bluuebunny/crossref_metadata_2025_split huggingface dataset:
BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer
Authors: Yokoyama Yuhki , Zhu Hengrui , Lee Jeong Heon , Kossenkov Andrew V. , Wu Sherry Y. , Wickramasinghe Jayamanna M. , Yin Xiangfan , Palozola Katherine C. , Gardini Alessandro , Showe Louise C. , Zaret Kenneth S. , Liu Qin , Speicher David , Conejo-Garcia Jose R. , Bradner James E. , Zhang Zhiguo , Sood Anil K. , Ordog Tamas , Bitler Benjamin G. , Zhang Rugang 
Published: November 2016

Abstract
The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. The clinically applicable small-molecule BET inhibitor JQ1 suppressed the outgrowth of cisplatin-treated ovarian cancer cells both in vitro and in vivo. Combination of JQ1 and cisplatin improved the survival of ovarian cancer–bearing mice in an orthotopic model. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and other stem-related genes in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using clinically applicable small-molecule inhibitors, such as JQ1, is a promising strategy for targeting ALDH activity in epithelial ovarian cancer. Cancer Res; 76(21); 6320–30. ©2016 AACR.
Insurance-Based Differences in Time to Diagnostic Follow-up after Positive Screening Mammography
Authors: Durham Danielle D. , Robinson Whitney R. , Lee Sheila S. , Wheeler Stephanie B. , Reeder-Hayes Katherine E. , Bowling J. Michael , Olshan Andrew F. , Henderson Louise M. 
Published: November 2016

AbstractBackground: Insurance may lengthen or inhibit time to follow-up after positive screening mammography. We assessed the association between insurance status and time to initial diagnostic follow-up after a positive screening mammogram.Methods: Using 1995–2010 data from a North Carolina population-based registry of breast imaging and cancer outcomes, we identified women with a positive screening mammogram. We compared receipt of follow-up within 60 days of screening using logistic regression and evaluated time to follow-up initiation using Cox proportional hazards regression.Results: Among 43,026 women included in the study, 73% were &lt;65 years and 27% were 65+ years. Median time until initial diagnostic follow-up was similar by age group and insurance status. In the adjusted model for women &lt;65, uninsured women experienced a longer time to initiation of diagnostic follow-up [HR, 0.47; 95% confidence interval (CI), 0.25–0.89] versus women with private insurance. There were increased odds of these uninsured women not meeting the Centers for Disease Control and Prevention guideline for follow-up within 60 days (OR, 1.59; 95% CI, 1.31–1.94). Among women ages 65+, women with private insurance experienced a faster time to follow-up (adjusted HR, 2.09; 95% CI, 1.27–3.44) than women with Medicare and private insurance. Approximately 10% of women had no follow-up by 365 days.Conclusions: We found differences in time to initial diagnostic follow-up after a positive screening mammogram by insurance status and age group. Uninsured women younger than 65 years at a positive screening event had delayed follow-up.Impact: Replication of these findings and examination of their clinical significance warrant additional investigation. Cancer Epidemiol Biomarkers Prev; 25(11); 1474–82. ©2016 AACR.
Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer
Authors: Win Aung Ko , Jenkins Mark A. , Dowty James G. , Antoniou Antonis C. , Lee Andrew , Giles Graham G. , Buchanan Daniel D. , Clendenning Mark , Rosty Christophe , Ahnen Dennis J. , Thibodeau Stephen N. , Casey Graham , Gallinger Steven , Le Marchand Loïc , Haile Robert W. , Potter John D. , Zheng Yingye , Lindor Noralane M. , Newcomb Polly A. , Hopper John L. , MacInnis Robert J. 
Published: November 2016

Abstract
Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.
Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.
Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age &lt;40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).
Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.
Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.
Survival of Lung Adenocarcinoma Patients Predicted from Expression of PD-L1, Galectin-9, and XAGE1 (GAGED2a) on Tumor Cells and Tumor-Infiltrating T Cells
Authors: Ohue Yoshihiro , Kurose Koji , Nozawa Ryohei , Isobe Midori , Nishio Yumi , Tanaka Tomonori , Doki Yoshinori , Hori Takashi , Fukuoka Junya , Oka Mikio , Nakayama Eiichi 
Published: November 2016

