bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1409: Is it what's on the inside that counts? Melanoma mutation profiling and outcomes with immunotherapy
Authors: Freeman Morganna L. , McLeod. Howard 
Published: July 2016

Abstract
Extraordinary advances have been made in the treatment of melanoma over the last few years; immune checkpoint blockade has provided durable responses and meaningful survival outcomes for patients with metastatic disease, yet predicting such responses remains a nascent science. More importantly, the toxicity and financial burden of receiving such therapy warrants a personalized, or precision medicine, approach to appropriate selection of treatment, thus molecular predictors of response may become as important as biomarkers such as PDL1 expression. Recently the high mutational burden of malignant melanoma was shown to be related to the degree of response to the anti-CTLA4 antibody ipilimumab, but mutational burden alone was not sufficient to predict benefit1. Another study has shown NRAS-mutant had a trend to superior outcomes compared with other cohorts in terms of response to therapy with anti-PD1 antibodies and progression-free survival2. Moreover, insight into the molecular evolution of melanoma was recently established3, wherein somatic mutations in oncogenes such as BRAF, NRAS, GNAQ, or GNA11 occur early during progression and additional mutations of TERT, CDKN2A, TP53, and PTEN are seen in late-stage disease. To better evaluate the relationship of these mutations to immunotherapy response, our institution has profiled 95 patients with melanoma with next-generation sequencing (NGS). Of the 95 patients profiled, the most common mutations identified were BRAF (38%), NRAS (21%), TP53 (18%), PTEN (14%), TERT (9%), and CDKN2A (8%). We are presently conducting a retrospective analysis of these selected oncogenes as they relate to clinical responses, and intend to report disease outcomes (duration of response, progression free survival, and overall survival) as they relate to checkpoint inhibition.
Citation Format: Morganna L. Freeman, Howard McLeod. Is it what's on the inside that counts? Melanoma mutation profiling and outcomes with immunotherapy. [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 1409.
Abstract 1424: Predicting response to immune checkpoint therapy using an mutation burden threshold
Authors: Panda Anshuman , Betigeri Anil , Subramanian Kalyanasundaram , Hirshfield Kim , Rodriguez Lorna , Ganesan Shridar , Bhanot Gyan 
Published: July 2016

Abstract
Treatment with antibodies to PD-1 or CTLA-4 leads to prolonged response in some cancer patients. Patients whose tumors have a high mutational burden have a better response to anti-CTLA-4 treatment with ipilimumab in melanoma5, and to anti-PD-1 treatment with pembrolizumab in non-small cell lung6 and colorectal cancer7. These results suggest that a sufficiently high non-synonymous somatic mutation burden in the tumor may lead to protein alterations that serve as neo-antigens to stimulate CD8 T-cell immune response. This immune response may be blocked by the tumor by engaging the immune checkpoint pathway, making such tumors especially vulnerable to immune checkpoint disruption. However, the specific criteria to identify patients likely to respond to immune checkpoint therapy have remained elusive so far.
Using somatic mutation and RNA-Seq data from TCGA, we propose that there exists a mutational threshold, which we call the “Activated Immune Mutational” (AIM) Threshold, which can identify patients likely to respond to immune checkpoint therapy. Compared to AIM- patients (potential non-responders), AIM+ patients (potential responders) have tumors that meet four criteria: (1) a high non-synonymous mutation burden; (2) a high level of immune infiltration in the tumor; (3) a high CD8 T cell fraction in the leukocyte component of the immune infiltrate plus high expression of the T cell marker CD8A; and (4) a high expression of immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA-4.
We find that in melanoma, endometrial, colon, cervical and breast cancer, a clear AIM threshold satisfying all four criteria exists. The distribution of mutations in AIM- versus AIM+ tumors for these cancers is very different. In the former, there are high frequency somatic mutations in only a few genes, while in the latter, high frequency somatic mutations are found in many genes distributed over the whole genome.
Pathological analysis of high-resolution images from 150 TCGA tumors (30 from each of the five tumor types) validated the presence of significantly higher lymphocytic infiltration in the AIM+ tumors compared to AIM- tumors. We show that AIM+ tumors can be identified using sequencing assays which are currently in clinical use. Finally, survival analysis in melanoma patients from TCGA treated with immunotherapy will be presented.
Citation Format: Anshuman Panda, Anil Betigeri, Kalyanasundaram Subramanian, Kim Hirshfield, Lorna Rodriguez, Shridar Ganesan, Gyan Bhanot. Predicting response to immune checkpoint therapy using an mutation burden threshold. [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 1424.
Abstract 143: Mutational landscape of colorectal adenomas reveals potential signatures for progression
Authors: Lin Shu-Hong , Raju Gottumukkala S. , Huff Chad , Gu Jian , Chen Jiun-Shen , Kopetz Scott , Menter David G. , Hawk Ernest , Mishra Lopa , Ye Yuanquing , Wu Xifeng 
Published: July 2016

