bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 126: MYC-driven lymphomas suppress NK surveillance by blocking maturation of early NK cells
Authors: Heftdal Line D. , Swaminathan Srividya , Felsher Dean W. 
Published: August 2018

Abstract
The MYC oncogene is commonly overexpressed in hematopoietic cancers. In a transgenic mouse model of MYC-induced T-cell lymphoma, we found that there was a systemic reduction in NK cell (CD3- NKp46High) numbers and activation in lymphoid organs such as spleen and bone marrow. MYC inactivation in lymphoma-bearing MYCON mice partially restored NK cell numbers and activation. Hence, the MYC oncogene appears to suppress NK cell-mediated immune surveillance of lymphomas. We evaluated whether reduction in mature and activated NK cells (CD3- NKp46High) in MYCON mice was due to increased death of NK cells in these mice when compared to normal and MYCOFF mice. Using flow cytometry, NK cells were measured in age matched spleens and bone marrows of normal (n = 8), MYCON (n = 8), and MYCOFF (n = 8) mice. Surprisingly, we observed a significant reduction in proportions of dead NK cells (NKp46+ PI+) in spleen and bone marrow of MYCON mice, in comparison to normal and MYCOFF cohorts. Hence, the reduction in activated NK cell numbers during MYC-driven lymphomagenesis does not occur because of increased death of NK cells. Next, we investigated whether MYC arrests early NK cell development in the bone marrow of lymphoma mice, leading to systemic NK suppression. NK cell lineage specification begins with CD122 expression, that is maintained throughout NK development starting at the precursor stage. NK precursors (NKP) transition to immature NK (iNK) cells by expressing the cytotoxicity marker NKp46. iNK cells leave the bone marrow to populate peripheral lymphoid organs. We measured NKP (CD122+ NKP46-), and iNK (CD122+ NKp46+) cells in bone marrow of normal (n = 8), MYCON (n = 8), and MYCOFF (n = 8) mice. We observed no significant changes in the percentages of NKP. However, the proportions of iNK cells were significantly reduced in MYCON mice, in comparison to MYCOFF and normal mice. Our results suggest that MYC may block transition from NKP to iNK stage during early NK cell development. The reduction of iNK cells in spleens of MYCON mice was concordant with the reduction of iNK cells in bone marrow from the same mice. We conclude that MYC-induced lymphomagenesis blocks early NK cell development, thereby suppressing NK-mediated immune surveillance.
Citation Format: Line D. Heftdal, Srividya Swaminathan, Dean W. Felsher. MYC-driven lymphomas suppress NK surveillance by blocking maturation of early NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 126.
Abstract 1264: Commensal microbiota is involved in anti-PD-1 mAb-mediated antitumor activity in a preclinical tumor model
Authors: Chen Fei , Ding Jian , Gu Xiangchao , Zhang Juan , Yang wenqing , Shi Qian 
Published: August 2018

Abstract
Background: A number of studies have shown that the gut microbiome may influence anti-tumor immune responses via innate and adaptive immunity, and the recent work in mice has highlighted the key roles of the gut microbiota in mediating tumor responses to chemotherapeutic agents and immunotherapies targeting PD-L1, PD-1 or CTLA-4. Multiple studies have demonstrated that the gut microbiome can markedly influence the outcome of PD-1 blockade in mice and patients and several commensal have been proved to be associated with favorable clinical outcome. Considering complexity of intestinal micro-organisms, a larger panel or wider spectrum of microbiota species maybe involved in this process.
Methods: Since compositional differences in the microbiome may influence cancer development and responses to therapies, we sought to determine whether intestinal bacterial composition and abundances of the tumor bearing mice were associated with a specific treatment outcome of immunotherapy. To test this, we analyzed and compared an enrichment of intestinal microbiota of CT26 syngeneic tumor bearing mice before and after a series of anti-PD-1 mAb treatment were given.
Results The results demonstrating that some strains were robustly enriched and this enrichment was associated with tumor response to anti-PD 1 therapy, while as other strains were down regulated upon the checkpoint blockade.
Conclusions: Upon further characterization and confirmation, these intriguing findings could lead to identification of one or more microbiota strains that could have biomarker potentials or therapeutic values for cancer immunotherapy.
Citation Format: Fei Chen, Jian Ding, Xiangchao Gu, Juan Zhang, wenqing Yang, Qian Shi. Commensal microbiota is involved in anti-PD-1 mAb-mediated antitumor activity in a preclinical tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1264.
Abstract 127: Exosomes derived from head and neck cancer enhance the cytotoxicities of NK cells by NAP1-IRF-3 pathway
Authors: Chen Wantao , Wang Yingnan , Zhang Jianjun 
Published: August 2018

