bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3085: Epithelial S100A2 reduced upper aerodigestive track carcinogenesis by immunomodulation
Authors: Wu Li-Wha 
Published: August 2018

Abstract
Upper aerodigestive track cancer (UATC) including oral and esophageal cancer is the 3rd leading cause of cancer death in the world. Most of these patients demonstrate compromised immunity systems. Myeloid-derived suppressor cells (MDSCs), a population of cells exerting immunosuppressive effects, can sustain cancer progression by providing a pro-tumor microenvironment through the enhancement of T-cell suppressive factors like arginase 1 (ARG1). MDSCs can subsequently facilitate the development of immunosuppressive regulatory T cells (Tregs). Tumor-associated macrophages (TAMs) produce multiple inflammation modulators and are other key players in tumor microenvironment and divided into M1 and M2 phenotypes with specific expression of different cytokines in each type. Several S100 proteins are recently shown to participate in tumor promotion or suppression through both autocrine and least known receptor-mediated paracrine release. RAGE and TLR4, frequently expressed on immune cells, are two known receptors for S100 proteins. Among many S100 proteins, we previously showed a tumor suppressor role of S100A2 in oral cancer. Whether S100A2 functions as a tumor suppressor in mice and plays any role in regulating these immune cell populations during upper aerodigestive track carcinogenesis remains elusive. Due to lack of S100A2 expression in mice, epithelial-specific human S100A2 transgenic mice and their wildtype littermates were used for tumor induction in upper areodigestive track by the co-treatment of 4NQO and arecoline. Epithelial S100A2 significantly repressed tumor formation in esophagus. To understand the involvement of immune cell recruitment in these mice, flow cytometry and qRT-PCR analyses were used. Among the key molecules associated with MDSCs, Tregs and TAMs, S100A2 preferentially induced tumor macrophage polarization to M1 phenotype with a marginal decrease of Tregs recruitment at 7 month post tumor induction. Together, epithelial S100A2 exerts anti-tumor effect in part through differential impact on immune cell recruitment although more studies are needed to underscore the action mechanism.
Citation Format: Li-Wha Wu. Epithelial S100A2 reduced upper aerodigestive track carcinogenesis by immunomodulation [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 3085.
Abstract 3099: Hydrocarbon carcinogenicity reexamined: An extremly potent direct-acting mutagen is common to smoke, soot and ash from a variety of combustion sources, including cigarette tobacco
Authors: Blackburn Gary R. 
Published: August 2018

Abstract
Percivall Pott (1714-1788), an English surgeon, is generally credited with being the first to suggest that cancer may be induced by exposure to environmental carcinogens – in his case, cancer of the scrotum in London chimney sweeps occupationally exposed to soot. It is perhaps not surprising, therefore, that combustion products became a primary focus of later research into the mechanisms of chemical carcinogenesis. Early on, those studies pointed toward a particular class of compounds as being primarily responsible for cancer induction by such materials, a group of environmentally ubiquitous compounds called polycyclic aromatic hydrocarbons, or PAHs. One such PAH, benzo[a]pyrene (BaP), is perhaps the most studied compound in all of cancer research. While there is little doubt that BaP and its congeners are the primary carcinogens in incomplete combustion products like coal tar, their concentrations in other hydrocarbon mixtures are too low to fully account for their overall carcinogenic potency. It is possible that other factors such as tumor promotion contribute to the additional potency, but it might also be expected that there are significant contributions from nitro-PAH derivatives, in particular the isomers of dinitropyrene (DNP) found in carbon black, diesel exhaust and other combustion products. One such isomer, 1,6-dinitropyrene was shown by Iwagawa et al. to have three-times the carcinogenic potency of BaP when injected directly into the lungs of rats. In order to indirectly test nitroaromatic contribution to combustion product carcinogenicity, extracts of smoke soot, ash and food products exposed to smoke during processing were fractionated by HPLC, and the fractions tested in the Ames Test without metabolic activation. All showed a common peak of extremely potent direct-acting mutagenicity at a retention time similar to that of dinitropyrene. Efforts are currently underway to fully characterize the mutagen by a combination of standard analytical means.
Citation Format: Gary R. Blackburn. Hydrocarbon carcinogenicity reexamined: An extremly potent direct-acting mutagen is common to smoke, soot and ash from a variety of combustion sources, including cigarette tobacco [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 3099.
Abstract 3100: Replacing fetal calf serum by human platelet lysate in cancer research and toxicology
Authors: Krämer Oliver H. 
Published: August 2018