Abstract
Introduction: Colorectal cancer (CRC) continues to rank as one of the most common cancers in the U.S. and around the world. Colorectal adenoma is the well-established precursor of CRC, yet only a very small proportion of adenomas progress to CRC. Therefore, identification of biomarker associated with adenoma progression is vital for risk stratification and development of intervention strategies. We hypothesize that genomic analysis of adenoma will lead to better understanding of tumorigenesis and identification of novel biomarkers.
Methods: We carried out whole exome sequencing (WES) on tissues and paired blood in 14 sessile serrated adenoma (SSA) and 36 tubulovillous adenoma (TVA) patients. Frequently mutated genes from TVA along with significantly mutated genes of TCGA colorectal adenocarcinoma were further investigated in an additional 100 pairs of TVA by targeted sequencing.
Results: 1) WES revealed similar somatic mutation frequency but distinctive mutated genes in TVA and SSA. 2) All adenomas included in WES were non-hypermutators with mutation frequency ranged from 0.55 to 3.71 (average: 1.49) non-silent somatic mutations per million base, which is significantly lower than that of TCGA non-hypermutators that ranged from 0.48 to 10.11 (average 4.47, p &lt; 2.2×10⁁-16). 3) MutSigCV v1.4 discovered shared and unique significantly-mutated genes (SMG) in TVA and SSA reflecting difference in biology. 4) Targeted sequencing confirmed the findings in WES with a better estimate of population frequency for genes of interest. 5) Unsupervised clustering achieved high discrimination between adenoma and adenocarcinoma. 6) A subset of mutations that best discriminate adenoma and adenocarcinoma were identified by random Forest.
Conclusions: We discovered a set of genes with distinctive mutation pattern between adenoma and adenocarcinoma. We are conducting functional analysis to explore the potential of these genes as progression driver and risk predictors. We predict that the findings of this project will help lay the foundation to inform development of surveillance program and preventive intervention in CRC.
Citation Format: Shu-Hong Lin, Gottumukkala S. Raju, Chad Huff, Jian Gu, Jiun-Shen Chen, Scott Kopetz, David G. Menter, Ernest Hawk, Lopa Mishra, Yuanquing Ye, Xifeng Wu. Mutational landscape of colorectal adenomas reveals potential signatures for progression. [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 143.
Abstract 1443: IL-18 is associated with the onset and progression of gastric cancer
Authors: Nguyen Paul , Busuttil Rita , Mielke Lisa , Belz Gabrielle , Boussioutas Alex , Ernst Matthias , Putoczki Tracy 
Published: July 2016

Abstract
INTRODUCTION: Gastric cancer (GC) is the fourth most prevalent, and the third most common cause of cancer-related death worldwide. The disease is generally asymptomatic, and consequently is often diagnosed at an advanced stage when metastasis is present, and limited treatment options are available. Chronic inflammation is recognized as an integral component in the development and progression of GC, and is associated with increased infiltration of immune cells into the tumor microenvironment. The production of pro-inflammatory cytokines by these cells may contribute to tumor progression through activation of pathways promoting tumor cell survival and proliferation. Previous work from our lab has shown that therapeutic inhibition of the inflammatory cytokine interleukin (IL)-11 is effective in ameliorating disease progression in gastrointestinal cancer, however, it is unclear what role other pro-inflammatory cytokines, such as IL-18, might have in disease progression.
METHODS: To characterize the role of different pro-inflammatory cytokines in GC, we first analyzed microarray and qRT-PCR data of from human GC specimens and adjacent non-tumor tissue. Following the generation of a candidate list of cytokines deregulated in human GC, the role of individual cytokines in disease progression was examined using a validated mouse model of intestinal-type GC, referred to as gp130Y757F, by crossing into cytokine knock-out strains and monitoring tumor burden and the expression of genes and proteins classically associated with tumorigenesis.
RESULTS: We found that the expression pro-inflammatory cytokines including IL-1β and IL-18 were significantly elevated in the tumors of human GC patients compared to non-tumor tissue. In gp130Y757F mice, genetic ablation of IL-18, but not of IL-1β significantly reduced gastric tumor burden, which was associated with a reduction in the number of intratumoral macrophages, but not lymphocytes. This observation correlated with decreased expression of pro-inflammatory (Ifng, Tgfb1), antimicrobial (Reg3b, Reg3g), and tissue remodeling (Mmp9) genes, and a reduction in apoptosis in the gastric lesions in these mice.
CONCLUSION: Our results demonstrate that IL-18 has an important role in GC disease progression, and may serve as a potential therapeutic target.
Citation Format: Paul Nguyen, Rita Busuttil, Lisa Mielke, Gabrielle Belz, Alex Boussioutas, Matthias Ernst, Tracy Putoczki. IL-18 is associated with the onset and progression of gastric 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 1443.
Abstract 1446: Discovery of a distinct human lung tissue microbiome and its epidemiologic and clinical features
Authors: Yu Guoqin 
Published: July 2016