Abstract
The immune status of tumors varies, and this may affect the overall survival (OS) of patients. We examined tumors from 120 patients with lung adenocarcinomas with a tissue microarray for T-cell infiltration and the expression of PD-L1 and Galectin-9 (both ligands for inhibitory receptors on T cells), and cancer/testis (CT) antigen XAGE1 (GAGED2a; a tumor antigen often found on lung tumors) expression, to determine their relevance to OS. Patients defined as pStage I–IIIA could be grouped, based on the expression profiles of PD-L1, Galectin-9, and XAGE1, into cluster A, who had prolonged survival, and cluster B, who had shorter survival. The difference in survival of the clusters was confirmed separately for pStage I and pStage II–IIIA patients. Cluster A patients who also had CD4 and CD8 T-cell infiltration showed even better survival, as expected. The findings were confirmed by examining an independent validation cohort of 68 pStage I lung adenocarcinoma patients. Our data showed that PD-L1 expression was a positive indicator, whereas Galectin-9 and XAGE1 expression was negative. In vitro analyses suggested that PD-L1 expression was upregulated by IFNγ secreted from activated T cells in the tumor and Galectin-9 expression was counteracting those T cells. Thus, use of these immune markers enables the creation of a discriminant function with which to classify tumors and predict survival. Cancer Immunol Res; 4(12); 1049–60. ©2016 AACR.
Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach
Authors: Johanns Tanner M. , Ward Jeffrey P. , Miller Christopher A. , Wilson Courtney , Kobayashi Dale K. , Bender Diane , Fu Yujie , Alexandrov Anton , Mardis Elaine R. , Artyomov Maxim N. , Schreiber Robert D. , Dunn Gavin P. 
Published: November 2016

Abstract
The “cancer immunogenomics” paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific “neoantigens” in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed. To establish the immunogenicities of H-2Kb and H-2Db candidate neoantigens, we assessed the ability of the epitopes predicted in silico to be the highest affinity binders to activate tumor-infiltrating T cells harvested from GL261 and SMA-560 tumors. Using IFNγ ELISPOT, we confirmed H-2Db–restricted Imp3D81N (GL261) and Odc1Q129L (SMA-560) along with H-2Kb–restricted E2f8K272R (SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3D81N and Odc1Q129L were detected within intracranial tumors as well as cervical draining lymph nodes by tetramer analysis. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell–activating immunotherapeutic approaches in preclinical models of glioblastoma. Cancer Immunol Res; 4(12); 1007–15. ©2016 AACR.
Immunological Mechanisms Underneath the Efficacy of Cancer Therapy
Authors: Galluzzi Lorenzo , Zitvogel Laurence , Kroemer Guido 
Published: November 2016

Abstract
Accumulating preclinical and clinical evidence indicates that the success of several anticancer agents—including some conventional chemotherapeutics, targeted anticancer agents as well as specific forms of radiotherapy—depends (at least in part) on their ability to stimulate anticancer immune responses. Such immunostimulatory effects can be “on-target,” i.e., they originate within cancer cells, or “off-target,” i.e., they develop from a heretofore unsuspected interaction between cancer therapy and the immune system. Here, we briefly discuss the immunologic mechanisms that underlie the efficacy of some forms of cancer therapy, as we highlight the rationale for combining these treatment modalities with immunotherapy to achieve superior therapeutic effects. Cancer Immunol Res; 4(11); 895–902. ©2016 AACR.
Abstract A005: Tumor- and host-intrinsic RIG-I signaling promote anticancer immunity by CTLA-4 blockade
Authors: Heidegger Simon , Wintges Alexander , Kreppel Diana , Bek Sarah , Bscheider Michael , Schmickl Martina , Brink Marcel R.M. van den , Peschel Christian , Haas Tobias , Poeck Hendrik 
Published: November 2016