Abstract
Experiments with cultured mammalian cells represent a common in vitro alternative to animal experiments. Fetal calf serum (FCS) is the most commonly used medium supplement. FCS contains a mixture of largely undefined growth factors and cytokines. Since FCS is received from unborn calves older than three months, it represents a massive burden for the pregnant cows and their fetuses. A needle is inserted into the heart of the fetus to collect blood. Since the animal is not under anesthesia, it may suffer pain and discomfort. Furthermore, the undefined nature of FCS is a source of experimental variation, undesired immune responses, and possible contaminations. Thus, alternative, defined, valid, and reliable medium supplements should be identified. We follow the principles of the 3Rs (Replacement, Reduction, Refinement). We established a method to receive human platelet lysate (hPL) from human blood platelets. We investigated if hPL represents potential true alternative for FCS in cell culture experiments and thereby the cruel slaughtering of unborn fetuses. hPL is received by freeze and thawing cycles and centrifugation steps. We successfully adapted three human leukemia cell lines (K562, NB4 and MV4-11) and HCT116 colon cancer cells to culture medium containing 1-5% hPL. We analyzed cell morphology by microscopy. Cell growth kinetics were examined by counting and cell cycle distributions were investigated by flow cytometry. Protein expression patterns were determined globally by global scale proteomics. We additionally determined possible FCS- or hPL-dependent reactions of cells to the well-established anti-cancer drugs Irinotecan, Hydroxyurea and Imatinib, and to epigenetic modulators of the HDAC inhibitor family (FK228 and the new, highly selective HDAC6 inhibitor Marbostat-100) by flow cytometry and Western blot. In these tests, we particularly focused on the expression of the pan-leukemic marker and transcription factor Wilms tumor 1 (WT1) and on the tumor suppressor p53. All tested cell lines grow with 5% FCS and 5% hPL. Cell morphology, cell cycle distribution, and protein expression patterns were not affected by such different culture conditions in resting and treated cells. We further show that the class I HDACs HDAC1-3, but not HDAC6, regulate WT1 and p53. Our findings demonstrate that hPL is a promising replacement for animal serum.
Citation Format: Oliver H. Krämer. Replacing fetal calf serum by human platelet lysate in cancer research and toxicology [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 3100.
Abstract 3104: Establishment of an oral tongue squamous cell carcinoma cell line from a never-smoking patient
Authors: Wang Steven J. , Asthana Saurabh , Zante Annemieke van , Olshen Adam B. , McCormick Frank , Tetsu Osamu 
Published: August 2018

Abstract
(Objective) The rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. (Materials and methods) Fresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109.(Results) UCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays and mouse xenografts supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed &gt;3- to 4-fold amplification and could be potential oncogenic drivers.(Conclusion) We have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers.
Citation Format: Steven J. Wang, Saurabh Asthana, Annemieke van Zante, Adam B. Olshen, Frank McCormick, Osamu Tetsu. Establishment of an oral tongue squamous cell carcinoma cell line from a never-smoking patient [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 3104.
Abstract 3107: Modeling DICER1 syndrome in cells
Authors: Wu Mona K. 
Published: August 2018

Abstract
DICER1 is an endoribonuclease central to generating microRNAs (miRNAs), small RNA molecules that downregulate the expression of approximately 30% of protein-coding genes. Germ-line mutations in DICER1 have been identified in patients afflicted with a pleiotropic tumor predisposition syndrome, usually referred to as DICER1 syndrome (OMIM 606241). DICER1 syndrome is thought to originate from a mesenchymal cell bearing a frameshift or nonsense mutation on one allele and a missense mutation affecting the RNase IIIb domain on the other allele. While interest in the role of DICER1 in normal development and pathogenesis has been explored in both the knockout and overexpression context, neither situation is relevant for understanding DICER1 syndrome. We hypothesize that defective DICER1 protein production in a mesenchymal stem cell at a critical time in development leads to altered miRNA populations that, in turn, initiate or prime cells for tumorigenesis. The goal of this study was to develop and characterize a model of the putative tumor-initiating cell namely a mesenchymal stromal cell (MSC) bearing a DICER1 RNase IIIb mutation. SV-40 immortalized mouse mesenchymal stromal cells (MSCs) containing a homozygous floxed exon for DICER1 were ex vivo cre inactivated to produce Dicer-/- MSCs. Into these Dicer-/- MSCs, a FLAG-tagged human DICER1, a FLAG-tagged RNase IIIa mutant DICER1, and a FLAG-tagged RNase IIIb mutant DICER1 were stably introduced. Cells were characterized by Western blot in response to serum starvation and stimulation. Their ability to form anchorage-independent colonies was assessed by soft agar assay pre- and post-oncogene introduction. Transcriptomes were interrogated by gene expression microarray.
Results: Alterations in protein expression were observed in cells in response to starvation and stimulation. Certain cell lines were able to produce anchorage-independent colonies.
Conclusions: We have created MSCs bearing RNase IIIb-mutated DICER1 to model DICER1 syndrome. We suggest that the ability for an MSC to produce only 3p miRNAs in the presence of an oncogene can allow for anchorage-independent growth.
Citation Format: Mona K. Wu. Modeling DICER1 syndrome in 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 3107.
Abstract 3118: Oncogenesis modeling in malignant pleural mesothelioma
Authors: Pruett Nathanael D. , Singh Anand , Bhattacharyya Nisan , Hoang Chuong D. 
Published: August 2018