Abstract
Objective: To examine the effect of tumor-derived exosomes (TEXs) from oral cancer on natural killer (NK) cells and to explore the underlying mechanism.
Materials and Methods: TEXs were isolated from the medium supernatant of oral cancer (OC) cells using ultrafiltration and affinity chromatography and were identified using electronic microscopy, nanoparticle tracking analysis and immunoblotting. The effects of TEXs on NK cells were analyzed using laser scanning confocal microscopy and several functional assays of NK cells. To explore the mechanism, antibody array, protein mass spectrometry and RNA interference were adopted.
Results: The particles isolated from the OC cells were identified as exosomes with satisfactory morphology, concentration and purity. The TEXs were internalized by the NK cells and then promoted the biologic functions of these cells, including proliferation, cytotoxicity and the release of perforin and granzyme M. Furthermore, we found that the TEXs increased the expression of interferon regulatory factor 3 (IRF-3) and phosphorylated IRF-3 by antibody array, which drove the expression of the type I interferon (IFN) gene and the chemokine (C-X-C motif) ligand (CXCL) genes, thereby promoting the function of NK cells. We also found that NF-κB-activating kinase-associated protein 1 (NAP1), an upstream activator of IRF-3, was enriched in TEXs, and treatment with TEXs increased NAP1 in NK cells. Importantly, NAP1-depleted TEXs obtained from OC cells dramatically weakened the influence of the TEXs on NK cells.
Conclusion: Our findings reveal a previously unrecognized function of exosome derived from oral cancer cells in enhancing the cytotoxicity of NK cells by NAP1- IRF-3 pathway.
This work was supported by the National Program on Key Research Project of China (2016YFC0902700).
Citation Format: Wantao Chen, Yingnan Wang, Jianjun Zhang. Exosomes derived from head and neck cancer enhance the cytotoxicities of NK cells by NAP1-IRF-3 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 127.
Abstract 1274: Effects of diet on lung adenoma carcinogenesis in metformin treated A/J mice
Authors: Souksavong Vannesa , Wuertz Beverly R. , Seabloom Donna , Ondrey Frank G. 
Published: August 2018

Abstract
There has been considerable interest in the effects of biguanides, utilized to treat type 2 diabetes, on human carcinogenesis. Several population studies established diabetes patients treated with metformin and other type 2 diabetes agents experience decreased cancers in several organ systems. However, the effects are not universal in all organ systems and metabolically complex. In the present study, we utilized a dosing regimen of dietary metformin in benzo[a]pyrene treated mice known to reduce lung adenoma formation in A/J mice by approximately 50% over controls. For the duration of this study we used several animal diets commonly employed for mouse chemoprevention experiments with and without 850 mg/kg/day metformin added to the diet. These included AIN93M, AIN76A, D62 (Dr. Lee Wattenberg's chemoprevention diet), a modification of D62 with added maltodextrin and sucrose, and Teklad 4% fat pellets from Envigo. At the conclusion of the study, animals were sacrificed and surface adenoma counts were performed on fresh lungs from each group of animals. We found 850 mg/kg/day metformin for 16 weeks reduced adenoma formation by 35-60% in the diets we employed for the study. Interestingly, the Teklad diet which contains dehulled soybean meal had significantly reduced tumor formation in the control animals, demonstrating some animal diets provide chemoprevention efficacy independent of any pharmaceutical effects. There was no observed toxicity of metformin in the animals; however we have observed significant differences in the average end weights of animals treated with metformin. We conclude metformin is an efficacious agent in lung adenoma chemoprevention and similar reductions in adenoma formation occurred in several of the diets commonly employed for chemoprevention studies in B[a]P treated mice. However, attention to diet formulation is vital due to potential chemoprevention and metabolic effects independent of metformin treatment.
Citation Format: Vannesa Souksavong, Beverly R. Wuertz, Donna Seabloom, Frank G. Ondrey. Effects of diet on lung adenoma carcinogenesis in metformin treated A/J mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1274.
Abstract 1284: How can you interpret gene lists from -omics experiments
Authors: Wong Jeffrey V. , Luna Augustin , Demir Emek , Rodchenkov Igor , Babur Özgün , Sander Chris , Bader Gary D. 
Published: August 2018

