bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-135: Biomarker utility of the E2/E6 ratio and L1 immunoreactivity for determining HPV16-positive ≥CIN2 lesions and cervical squamous cell carcinoma
Authors: Choi Youn Jin , Lee Sung-Jong 
Published: August 2018

Abstract
Objectives: Human papillomavirus (HPV)16 is the most carcinogenic HPV genotype. The objective of this study was to identify whether expression of the HPV16 L1 capsid protein and the E2/E6 ratio—both determined by cervical cytology—could be used as biomarkers of cervical pre-malignancy and cancer.
Methods: Cervical specimens were obtained from 226 patients with HPV16 single infection at Seoul St. Mary's Hospital. A Cytoactiv®HPV L1 screening set was prepared to detect the L1 capsid protein, and real-time polymerase chain reaction (PCR) was performed to determine the E2/E6 ratio of HPV16 DNA. Cytology results then were compared to results of conventional histologic analysis of cervical tissues (cervical intraepithelial neoplasia [CIN]1-3 and squamous cell carcinoma [SCC]) to evaluate the association.
Results: We found that the mean E2/E6 ratios of specimens graded as SCC (0.355) and of those graded as CIN2/3 (0.481) were significantly lower than the mean E2/E6 ratios for specimens graded as CIN1 (0.736) and those regarded as normal (0.792) (P &lt; 0.05). Cytologic detection of HPV L1 enabled prediction of ≥CIN2 cervical lesions and differentiation of CIN2/3 from SCC (P &lt; 0.05). Based on findings expressed as area under the receiver operating characteristic curve (AUC), the combination of HPV L1 immunohistochemistry and the E2/E6 ratio predicted ≥CIN2 cervical lesions (AUC, 0.871; 95% confidence interval, 0.826-0.917) better than either individual test.
Conclusions: To our knowledge, this study is the first to validate the expression of the HPV L1 capsid protein and a decreased HPV E2/E6 ratio as valuable predictive markers of ≥CIN2 cervical lesions, thereby discriminating cervical pre-malignancy and cancer. Cervical cytology can be analyzed on an outpatient basis with noninvasive procedures, in contrast to conventional histologic analysis, which is invasive. Moreover, cervical cytology can be conducted longitudinally to evaluate disease progression/regression without repeated invasive procedures.
Citation Format: Youn Jin Choi, Sung-Jong Lee. Biomarker utility of the E2/E6 ratio and L1 immunoreactivity for determining HPV16-positive ≥CIN2 lesions and cervical squamous cell 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 LB-135.
Abstract LB-166: Antibiotic prescriptions and colorectal cancer recurrence risk: A Danish nationwide prospective cohort study
Authors: Fedirko Veronika , Cronin-Fenton Deirdre , Riis Anders Hammerich , Sørensen Henrik Toft , Andersen Claus Lindbjerg , Thorlacius-Ussing Ole , Lash Timothy 
Published: August 2018

Abstract
The large number of colorectal cancer survivors, coupled with the financial burden of colorectal cancer, makes it critical to identify factors associated with cancer recurrence. The human gut microbiome is one of the most densely populated bacterial communities known to exist. It plays a vital role in the host's gut physiology and potentially contributes to colorectal cancer progression. Given the prevalence and often overuse of antibiotics in the population, and their effects on the gut microbiome, the potential influence of antibiotics on the clinical course of colorectal cancer is of great public health importance. Using data from Danish medical registries, we followed 21,152 patients (5,036 with recurrences) diagnosed with stage I-III colorectal cancer from 2001 to 2011. We examined the association between pre- and post-diagnostic antibiotic use and cancer recurrence. After adjustment for potential confounders (age at diagnosis, sex, year of diagnosis, stage, tumor location, cancer treatment, comorbidities, inflammatory bowel disease, and use of statins, non-steroidal anti-inflammatory drugs and aspirin), any antibiotic prescription 90 days prior to colorectal cancer diagnosis was not associated with recurrence [adjusted hazard ratio (aHR) = 1.06, 95% confidence interval (CI): 0.98, 1.14]. However, antibiotic use after cancer diagnosis was associated with a higher risk of recurrence (aHR = 1.23, 95% CI: 1.16, 1.31). Additional ongoing analyses address cancer-specific and all-cause mortality and different time-lag periods. Their results also will be presented at the meeting. Our preliminary findings support further investigation into the possible roles of the gut microbiome and agents that alter its composition and diversity in colorectal cancer progression.
Citation Format: Veronika Fedirko, Deirdre Cronin-Fenton, Anders Hammerich Riis, Henrik Toft Sørensen, Claus Lindbjerg Andersen, Ole Thorlacius-Ussing, Timothy Lash. Antibiotic prescriptions and colorectal cancer recurrence risk: A Danish nationwide prospective cohort study [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 LB-166.
Abstract LB-171: Potential chemopreventative treatments in Fanconi anemia related HNSCC
Authors: Miller Kimberly A. , Wuertz Beverly R. , Haynes Anna M. , Potter David A. , Ondrey Frank G. 
Published: August 2018