Abstract
Malignant pleural mesothelioma (MPM) is causally associated with exposure to asbestos and accounts for roughly 75% of mesothelioma cancers. It is an aggressive tumor with a median survival time of approximately 12 months. Treatment options are limited, largely palliative, and still based on cisplatin and pemetrexed, a regimen that remains unchanged since 2003. Despite widespread study, the complexities of MPM biology remain poorly described, especially at the point of tumor initiation where development of novel clinical interventional strategies would be expected to yield the most effect. The extended latency period in humans consisting of decades (over 20-30 years) remains a prohibitive barrier to gain accurate, in vivo insights about MPM oncogenic processes. As such, all in vitro MPM models, which are designed to accelerate tumor development as a practical endpoint of study, to date have not yielded clinically translatable molecular targets. Here, we present a novel in vitro model system for exploring the earliest molecular mechanisms contributing to the development of MPM using normal, human mesothelial cell lines (MeT-5a and LP9-hTERT) engineered to harbor constitutively enhanced NFkB signaling activity. Both 3D-sphere and soft agar assays were used to assess cellular transformation status in these induced cells compared to their wild-type counterparts. Heterotopic xenograft implantation studies were performed in NOD scid-gamma (NSG) immunocompromised mice (sub-cutaneous dorsal flank injection) for tumorigenic potential. In all cases, these induced cells (despite the complete absence of asbestos exposure) exhibited a significant malignant-like phenotype. Tumor growth in mouse xenograft models occurred very rapidly, and was marked by extensive vascular recruitment with invasion into surrounding tissues. In addition, these transformed cells expressed typical mesothelioma markers such as Wilms tumor protein (WT1 gene product) as revealed by immunohistofluorescence. This new MPM model system could represent a powerful construct to explore the early molecular events involved in transformation of normal mesothelial cells leading to malignancy.
Citation Format: Nathanael D. Pruett, Anand Singh, Nisan Bhattacharyya, Chuong D. Hoang. Oncogenesis modeling in malignant pleural mesothelioma [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 3118.
Abstract 3120: Tumor-infiltrating lymphocyte profiling in hepatitis B virus pre-S2 mutant-positive hepatocellular carcinoma
Authors: Teng Chiao-Fang , Shyu Woei-Cherng , Jeng Long-Bin 
Published: August 2018

Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), the leading cause of cancer-related deaths worldwide. Pre-S2 mutant is well demonstrated as a HBV oncoprotein that disturbs multiple cellular signaling pathways, leading to HCC development. HCC patients with pre-S2 mutant are recognized as a high-risk population for postoperative recurrence. Plentiful evidences reveal that tumor infiltrating lymphocytes (TILs) play an essential role in the stepwise progression of HCC development, and are closely associated with clinical outcomes. However, to date, the role of pre-S2 mutant in regulation of TILs distribution in HCC remains totally unknown. In this study, we collected plasma and paraffin-embedded liver samples from HBV-related HCC patients. The plasma samples were used for detection of the pre-S2 mutant with polymerase chain reaction-based method. As a result, the patients were divided into two groups: the pre-S2 mutant-positive and -negative groups. The paraffin-embedded liver samples were used for examination of the distribution of specific population of TILs with fluorescent immunohistochemistry staining. We analyzed 6 cases of HBV-related HCC samples, half of which were detected as pre-S2 mutant-positive. The distribution level of the cytotoxic CD3+CD8+ TILs in HCCs was examined. We found that patients with pre-S2 mutant had a considerably lower density of cytotoxic CD3+CD8+ TILs in HCC tissues than patients without pre-S2 mutant. The mean ± SEM of cytotoxic CD3+CD8+ TILs density was 3.74 ± 0.60 and 6.66 ± 0.66 in patients with and without pre-S2 mutant, respectively (p value=0.031). Our result suggests that pre-S2 mutant may have a role in regulation of TILs distribution in HBV-related HCCs. Systematic evaluation of specific population of TILs may help guide development of novel strategies for prognosis and/or therapies of HCC, especially for the HBV-related pre-S2 mutant-positive high-risk patient population.
Citation Format: Chiao-Fang Teng, Woei-Cherng Shyu, Long-Bin Jeng. Tumor-infiltrating lymphocyte profiling in hepatitis B virus pre-S2 mutant-positive hepatocellular carcinoma [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 3120.
Abstract 3124: Cytotoxic effects of tumor-specific T lymphocytes on autologous cancer initiator stem-like glioblastoma cells
Authors: Huang Yin-Cheng , Wei Kuo-Chen , Chang Chen-Nen , Yang Wen K. 
Published: August 2018

