bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY06-03: Reprogramming the tumor microenvironment to improve responses to therapy
Authors: Denardo David G. 
Published: July 2017

Abstract
Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells, and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists, leading to a near tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy. To test this hypothesis in human PDAC patients, we have opened a phase I clinical trial testing the safety and impact on the tumor microenvironment of the FAK inhibitor defactinib, in combination with pembrolizumab and gemcitabine (NCT02546531). These studies are ongoing in patients with advanced cancer, including metastatic PDAC. Early biomarker studies on PDAC tissue collected pre- and post-therapy suggest that this combination impacts the immunosuppressive TME.
Citation Format: David G. Denardo. Reprogramming the tumor microenvironment to improve responses to therapy [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 SY06-03. doi:10.1158/1538-7445.AM2017-SY06-03
Abstract SY07-02: Adipose stromal cells: A player in cancer progression and a therapeutic target
Authors: Kolonin Mikhail 
Published: July 2017

Abstract
Prostate cancer (PCa) is promoted by white adipose tissue (WAT) overgrown in obesity. As an underlying mechanism, we have discovered the recruitment of adipose stromal cells (ASC) by tumors. We reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing its receptor CXCR1. As a candidate upstream mechanism, we identified interleukin 22 secreted by WAT-infiltrating leukocytes and signaling through IL-22R in cancer cells. Our experiments in Hi-Myc mice indicate that obesity promotes epithelial-mesenchymal transition (EMT). We show that ASC directly induce EMT in adenocarcinoma cells. To test whether cancer progression can be blocked by ASC targeting, we have used a hunter-killer peptide D-WAT composed of an ASC-homing and a pro-apoptotic domain. D-WAT administration depleted prostate stromal cells expressing a chemokine SDF1α and suppressed the EMT. Our results indicate that ASC promote the EMT, at least in part, via SDF1a paracrine signaling and validate ASC as a therapeutic target.
Citation Format: Mikhail Kolonin. Adipose stromal cells: A player in cancer progression and a therapeutic target [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 SY07-02. doi:10.1158/1538-7445.AM2017-SY07-02
Abstract SY09-02: A novel genetic mechanism of evading antitumor immunity in multiple human cancers
Authors: Ogawa Seishi 
Published: July 2017

Abstract
Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment. Surprising therapeutic responses to these agents are obtained in many advanced cancer patients with different tumor types, such as melanoma, non-small-cell lung cancer, kidney cancer, and Hodgkin lymphoma, suggesting that cancer cells depend critically on evading immune surveillance for their malignant growth. Accumulating evidence suggests that these antibodies convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash antitumor immune responses. However, the genetic basis for the PD-1/PD-L1-mediated immune escape has not been fully elucidated, with the exception of enhanced PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, which were reported in Hodgkin and other B-cell lymphomas as well as stomach adenocarcinoma. Only a few genetic markers are currently available to reliably predict response to anti-PD-1/PD-L1 therapy as well. I will show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumor cells with elevated PD-L1 expression in vivo, which is effectively inhibited by PD-1/PD-L1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade antitumor immunity through PD-L1 overexpression.
Citation Format: Seishi Ogawa. A novel genetic mechanism of evading antitumor immunity in multiple human cancers [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 SY09-02. doi:10.1158/1538-7445.AM2017-SY09-02
Abstract SY19-03: Inflammation-driven cancer: Host and microbial pathways
Authors: Powrie Fiona , McCuaig Sarah , West Nathan , Ryzhakov Grigory 
Published: July 2017