Abstract
Fanconi anemia (FA) is a DNA repair mechanism genetic disorder which leads to bone marrow failure and cancer. Risk of solid tumor malignancy in FA patients occurs decades earlier and at a rate several hundred-fold higher than the general population, necessitating regular cancer surveillance. Development of an adjunct therapy or preventative survival-enhancing therapy with a minimal side effect profile will benefit this population in which chemotherapy and radiation are particularly damaging. To this end, we established a cell line from a post bone marrow transplant FA patient with a T2N2bM0 oral SCC grown as an adherent monolayer culture. We tested pioglitazone, metformin, and N1-hexyl-N5-benzyl-biguanide (HBB), emerging chemopreventative therapies for head and neck squamous carcinoma, for growth inhibition in head and neck cancer cell lines, including our FA SCC cell line. Additional cell lines include UMSCC 11A (laryngeal squamous cell carcinoma), CA 9-22 (oral squamous cell carcinoma), Beas2B (SV40 immortalized normal bronchial epithelium), and MSK Leuk1 (oral leukoplakia cell line). All cell lines are HPV negative. MTT assays determined cell viability after 1, 2, and 3 days of treatment. Pioglitazone at all concentrations (5, 10, 20, 40 μM) decreases cell proliferation compared to solvent controls (P&lt;0.0001). Metformin (1 μM - 1 mM) unexpectedly increased cell proliferation or was otherwise equal in growth with the controls, and at higher doses (10 mM - 100 mM) metformin decreased cell proliferation or resulted in cytotoxicity (P&lt;0.0001). Pioglitazone (10 μM) and metformin (above 1 mM) resulted in larger, cell line dependent, decreases in cell proliferation than either agent alone. In the FA cell line, pioglitazone and HBB resulted in increased efficacy. HBB treatment resulted in decreases in proliferation and percent live cells at 20 μM equivalent to the effect of 10 to 100 mM metformin. Combining HBB with 10 μM pioglitazone decreased cell proliferation and percent live cells over pioglitazone alone. HBB also caused S phase blockade in a pilot FA cell cycle experiment. Pioglitazone combined with HBB appears to be a promising chemopreventative adjunct treatment for HNSCC in FA patients. Further studies are underway to evaluate the relative contribution of HBB to decreased cell proliferation versus apoptotic mechanisms. Recent studies of HBB in breast cancer indicate cytochrome P450 arachidonic acid epoxygenase activity as an HBB target and suggest further exploration of this target in head and neck squamous cell carcinoma.
Citation Format: Kimberly A. Miller, Beverly R. Wuertz, Anna M. Haynes, David A. Potter, Frank G. Ondrey. Potential chemopreventative treatments in Fanconi anemia related HNSCC [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 LB-171.
Abstract LB-173: Epitope mapping of mTERT for vaccine development
Authors: Song Yurong , Marshall Jason , Das Sudipto , Andresson Thorkell , Corbel Amanda , Sei Shizuko , Shoemaker Robert H. , Pinto Ligia 
Published: August 2018

