Recent advances in DNA sequencing technologies have revolutionized approaches to the prevention, risk assessment, early detection, diagnosis, and treatment of cancers. However, many ethnic groups, especially non-European populations, have been significantly under-represented in cancer research, including clinical trials, and have not received equal benefits in clinical practice. As a result, our current knowledge about tumor biology, cancer risk, and response to treatment has primarily been derived from patients of European descent. These inequities limit our understanding of the many types of cancer and may exacerbate health disparities in the United States. This multi-institutional study, named Polyethnic-1000, aims to address both the scientific and social issues by creating a dynamic research platform within the ethnically diverse greater New York City area.
Methods and results Polyethnic-1000 is a collaborative effort organized by the New York Genome Center (NYGC), involving staff and patients at academic centers and partnering hospitals in the New York City region. The genomics and informatics capabilities of the NYGC will be used to determine how inherited and somatically acquired genetic variations affect the behavior of cancers occurring in ethnically diverse populations. In a first, retrospective stage we are establishing the necessary infrastructure and workflow from sample acquisition to whole-exome and RNA sequencing, data analysis and data sharing within the consortium. Then we will start a prospective study enabling the formation of cohorts of interest for particular cancer types and particular ethnicities, with uniform consent allowing germline and somatic sequencing with broad data sharing of the somatic variants identified.
Conclusion By establishing a collaborative network, Polyethnic-1000 will deepen our understanding of the contributions that ethnicities make to the incidence and biology of cancers, potentially improving outcomes for patients who currently lack access to the most recent advances in medical science.
Citation Format: Fieke E. Froeling, Nicolas Robine, Benjamin Hubert, Michael Zody, Dayna Oschwald, Harold E. Varmus, Charles L. Sawyers, David A. Tuveson, On behalf of the NYGC P1000 Consortium. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5128.
Abstract 5129: Actionable activating oncogenic HER2 transmembrane and juxtamembrane domain mutations
Authors: Bajaj Kanika 
Published: August 2019

Abstract
Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) including G660D, R678Q, E693K and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade.
Citation Format: Kanika Bajaj. Actionable activating oncogenic HER2 transmembrane and juxtamembrane domain mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5129.
Abstract 5137: Comprehensive analysis of POLE and POLD1 mutation in 9322 Chinese cancer patients
Authors: Dong Hua , Bai Yuezong , Cao Xinkai , Wang Yanyan , Shi Lin , Li Fugen , Ye Yizhou , Sun Shuyang 
Published: August 2019

Abstract
POLE and POLD1 proofreading mutations can cause ultra-hypermutant-phenotype in cancer, but the distribution of POLE and POLD1 mutation frequency in Chinese population are not clear compared to microsatellite instability (MSI) and tumor mutation burden(TMB). Herein, we examined mutation profiles of POLE and POLD1 in 9322 Chinese cancer patients by two target sequencing panels including POLE and POLD1 gene. Tissue samples from 5866 patients were sequencing with a lab validated CP381 gene panel while plasma samples from 3155 patients were sequencing with a lab validated CT150 gene panel in a CAP certified lab 3DMed. Wet lab experiments and dry lab bioinformatics analysis were done by standard FFPE and ctDNA sample processing and analysis pipeline. POLE and POLD1 pathogenic mutation was defined by published research evidence. Of the 9322 cancer patients, 23 cases showed POLE and POLD1 pathogenic mutations (20 POLE and 3 POLD1), with the total mutation frequency 0.25% (0.35% for tumor sample and 0.006% for plasma sample). However, except for two Intrahepatic cholangiocarcinoma, one melanoma and one endometrial cancer patients, all the left mutation were from colon and rector cancer (CRC), account for a total mutation frequency 1.4% in CRC (19/1335). Although Endometrial cancer is reported with high POLE/POLD1 mutation, there were only 49 endometrial cancer patients in our cohort with mutation frequency 2%(1/49). POLE/POLD1 pathogenic mutations are micro satellite stable (MSS) in 20 cases while the left 3 were MSI-H. Eight cases have co-occurrence with MMR pathway gene loss of function mutation (any one of MSH2/MSH6/MLH1/PMS2), we infer those MMR gene mutations are not driver mutation but passenger mutation induced by POLE and POLD1 proofreading mutations as those eight cases are mostly MSS. Two patients with POLE pathogenic mutation with immune checkpoint inhibitor treatment were followed up for further response evaluation. POLE-and POLD1 pathogenic mutation are very rare in Chinese cancer patients, enrich in CRC type with 2.9% mutation frequency. POLE/POLD1 pathogenic mutations are usually exclusive to MSI-H patients, thus could expand the patient population in colon cancer which have potential to benefit from immune-therapy.
Citation Format: Hua Dong, Yuezong Bai, Xinkai Cao, Yanyan Wang, Lin Shi, Fugen Li, Yizhou Ye, Shuyang Sun. Comprehensive analysis of POLE and POLD1 mutation in 9322 Chinese cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5137.
Abstract 5140: Discovery of biomarkers predicting response to radiation and anti PD1 therapy in head and neck squamous cell cancer
Authors: Lee Joon Sang , Sanicola-Nadel Michele , Protopopov Alexei , Wang Emma , Theilhaber Joachim , Lin Tun Tun , Korrer Michael , Roy Sohini , Kim Young Jun , Pollard Jack 
Published: August 2019

Abstract
Introduction: Treatment of head and neck squamous cell cancer (HNSCC) frequently includes surgery, radiation, chemotherapy, targeted agents, and increasingly combination of the former with immune checkpoint inhibition. An understanding of the mechanisms mediating response to these therapies as well as biomarkers that can better tailor therapy on an individualized basis and reduce treatment-related toxicity would benefit patients.
Methods: To uncover these mechanisms and biomarkers, we analyzed whole transcriptome RNA-Seq data of two different cohorts of head and neck squamous cell cancer patients: pre and post-treatment samples from radiation therapy and pre-treatment samples from anti-PD1 therapy. We evaluated the abundance of eight immune and two stromal cell populations and pathway activity changes by using Gene Set Variation Analysis (GSVA).
Results and Conclusions: Following radiation genes involved in epithelial to mesenchymal transition, extracellular matrix remodeling, and wound healing are upregulated. Additionally, there is evidence of tumor microenvironment remodeling post-radiation consistent with increased fibroblast abundance and decreased immune cell infiltration. Furthermore, innately resistant tumors to anti-PD1 also display similar signatures of gene regulation, suggesting a common mechanism mediating response to both types of treatment. Notably, these signatures are strongly correlated to activation of the transforming growth factor (TGF-β) signaling pathway and suggest that attenuating its signaling may improve anti-PD-1 response and also response to radiation treatment in head and neck squamous cell cancer.
Citation Format: Joon Sang Lee, Michele Sanicola-Nadel, Alexei Protopopov, Emma Wang, Joachim Theilhaber, Tun Tun Lin, Michael Korrer, Sohini Roy, Young Jun Kim, Jack Pollard. Discovery of biomarkers predicting response to radiation and anti PD1 therapy in head and neck squamous cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5140.