Abstract
Understanding the mechanisms responsible for a cellular behaviour often begins with observations of genes and gene products. Depending on the type of experiment, the number of resulting genes can be small, but increasingly, researchers are faced with many thousands of measurements, as in the case of transcriptomic or protein-DNA binding observations. Here, we describe ways to pair experimental results consisting of one or more genes with analysis tools with the overall aim being to make results more biologically interpretable. In certain cases, experimental approaches such as screens for essential genes can generate one or a few ‘genes of interest' and there is a desire to understand their relationship to one another as well as discover links to additional, interesting genes. To this end, ‘GeneMANIA' is a web tool that accepts gene names and returns a network visualization of related genes based on similarity in expression, localization, protein domains and those involved in physical interactions. Likewise, ‘PCViz' is a web tool that displays a network of interactions drawn from Pathway Commons, a web resource for pathway and interaction knowledge. In cases where experiments generate a lengthy list of genes, for instance, transcriptomic measurements, there is a desire to understand their relevance to a phenotype of interest. Pathway enrichment analysis methods aim to summarize gene lists as pathways, which have a closer link to cell function. An online ‘Guide' by Pathway Commons includes workflows that illustrate how to chain together software tools to identify pathways from the corresponding gene-level data then organize and summarize the pathway-level results in an interactive visualization known as an Enrichment Map. For those wishing to drill-down to individual pathways, Pathway Commons offers a set of web apps, including ‘Search' that enables users to query by keyword and visualize ranked search results. Ongoing development of web apps aims to enhance the accessibility to pathways and integrate support for analysis and visualization of experimental data. The full complement of data, tools and resources offered by Pathway Commons in support of pathway analysis are described.
Citation Format: Jeffrey V. Wong, Augustin Luna, Emek Demir, Igor Rodchenkov, Özgün Babur, Chris Sander, Gary D. Bader. How can you interpret gene lists from -omics experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1284.
Abstract 1294: Preoperative prediction of microvascular invasion in HCC using radiomics on multisequence gadoxetic acid-enhanced MR images
Authors: Wei Jingwei , Gu Dongsheng , Dong Di , Zhang Shuaitong , Jin Yushen , Tian Jie 
Published: August 2018