Abstract
The gastrointestinal (GI) tract is home to a large number and vast array of bacteria that play an important role in nutrition, immune system development, and host defense. In inflammatory bowel disease (IBD) there is a breakdown in this mutualistic relationship, resulting in aberrant inflammatory responses that can progress to colon cancer. Our studies in model systems have implicated innate lymphoid cells and production of IL-22 as key drivers of neoplasia and cancer in the intestine. In this presentation I will discuss new checkpoints that control bacteria-driven innate inflammation in the intestine as well as the functional effects of IL-22 on intestinal epithelial cells and interactions between IL-22 signaling and oncogenic mutations. Further understanding of the interactions between host genetics, gut microbiota, and deranged inflammatory pathways will yield new approaches to patient stratification and personalized therapy.
Citation Format: Fiona Powrie, Sarah McCuaig, Nathan West, Grigory Ryzhakov. Inflammation-driven cancer: Host and microbial pathways [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 SY19-03. doi:10.1158/1538-7445.AM2017-SY19-03
Abstract SY21-03: Cancer evolution as a therapeutic target
Authors: Bardelli Alberto 
Published: July 2017

Abstract
When metastatic cancers are challenged with targeted agents, almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor’s evolution, the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells; that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. Another approach is to unleash the ability of the immune system to recognize drug-resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that manipulation of the mutational loads can trigger prolonged therapeutic responses that are not observed when cancer cells are challenged with targeted drugs alone. We postulate that rationally combined targeted therapies and immunotherapies can restrain tumor evolution and can limit the emergence of drug resistance, thus leading to long-term responses.
Citation Format: Alberto Bardelli. Cancer evolution as a therapeutic target [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 SY21-03. doi:10.1158/1538-7445.AM2017-SY21-03
Abstract SY23-01: KSHV: Immune evasion and oncogenesis
Authors: Damania Blossom A. 
Published: July 2017

Abstract
Infection of cells with oncogenic DNA viruses, including herpesviruses, triggers innate immune responses mediated by DNA sensors. Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor that upon activation produces the cyclic dinucleotide cGAMP, which binds and activates Stimulator of Interferon Genes (STING), leading to interferon production and an antiviral response. Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked to several human malignancies including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). We have found that KSHV infection activates the cGAS-STING pathway and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. Furthermore, we have identified several KSHV viral proteins that inhibit the cGAS-STING pathway. It appears that modulation of this pathway is important for viral transmission and the lifelong persistence of oncogenic herpesviruses in the human population.
Citation Format: Blossom A. Damania. KSHV: Immune evasion and oncogenesis [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 SY23-01. doi:10.1158/1538-7445.AM2017-SY23-01
Abstract SY28-02: The adipose-cancer link: From microenvironment to metabolomics
Authors: Ulrich Cornelia M. 
Published: July 2017

Abstract
This presentation will showcase the interface of systemic and localized disturbances in metabolism with tumor development, specifically focusing on colorectal cancer. Colorectal cancer is the second leading cause of cancer-related death worldwide among both men and women. Risk and preventive factors are well established and include, among others, lack of physical activity and obesity (risk) as well as aspirin use and screening (prevention). Adipose tissue is emerging as a key player in carcinogenesis through the secretion of proinflammatory cytokines and adipokines. The colon is surrounded by adipose tissue, which supports the direct (paracrine) adipose-colon crosstalk and influence as a tumor microenvironment, as well as systemic influences on colon carcinogenesis factors secreted into the bloodstream. As part of the ColoCare cohort, an international, multicenter cohort of colorectal cancer patients, we have investigated adipose tissue distribution, composition, characteristics, and possible influence on colorectal tumors. In an integrated analysis of the transcriptome and metabolome of visceral and subcutaneous adipose tissue (VAT and SAT, respectively), we showed that there are distinct differences that may play a central role in driving carcinogenesis (1). These analyses are ongoing and have been extended to blood-based measures of the inflammasome and metabolome, as well as tumor characteristics. Adipose tissue biology can also be directly affected by weight-loss interventions through diet and exercise. As part of the Nutrition and Exercise in Women (NEW) study, we showed that weight loss results in changes in adipose tissue gene expression as well as corresponding reductions in biomarkers, including inflammatory biomarkers (2, 3).
References
1. Liesenfeld DB, Grapov D, Fahrmann JF, Salou M, Scherer D, Toth R, et al. Metabolomics and transcriptomics identify pathway differences between visceral and subcutaneous adipose tissue in colorectal cancer patients: the ColoCare study. Am J Clin Nutr 2015;102(2):433-43.
2. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, et al. Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 2012;72(9):2314-26.
3. Campbell KL, Foster-Schubert KE, Makar KW, Kratz M, Hagman D, Schur EA, et al. Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss. Cancer Prev Res 2013;6(3):217-31.
Citation Format: Cornelia M. Ulrich. The adipose-cancer link: From microenvironment to metabolomics [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 SY28-02. doi:10.1158/1538-7445.AM2017-SY28-02
Abstract SY29-01: Targeting DNA repair factor dysfunction in advanced prostate cancer
Authors: Knudsen Karen E. 
Published: July 2017