Abstract
The human lung tissue microbiota remains largely uncharacterized although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the microbiota taxonomic and derived functional profiles in 165 non-malignant lung tissue samples from cancer patients. We show that the lung microbiota is unique, differing from the microbiota of oral, nasal, stool, skin, and vagina samples. Microbiota diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking. Moreover, the non-malignant lung tissue microbiota is altered in subjects with chronic bronchitis or advanced stage of lung cancer, and differs significantly from the microbiota in lung tumor samples. These findings provide insights on the human lung microbiota composition and function, and their link to human life style and clinical outcomes.
Citation Format: Guoqin Yu. Discovery of a distinct human lung tissue microbiome and its epidemiologic and clinical features. [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 1446.
Abstract 1449: In vivo targeted silencing of CCR1 and CCR5 repolarizes pro-tumoral myeloid cells in retinoblastoma positive neutrophils with a strong anti-tumor activity
Authors: Zilio Serena , Vella Jennifer , De La Fuente Adriana , Bronte Vincenzo , Mazza Emilia , Bicciato Silvio , Serafini Paolo 
Published: July 2016

Abstract
Introduction: Depending on their polarization, myeloid cells can either promote or restrain tumor progression. By secreting myelopoietic factors tumours promote myeloid cells polarization toward a phenotype that provides immune protection and that stimulate neoplastic cells growth, invasiveness, and metastasis. Chemokines and their cognate receptors are thought to play a key role in myeloid cell trafficking, however, their study in vivo is hindered by their signal redundancy and integration.
Methods: By taking advantage of a newly developed nanoplatform that allows the in vivo preferential transfection of tumor infiltrating myeloid cells (TIMC, aka Myeloid derived suppressor cells, MDSC, and tumor associated macrophages, TAM), we evaluated the effect of CCR-1, CCR-2, CCR-4, CCR-5 and/or CCR-7 silencing on TAMC trafficking, phenotype, and function.
Results: While CCR-4 and -7 targeted silencing did not affect tumor progression, simultaneous silencing of CCR-1 and CCR-5 significantly restrained tumor growth and greatly modifies tumor micro-environment. Mechanistic in vivo and in vitro analysis surprisingly indicate that myeloid cell trafficking was not altered whereas myeloid cell polarization was. In particular, CCR-1 and CCR-5 blockade restrained MDSC differentiation and promote the accumulation of retinoblastoma positive, neutrophil-like cells with a strong tumoricidal activity.
Discussion: Our data indicate that CCR-1 and CCR-5 engagement (most likely via CCL-3 and CCL-4) is necessary for the pro-tumoral polarization of myeloid cells in cancer. Our findings not only improve our understanding of myeloid cells differentiation in cancer but, also, strongly suggest that targeted inhibition of CCR1 and CCR5 on TIMC can be a new and effective anti-tumor immune-therapeutic strategy that convert pro-tumoral MDSCs into tumoricidal neutrophils.
Citation Format: Serena Zilio, Jennifer Vella, Adriana De La Fuente, Vincenzo Bronte, Emilia Mazza, Silvio Bicciato, Paolo Serafini. In vivo targeted silencing of CCR1 and CCR5 repolarizes pro-tumoral myeloid cells in retinoblastoma positive neutrophils with a strong anti-tumor activity. [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 1449.
Abstract 1452: IL-15 overexpression protects cerulein-induced fibrosis in the mouse model of chronic pancreatitis
Authors: MANOHAR MURLI , UPPARAHALLI VENKATESHAIAH SATHISHA , PUTANAPURA MAHADEVAPPA CHANDRASHEKARA , KUMAR VERMA ALOK , MISHRA. ANIL 
Published: July 2016