Abstract
Micro-vascular invasion (MVI) is underscored as a judicious risk factor for early-stage recurrence and poor prognosis of hepatocellular carcinoma (HCC). Preoperative knowledge of MVI would assist in therapy decision making beforehand, thus prolong the survival of HCC patients. However, current diagnosis of MVI could only be obtained by pathological confirmation after the surgery or through punctures, which hinders timely therapeutic regime plan or causes needless suffering for the patients. In this study, we aimed to perform a preoperative prediction on MVI using multi-sequence Radiomics on gadoxetic acid-enhanced MR images, along with multi-variable clinical factor analysis. A cohort of 208 patients diagnosed with HCC was enrolled with institutional review board approval. Radiomic features including shape and size, intensity, textural and wavelet features were extracted on segmented region of interest. The least absolute regression modeling was used to select the most effective radiomic features which had potential for MVI identification. We finally utilized logistic regression modelling to generate the single radiomics signature for each sequence with Akaike information criteria as the stopping rule. Gadoxetic acid-enhanced hepatobiliary phase (HBP) T1-weighted image and HBP T1 map turned out to be the best-performed sequences with AUC over 0.7 on both training and validation cohorts. The fusion radiomics signature incorporating effective features from these two sequences achieved the optimal prediction with AUC of 0.895 on the training cohort and 0.837 on the validation cohort. Adding the pertinent clinical and radiological factors: AFP, irregular tumor border and arterial peritumoral enhancement, the final combined model could successfully predict the MVI with AUC of 0.943 on the training cohort and 0.861 on the validation cohort. Our study revealed the archetypal radiomic features related MVI and highlighted the fusion radiomics signature as a powerful imaging marker for MVI preoperative prediction. Radiomics combined with traditional clinic-radiological information would no doubt improve the clinical decision making in HCC therapy.
Citation Format: Jingwei Wei, Dongsheng Gu, Di Dong, Shuaitong Zhang, Yushen Jin, Jie Tian. Preoperative prediction of microvascular invasion in HCC using radiomics on multisequence gadoxetic acid-enhanced MR images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1294.
Abstract 1295: Single cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes
Authors: Ma Keyue , Schonnesen Alexandra A. , Eckhardt S. Gail , Jiang Ning 
Published: August 2018

Abstract
Immunotherapies have been the most promising approaches to treating cancers, while the partial responses in multiple clinical trials suggest the significance of characterizing intertumoral and intratumoral heterogeneity for better prognosis and decision-making in treatment. The lack of intratumoral characterization of immune response-related genes in cancer cells, however, hinders the further development of metrics to select and predict immunotherapies. Therefore, we applied single cell RNA-seq data from lung adenocarcinoma patients to identify intratumoral heterogeneity of immune response-related genes and demonstrated its potential effect on immunotherapy efficacy. We found IFNγ signaling pathway genes are heterogeneously expressed and co-regulated in cancer single cells, including MHC class II molecules (MHCII), a set of favorable prognosis markers. The upregulation of MHCII is also mutually exclusive with upregulation of cell cycle pathways, which are associated with unfavorable prognosis. Moreover, analysis of two candidates of cancer vaccination approaches, neoantigens and cancer testis antigens, revealed their ectopic expression in single cells. These analyses provide the rationale of applying combinatorial therapies to prevent tumor escape and basis for future development of prognosis metrics based on intratumoral heterogeneity.
Citation Format: Keyue Ma, Alexandra A. Schonnesen, S. Gail Eckhardt, Ning Jiang. Single cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1295.
Abstract 130: Cancer teammate survives longer: Role of cancer-associated a2 V-ATPase in regulation of neutrophil survival
Authors: Ibrahim Safaa A. , Kulshrestha Arpita , Katara Gajendra K. , Sahoo Manoranjan , Beaman Kenneth D. 
Published: August 2018