Abstract
Prostatic adenocarcinoma (PCa) is the third leading cause of cancer death in U.S. men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct androgen receptor (AR) antagonists, as PCa is exquisitely dependent on AR activity for cell survival and proliferation. Unfortunately, relapse is common; recurrent disease arises largely due to resurgent AR activity with 2-3 years, and there is no cure for this castration-resistant phase (castration-resistant PCa; CRPC). Thus, there is a significant need to develop new means for targeting recurrent AR activity or to develop adjuvant therapies in advanced PCa. Emerging data from our laboratory and others strongly support the concept that alterations in DNA damage repair (DDR) pathways are more common than previously thought in sporadic PCa, and that alterations in these pathways may afford new, more effective means of therapeutic intervention. New studies to be discussed will address underlying mechanisms of action with regard to the pathway and identify clinically actionable ramifications of DNA repair dysfunction. Major concepts to be considered include 1) new findings implicating differential functions of p53 somatic mutations on PCa behavior and response to therapeutic intervention and 2) differential roles of DNA-dependent protein kinase (DNAPK) in controlling PCa progression. Findings to be discussed strongly support a model wherein selected DDR pathways can be developed as therapeutic targets to tailor treatment for prostate cancer and improve outcome for advanced disease.
Citation Format: Karen E. Knudsen. Targeting DNA repair factor dysfunction in advanced prostate 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 SY29-01. doi:10.1158/1538-7445.AM2017-SY29-01
Abstract SY32-04: About Chomsky, patterns, and noncoding RNAs cancer therapeutics
Authors: Calin George A. 
Published: July 2017

Abstract
Resistance to therapy is an important issue in the treatment of cancer, responsible for many cancer-related deaths. Despites decades of research into overcoming this resistance, only modest advances have been made and the resistance mechanisms remain poorly understood. Although to date the most studied noncoding RNAs (ncRNAs) are miRNAs, the importance of long noncoding RNAs (lncRNAs) in cancer is increasingly being recognized. Here we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges. We are further presenting a novel strategy to identify new therapeutic ncRNA targets by using Chomsky-type grammars based on combinatorial use of coding and noncoding RNAs.
Citation Format: George A. Calin. About Chomsky, patterns, and noncoding RNAs cancer therapeutics [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 SY32-04. doi:10.1158/1538-7445.AM2017-SY32-04
Further Improvement of the Heavy Orographic Rainfall Retrievals in the GSMaP Algorithm for Microwave Radiometers
Authors: Yamamoto Munehisa K. , Shige Shoichi , Yu Cheng-Ku , Cheng Lin-Wen 
Published: July 2017