Abstract
Introduction: Targeting inhibitory T-cell receptors such as CTLA-4 has shown great promise in cancer therapy. However, strong inter-individual variation in clinical response to checkpoint inhibitors remains a major challenge. Expression of viral defense genes in human melanomas including the cytosolic RNA receptor RIG-I (DDx58) has recently been associated with clinical benefit to CTLA-4 blockade.
Methods: Using CRISPR/Cas9 technology to generate B16 melanoma cells lines that lack nucleic acid receptors or downstream signaling molecules (RIG-I, STING, IRF3/7) together with available genetically deficient mouse models, we address the importance of nucleic acid receptor signaling for the efficacy of anti-CTLA-4 immunotherapy.
Results: We provide experimental proof that anti-CTLA-4 immunotherapy indeed relies on tumor cell-intrinsic RIG-I/MAVS but not cGAS/STING signaling. Consistently, therapeutic targeting of RIG-I with the specific ligand 5'‑triphosphate-RNA (3pRNA) potently augments the efficacy of CTLA-4 checkpoint blockade. In situ vaccination by intratumoral 3pRNA injection enhanced cross-presentation of tumor-associated antigens by CD103+ migratory DCs in local draining lymph nodes. Subsequent expansion of tumor-specific CD8+ T cells resulted in control of local and distant tumors, otherwise resistant to anti-CTLA‑4 monotherapy. These processes were critically dependent on tumor cell-intrinsic RIG-I-mediated immunogenic cell death (ICD), but not tumor-derived type I IFN release. In such, the synergistic therapeutic effect of RIG-I activation and anti-CTLA-4 was restricted to tumor models that showed susceptibility to RIG‑I-mediated ICD. Furthermore, systemic antitumor immunity following anti-CTLA-4 +/- 3pRNA treatment required RIG-I signaling in both tumor and non-malignant host cells.
Conclusion: Our study identifies a hitherto unrecognized role of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer. Therapeutic targeting of RIG-I using specific agonists strongly augments the efficacy of anti-CTLA-4 blockade and may thus serve as the basis for new combinatorial approaches.
Citation Format: Simon Heidegger, Alexander Wintges, Diana Kreppel, Sarah Bek, Michael Bscheider, Martina Schmickl, Marcel R.M. van den Brink, Christian Peschel, Tobias Haas, Hendrik Poeck. Tumor- and host-intrinsic RIG-I signaling promote anticancer immunity by CTLA-4 blockade [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A005.
Abstract A062: The effects of cellular context on miR-155 mediated regulation of gene expression
Authors: Hsin Jing-Ping , Lu Yuheng , Leslie Christina S. , Rudensky Alexander Y. 
Published: November 2016

Abstract
MicroRNA-155 (miR-155) is involved in differentiation and regulation of responses of multiple haematopoietic cell types. Its dysregulation is implicated in many human malignancies, e.g. Hodgkin, diffuse large B lymphomas, and breast cancer. Many microRNAs and their target mRNAs are co-expressed in diverse types of cells and tissues. To what extent the interaction between a specific microRNA and its target mRNAs is preserved in different cellular context is largely unknown. We employed genome-wide approaches to investigate whether regulation of commonly expressed mRNA by miR-155 operates in a cell type-specific manner in analogy to cell-context dependent regulation by transcription factors. We first performed RNA-Seq to quantitatively measure mRNA expression levels in primary B cells, dendritic cells, macrophages, and CD4+ T cells from wild type and miR-155 knockout mice. We found many miR-155 target mRNAs that contain seed matches in 3' untranslated regions (3'UTRs) were differentially repressed between four types of primary immune cells. Next, we performed iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation) to precisely map Argonaute 2 binding. Quantitative analysis of iCLIP in both wild type and miR-155 KO primary cells uncovered hundreds of miR-155 bound genes, a large number of which overlapped the cohorts of genes that were identified by RNA-Seq as differentially regulated by miR-155. Most mRNAs are alternatively polyadenylated, and through alternative polyadenylation (ApA) mRNAs can acquire or lose microRNA sites. To account for ApA, we carried out PolyA-Seq to measure polyadenylation site usage, and found that ApA contributed to differential miR-155 regulation of a number of genes. However, in many cases the same target 3'UTR isoforms were differentially regulated between cell types, suggesting ApA-independent mechanisms of miR-155 specificity, and cellular context dependent miR-155-mediated regulation of gene expression. This research will elucidate mechanistic underpinning of cell-context dependent microRNA function, and help understand miR-155 functions in disease, specifically in lymphomas and other cancers.
Citation Format: Jing-Ping Hsin, Yuheng Lu, Christina S. Leslie, Alexander Y. Rudensky. The effects of cellular context on miR-155 mediated regulation of gene expression [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A062.
Abstract A102: The fat in ovarian cancer: Immune-dependent tumor-promoting effects
Authors: Suarez-Carmona Meggy , Heinzelmann Anita , Valous Nektarios A. , Hampel Mareike , Berthel Anna , Schott Sarah , Zörnig Inka , Jäger Dirk , Halama Niels 
Published: November 2016