Abstract
Tumor associated neutrophils (TAN) represent a significant portion of tumor leukocytes and accumulate in many types of cancer. TAN can survive for weeks in cancer tissues and have been proposed as key mediator of malignant transformation, tumor progression, angiogenesis and in the modulation of the antitumor immunity. Identifying cancer associated factors that promote the survival and protumorigenic properties of neutrophils will provide new targets for cancer therapy. Cancer cells secrete a peptide from the Nterminal domain of a2isoform vacuolar ATPase (a2NTD) that promotes the protumorigenic properties of neutrophils that enhances angiogenesis and tumor cell invasiveness. The present study attempts to decipher the role of a2NTD in the regulation of neutrophil apoptosis. The treatment of human neutrophils with recombinant a2NTD led to 2.1 fold increase in the percentage survival of neutrophils (P &lt; 0.001). a2NTD treatment activates NF- kBp65 by activating reactive oxygen species (ROS) generation in neutrophils. Activation of NF- kB pathway leads to upregulation of the gene expression of anti-apoptotic factors; Bcl2-A1, Bcl-xL, c-Flip, G-CSF and downregulates the pro-apoptotic factors such as BAX. Parthenolide; NF-kB inhibitor, negated the effect of a2NTD on enhancing neutrophil survival confirming the involvement of NF-kB pathway in the a2NTD mediated increase of neutrophil survival. Further analysis showed that a2NTD treatment stabilizes the neutrophil mitochondrial membrane potential and decreases Bax translocation to the mitochondria that was associated with a decrease in caspase 9 and caspase 3 activity. Since there is a direct link between the intrinsic and the extrinsic pathways of apoptosis, our results showed that there was no change in the Fas and Fas ligand expression upon a2NTD treatment. Further analysis would uncover the effect of a2NTD treatment on the extrinsic pathway of apoptosis in neutrophils. Together, our results demonstrate a novel role of the cancer associated a2-vacuolar ATPase on retarding the mitochondrial death pathway in neutrophils by the action of a2NTD.
Citation Format: Safaa A. Ibrahim, Arpita Kulshrestha, Gajendra K. Katara, Manoranjan Sahoo, Kenneth D. Beaman. Cancer teammate survives longer: Role of cancer-associated a2 V-ATPase in regulation of neutrophil survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 130.
Abstract 1306: Density-based mutation clustering in 3D space
Authors: Weerasinghe Amila , Sengupta Sohini , Scott Adam D. , Bailey Maththew H. , Wendl Michael C. , Chen Ken , Mills Gordon , Ding Li 
Published: August 2018

Abstract
Cancer driver mutation and gene discovery has been a major challenge in cancer research. Several computational tools focus on clustering mutations on 3D protein structures to identify cancer drivers, including HotSpot3D, CLUMPS, HotMAPS, 3DHotSpots.org and e-Driver. While other tools provide a single snapshot of mutation clusters on the 3D structure, HotSpot3D utilizes a unique density-based clustering module capable of providing a full dynamical profile of clusters with varying densities. The density module (DM) is capable of detecting subtle variation in the density of mutations in 3D structures with little computation time and complexity. DM gives users the ability to detect the bridging effect, where more dense subclusters form a less dense supercluster due to a small number of mutations in between the subclusters connecting them. In addition to clustering based on physical density of mutations, DM is capable of clustering by additional biologic properties, including mutation recurrence and pathogenicity. Moreover, the underlying OPTICS algorithm utilized in the DM is inherently a “fuzzy” clustering algorithm, allowing slight variation of clusters based on the start point of the clustering algorithm from one run to another. Therefore, the DM provides a cluster membership probability measure for each mutation, giving the user the ability to choose the preferred stringency. Additionally, DM allows users to visualize the density clusters using Pymol. Since the whole dynamical set of clusters is produced by a single run, the visualization is performed so that one can reveal other clusters with higher densities by zooming in and out. Using a curated set of experimentally validated oncogenic mutations, we evaluated the performance of DM in detecting functionally activating mutations; our tool performed well in identifying driver mutations at high density thresholds. Moreover, the DM was able to identify mutations clustering at high density in BRAF, PIK3CA and KEAP1, which were not detected by other 3D clustering tools and sequence-based tools (SIFT, PolyPhen2, CHASM, etc.). The DM was also better at detecting clusters along the interface of protein-protein complexes (e.g., BRAF-KEAP1) compared to other 3D tools. In summary, HotSpot3D-DM allows for dynamical clustering, improved visualization, and identifies novel driver mutations missed by previous tools.
Citation Format: Amila Weerasinghe, Sohini Sengupta, Adam D. Scott, Maththew H. Bailey, Michael C. Wendl, Ken Chen, Gordon Mills, Li Ding. Density-based mutation clustering in 3D space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1306.