Abstract
Introduction: Earlier, interleukin (IL)-6, IL-8, IL-1β and IL-10 are implicated in the pathogenesis of pancreatitis. Recently, we observed reduced level of IL-15 in cerulein- induced acute and chronic mouse model of pancreatitis. IL-15 is a pleiotropic cytokine that has an important role in innate immunity. Therefore, we tested the hypothesis that IL-15 overexpression improves the pathogenesis of cerulein-induced pancreatitis.
Experimental procedure: Accordingly, we tested our hypothesis by inducing chronic pancreatitis in rIL-15 pretreated Balb/c mice. Cerulein was given by repetitive intraperitoneal (i.p.) injections as reported earlier (50 μg/kg, 6 hourly injections/day, 3 days/week) along with the rIL-15 (5 μg in 100μl saline/ two-times/week/mice) for up to 4 weeks; the control mice received 100μl saline or saline with 5 μg IL-15. Mice were sacrificed 3 days after the last cerulein injection. Histopathological evaluation of H&E stained tissue sections was performed including tissue remodeling and the accumulation of collagen by Masson's trichrome stain in the tissue sections. Additionally, pro-inflammatory and pro-fibrotic gene i.e. TGF-β1, IL-6, IL-8, Collagen 1 and α-SMA levels were measured by ELISA, immunofluorescence, qPCR and immunoblot analysis.
Summary: We report acinar cells atrophy, induced inflammatiory cells and cytokines in the pancreas of cerulein treated mice along with perivascular collagen deposition compare to saline treated mice. Interestingly, rIL-15 treated and cerulein given mice showed significantly improved morphology of acinar cells and reduced perivascular collagen. Further, we also report that protein levels of TGF-β1 and α-SMA is also reduced in the pancreas of cerulein injected and IL-15 treated mice compare to cerulein treated mice by performing western blot and immunohistochemistry.
Conclusion: Our data show that IL-15 overexpression protects mice from cerulein-induced pancreatic pathogenesis including fibrosis. Taken together, rIL-15 therapy may be a novel strategy to treat pancreatic fibrosis, and may also helpful to treat pancreatic cancer patients by down-regulating tissue fibrogenesis.
Funding: NIH R01 DK067255 (AM), NIH R01 AI080581 (AM),
Citation Format: MURLI MANOHAR, SATHISHA UPPARAHALLI VENKATESHAIAH, CHANDRASHEKARA PUTANAPURA MAHADEVAPPA, ALOK KUMAR VERMA, ANIL MISHRA. IL-15 overexpression protects cerulein-induced fibrosis in the mouse model of chronic pancreatitis. [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 1452.
Abstract 1454: IL-4 modulate the tumor microenvironment and response to cancer therapies
Authors: Ito Shuku-ei A. , Shirota Hidekazu , Ishioka Chikashi 
Published: July 2016

Abstract
recent findings show that immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4 in particular is up-regulated. Thus, we tested whether depletion of IL-4 affected in tumor immunity. Current results demonstrate that administration of neutralizing antibody against IL-4 enhances anti-tumor immunity and improve the response to Taxol-based chemotherapy and CpG ODN immunotherapy. Depletion of IL-4 also alter the tumor microenvironment, reducing the generation of immunosuppressive M2 macrophages and myeloid derived suppressor cells and enhancing tumor specific CTLs. These findings suggest that IL-4 impact anti-tumor immunity and constitute an attractive therapeutic target to reduce immune suppression in the tumor microenvironment and thus enhance the efficacy of cancer therapy.
Citation Format: Shuku-ei A. Ito, Hidekazu Shirota, Chikashi Ishioka. IL-4 modulate the tumor microenvironment and response to cancer therapies. [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 1454.
Abstract 146: Genomic analysis of endometrial stromal sarcoma of uterus
Authors: Choi Youn Jin , Hur Soo Young , Park Jong Sup , Lee Keun Ho , Lee Yoon Kyung 
Published: July 2016

Abstract
Although recurrent gene fusions such as JAZF1-JJAZ1 are considered driver events for endometrial stromal sarcoma (ESS) development, other genomic alterations remain largely unknown. In this study, we performed whole-exome sequencing, transcriptome sequencing and copy number profiling for five ESSs (three low-grade ESS (LG-ESS) and two undifferentiated uterine sarcomas (UUSs)). All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not. All ESSs except one LG-ESS exhibited copy number alterations (CNAs), many of which encompassed cancer-related genes. In UUSs, five CNAs encompassing cancer-related genes (EZR, CDH1, RB1, TP53 and PRKAR1A) accompanied their expressional changes, suggesting that they might stimulate UUS development. We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations. However, they were non-recurrent and did not include any well-known mutations, indicating that point mutations may not be a major driver for ESS development. Our data show that gene fusions and CNAs are the principal drivers for LG-ESS and USS, respectively, but both may require additional genomic alterations including point mutations. These differences may explain the different biologic behaviors between LG-ESS and UUS. Our findings suggest that ESS development requires point mutations and CNAs as well as the gene fusions. Clinical and histologic characteristics of five endometrial stromal sarcomasAgeHistopathology gradeDiagnosisSpecimen statusTNMCase 132Low-gradeLG-ESSPrimaryT1bN0M0Case 234Low-gradeLG-ESSPrimaryT1bN1M0Case 357Low-gradeLG-ESSPrimaryTxNxM1Case 465High-gradeUUSMetastaticT2aN0M0Case 557High-gradeUUSMetastaticTxNxM1
Citation Format: Youn Jin Choi, Soo Young Hur, Jong Sup Park, Keun Ho Lee, Yoon Kyung Lee. Genomic analysis of endometrial stromal sarcoma of uterus. [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 146.