Abstract
[Purpose] In clinical trial of autologous dendritic cell/autologous tumor cell antigens (ADCTA) adjuvant immunotherapy of glioblastoma multiforme (GBM), we studied if and how GBM CD133(+) stem-like initiator cells are susceptible to immune cytotoxic eradication
[Methods] Tumor-infiltrating T lymphocytes (TILs) were isolated from GBM patients after the ADCTA vaccination and tested for their effects on CD133(+) and CD133(-) glioma cells separated from the same patients.
[Results] TILs isolated from GBM patients after ADCTA vaccination were cytotoxic to both CD133(+) and CD133(-) autologous glioma cells. However, the cell lysis was detectable in CD133(-) in 4 hours but did not occur until more than 18 hours later in the CD133(+) cancer stem-like initiator cells. Surprisingly, we found that, upon exposure to the TILs, the GBM tumor cells showed phenotype shift from CD133(+) to CD133 (-). Similar CD133(+) to CD133(-) phenotype shift was also observed by exposure to culture condition medium of the TILs. The responsible factors secreted by the TILs that caused the phenotype shift was determined to be INFγ and TNFα.
[Conclusion] ADCTA vaccination in GBM patients would generate TILs that are not only specifically cytotoxic to autologous CD133(-) glioma cells but also secret INFγ and TNFα etc to induce phenotypic shift of the resistant CD133(+) stem-like GBM to susceptible CD133(-) glioma cells.
Citation Format: Yin-Cheng Huang, Kuo-Chen Wei, Chen-Nen Chang, Wen K. Yang. Cytotoxic effects of tumor-specific T lymphocytes on autologous cancer initiator stem-like glioblastoma 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 3124.
Abstract 3127: Peripherally induced Tregs or pTregs are the potent tolerance inducer for the growth and metastasis of cancer
Authors: Hegde Upendra P. , Chakraborty Nitya G. 
Published: August 2018

Abstract
Regulatory T cells act as the most important tolerance inducer for the growth and metastasis of cancer. It remains a wonder how Tregs induce tolerance for the development of cancer. Previously we have shown with melanoma patients that, increase in pTreg cell number in blood are related to the poor prognosis of the disease. pTreg and iTreg are remarkably similar and significantly different in functionality from tTreg. Here, we worked with four melanoma patients two HLA A2 + and two HLA A2 negative. PBL and tumor cells were obtained from the patients with informed consent. Treg cells were generated in four different culture conditions: isolated from tumor +PBL IVC or peptides, Mart-1 A2 or Flu A2 pulsed DC + PBL IVC, with purified CD4 cells stimulated with anti CD3 and antiCD28 plus IL-2 with or without TGF-b. Here we show some phenotypic and functional characteristics of the induced Treg cells in cultures from the patients' PBL derived CD4+CD5- cells and analyzed those in separate CTL generation assays. We observed that induced Treg cells under different conditions do not uniformly express CD25, FoxP3, PDL-1 or CTLA 4 as the known surface markers. When analyzed for their functionality, with adjusted number of cells, in suppressing the anti tumor CTL response, a significant difference was observed. The most effective Tregs cells were found to be those isolated from autologous tumor +PBL IVC or from Mart-1 peptide pulsed IVC. Those cells completely blocked the CTL induction and secreted huge amount of IL-10 upon re-stimulation. Further analysis with these different types of induced Treg cells in terms of various gene expressions will be useful to find a target molecule to block such expansion of pTregs cells for better therapeutic outcome.
Citation Format: Upendra P. Hegde, Nitya G. Chakraborty. Peripherally induced Tregs or pTregs are the potent tolerance inducer for the growth and metastasis of cancer [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 3127.