AbstractAn orographic/nonorographic rainfall classification scheme has been introduced for the operational algorithm of the Global Satellite Mapping of Precipitation (GSMaP) for passive microwave radiometers. However, problems of overestimations and false alarms of heavy orographic rainfall remain unresolved. This is because the current scheme selected lower constant thresholds of orographic rainfall conditions for global application and used values of orographically forced upward motion w derived from near-surface atmospheric data. This study improves the conceptual model of the warm-rain process for considering the strength of the upstream flow of the low-level troposphere. Under a weak upstream current, rain reaches the foothills of the windward mountain slope because of sufficient time for condensation and precipitation enhancement by the topography. Conversely, under a strong upstream current, precipitation enhancement occurs nearer to the mountain peak. This is because the upstream current flows so quickly that there is insufficient time for enhancement of precipitation over the foothills of the windward mountain slope. After implementing a variable threshold for w that depends on the mean horizontal low-level wind, the area of orographic enhancement of rain was detected reasonably well in cases of both strong and weak winds. To improve the accuracy of estimates of orographic rainfall, an adjustment to the rain estimation was introduced using a lower-frequency channel. The biases of the rainfall estimate for the adjusted scheme from the Tropical Rainfall Measuring Mission Precipitation Radar were improved for the cases considered here as well as for the Asian region of heavy orographic rainfall over land.
Recent Changes in U.S. Regional Heat Wave Characteristics in Observations and Reanalyses
Authors: Schoof J. T. , Ford T. W. , Pryor S. C. 
Published: July 2017

AbstractHumidity is a key determinant of heat wave impacts, but studies investigating changes in extreme heat events have not differentiated between events characterized by high temperatures and those characterized by simultaneously elevated temperature and humidity. The authors present a framework, using air temperature (T) and equivalent temperature (TE; a measure combining temperature and specific humidity), to examine changes in local percentile-based extreme heat events characterized by high temperature (T only) and those with high temperature and humidity (T-and-TE events). Application to one observational dataset (PRISM), four reanalysis products (1981–2015), and seven U.S. regions reveals widespread changes in heat wave characteristics over the 35-yr period. Agreement among the datasets employed on several heat wave metrics suggests that many of the findings are robust. With the exception of the northern plains region, all regions experienced increases in both T-only and T-and-TE heat wave day (HWD) frequency in each of the reanalyses. In the northern plains, all datasets have negative trends in T-only HWD frequency and positive trends in T-and-TE HWD frequency. Trends in HWD frequency were generally accompanied by changes in the spatial footprint in heat wave conditions. Temperature has increased significantly during T-only HWDs in the western regions, while increases in TE during T-and-TE HWDs have occurred in the central United States and Northeast region. These findings suggest that equivalent temperature provides an alternative perspective on the evolution of regional heat wave climatology. Studies considering changes in regional heat wave impacts should carefully consider the role of atmospheric moisture.
Sex-related differences in bronchial parameters and pulmonary function test results in patients with chronic obstructive pulmonary disease based on three-dimensional quantitative computed tomography
Authors: Li Yan , Dai Yong-liang , Yu Nan , Guo You-min 
Published: July 2017

Objective This study was performed to evaluate the effect of sex on bronchial parameters and the predicted forced expiratory volume in 1 s expressed as a percentage of the forced vital capacity (FEV1% pred) on pulmonary function testing. Methods The data of 359 patients with chronic obstructive pulmonary disease (COPD) with available FEV1% pred and computed tomography (CT) images were retrospectively reviewed. FACT-Digital lung TM software (DeXin, Xi’an, China) was used to perform fully automated three-dimensional CT quantitative measurements of the bronchi. Generation 5 to 7 bronchi were measured, and the parameters analyzed were the lumen diameter (LD), wall thickness (WT), lumen area (LA), and WA% [WA / (WA + LA) × 100%]. Results In the smoking, smoking cessation, and nonsmoking groups, women had a significantly larger WA% and smaller LD, WT, and LA than men. The FEV1% pred was significantly lower in women than men in the smoking and smoking cessation groups. The FEV1% pred was significantly higher in women than men in the nonsmoking group. Conclusion Sex-related differences may partially explain why smoking women experience more severe pulmonary function impairment than men among patients with COPD.