Abstract
Because of the particular anatomy of ovaries, which are in close contact with the adipocyte-rich omentum, ovarian cancer frequently presents itself with established metastasis-like disseminated tumor islets along the omentum.
The tropism of ovarian cancer cells for fat is well described. Indeed, adipocyte-derived free fatty acids have been causatively linked to cancer cell proliferation and invasive properties. Obesity is additionally linked to increased risk of ovarian cancer onset and, in ovarian cancer patients, to worse outcome. However, there is to our knowledge no clear association between omentum-anchored dissemination and the anti-tumor immune response.
Here we describe an unsuspected association between the presence peritoneal fat in ovarian tumors and massive tumor infiltration by T cells. Still, this massive T cell influx seems to fail in its anti-tumor activity since (1) tumor-infiltrating T cells seem to be hijacked away from tumor cells and accumulate around fatty areas and (2) tumor-infiltrating T cells display an exhausted phenotype.
In this presentation, we also describe a new model of tissue culture of explants from primary human tumors that are treated with various drugs in an attempt to circumvent this fat-derived immune exhaustion and restore an efficient anti-tumor immune response.
Citation Format: Meggy Suarez-Carmona, Anita Heinzelmann, Nektarios A. Valous, Mareike Hampel, Anna Berthel, Sarah Schott, Inka Zörnig, Dirk Jäger, Niels Halama. The fat in ovarian cancer: Immune-dependent tumor-promoting effects [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A102.
Abstract A114: Effect of different standard of care chemotherapeutics on anti-PD-L1 responses in syngeneic mouse tumor models
Authors: Cubas Rafael , Moskalenko Marina , Cheung Jeanne , Luoh Shiuh-Ming , McNamara Erin , Belvin Marcia , Kim Jeong , Gould Stephen 
Published: November 2016

Abstract
Immunotherapy with checkpoint inhibitors has proven to be highly effective, with durable responses in a subset of patients. In an effort to broaden the number of responding individuals, overcome resistance to single-agent therapy and extend the duration of responses, combination of immunotherapy with other treatments such as chemotherapy is currently being tested in multiple clinical trials. Importantly, combination of immunotherapy with standard of care chemotherapy could bring the benefits of immunotherapy into earlier lines of treatment.
Here, we have evaluated the effects of different classes of chemotherapeutic agents alone or in combination with anti-PD-L1 treatment in syngeneic murine tumor models. We have found that combination of anti-PD-L1 with various alkylating agents, taxanes and platins caused differential changes on the frequency and number of intratumoral immune cell subsets, but did not antagonize the functional changes mediated by anti-PD-L1 treatment. Importantly, by comparing the effects of these chemotherapies in different tumor models, we have observed that their effects are model-specific. These differences may be due to tumor-specific immune composition and tumor intrinsic responses to different chemotherapies.
Our results demonstrate that in the models we have tested, chemotherapeutic agents do not appear to directly antagonize the activity of anti-PD-L1 as measured by pharmacodynamic changes in immune cell activation although some differences can be observed in the frequency and number of certain intratumoral immune cell subsets. Additionally, our findings also reveal that tumor models might respond differently to the same chemotherapeutic treatment adding complexity to how we evaluate the effect of combination treatments with chemotherapy. Nonetheless, our results suggest a rationale for combining immunotherapy with chemotherapy in the clinic, although consideration should be taken when generalizing results from mouse tumor models.
Citation Format: Rafael Cubas, Marina Moskalenko, Jeanne Cheung, Shiuh-Ming Luoh, Erin McNamara, Marcia Belvin, Jeong Kim, Stephen Gould. Effect of different standard of care chemotherapeutics on anti-PD-L1 responses in syngeneic mouse tumor models [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A114.