Abstract
Telomerase reverse transcriptase (TERT) is one of two essential components of telomerase, an enzyme complex that generates and maintains telomeres. Telomerase is expressed mainly in embryonic and adult stem cells. Telomere biology has recently been implicated in the pathogenesis of a variety of diseases, and mutations in telomerase components result in a predisposition to solid malignancies. More recent findings show that TERT is not only expressed in late stage primary tumor cells and metastatic cells, but also expressed in incipient cancer stem cells and/or tumor-initiating cells, indicating that TERT has essential roles at every stage of tumorigenesis. However, the clinical benefit of a TERT (hTERT)-targeting vaccine, given as a single agent or in combination with chemotherapeutic agents, has been limited in patients with advanced cancer, possibly due to insufficient epitope coverage as well as tumor-induced immune suppression. Thus, targeting TERT in tumor-initiating cells in early stage lesions may be more effective in preventing cancer development and progression. To develop cancer preventive TERT vaccines, novel immunogenic epitopes must be first identified and evaluated in a relevant preclinical model of tumorigenesis. The goal of this project is to identify the epitopes of mouse TERT (mTERT) with high immunogenicity via epitope mapping using two approaches. The first one consists in washing off the MHC I-bound mTERT peptides (Mild Acid Elution; MAE) from the cell surface of mTERT-overexpressing cells (SPON-10-mTERT cells generated from spontaneous lung tumors developed in an A/J mouse), followed by mass spectrometry analysis. The initial mass spec analysis showed one 14-mer peptide from MAE with 22 PSMs, with a good XCorr score compared to peptide from PBS elution control with only 1 PSMs, with lower XCorr score. The second approach is to inject overlapping mTERT peptides covering the whole protein sequence in mice, and then splenocytes from these mice will be stimulated in vitro using mTERT peptide library to determine immunogenic peptides. Both approaches are in progress to identify potential mTERT epitopes.
Funded by NCI Contract No. HHSN261200800001E
Citation Format: Yurong Song, Jason Marshall, Sudipto Das, Thorkell Andresson, Amanda Corbel, Shizuko Sei, Robert H. Shoemaker, Ligia Pinto. Epitope mapping of mTERT for vaccine development [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 LB-173.
Abstract LB-175: The malignancy associated change hypothesis tested through 3D cellular imaging
Authors: Meyer Michael , Kelbauskas Laimonas , Katdare Rahul , Presley Chris , Hamilton Celeste , Sussman Daniel , Bell Tim , Nelson Alan 
Published: August 2018

Abstract
Early detection remains by far the most reliable and potent strategy in curing lung cancer. Many current approaches, however, are limited by poor sensitivity or specificity that increase health care costs and potentially risk patient health through unneeded and invasive procedures.
The association between cell morphology and cancer has been established in the cytology literature. However, the tumor field effect potentially introduces subtle changes into non-tumor cells that reside in the tumor microenvironment. This phenomenon has given rise to the malignancy associated change (MAC) hypothesis.
The Cell-CT™ platform and LuCED® test represent a promising new method for detecting lung cancer with high (92%) sensitivity and (95%) specificity that is based on alterations in cellular morphology.
We present a study of 3D morphological alterations in non-tumor cells obtained from sputum of healthy subjects and biopsy confirmed lung cancer patients. Three major cell types were analyzed from 235 patients: bronchial epithelial columnar, squamous intermediate, and mature macrophages (dust cells). We used the Cell-CT platform to measure over 700 different structural biosignatures for each cell. A classifier to test the degree to which the features discriminate between cells from normal or cancer patients was developed and its performance characterized by the area under the ROC curve (aROC) (Table 1). Hierarchical clustering analysis revealed biosignatures of nuclear chromatin organization to be the most differentiating between macrophages from healthy subjects and patients with cancer.
Table 1. Classifier development and performance characteristics
Cell TypeNumber of cells from cancer patientsNumber of cells from normal patientsSupervised Learning – aROCSquamous Intermediate4,6849530.70Macrophages7,2191,3660.75Columnar cells11,7742,9110.80
Our results confirm the MAC hypothesis based on 3D cellular imaging and suggest that cancer presence in the lung can be detected in patient's sputum based on the morphologic alterations in non-tumor cells. This is important as cancer cells are rare in early stages of cancer, posing challenges in terms of detection sensitivity and specificity.
Further work will emphasize boosting of the performance figures above based on the combination of results from the differing methods presented.
Citation Format: Michael Meyer, Laimonas Kelbauskas, Rahul Katdare, Chris Presley, Celeste Hamilton, Daniel Sussman, Tim Bell, Alan Nelson. The malignancy associated change hypothesis tested through 3D cellular imaging [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 LB-175.
Abstract LB-186: Evaluation of EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells compared to EGFR-TKI sensitive cells
Authors: Norma Hernandez-Pedro Y. , Giovanny Soca-Chafre , Mario Orozco-Morales , Pedro Barrios-Bernal , Oscar Arrieta 
Published: August 2018

Abstract
The resistance mechanisms to EGFR-TKIs in Non-Small Cell Lung Cancer (NSCLC) are not well elucidated. Here we evaluate EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant NSCLC cells (H1975) compared to EGFR-TKI sensitive cells (HCC827). After erlotinib treatment, EGFR protein half-life was quantified by cycloheximide chase. EGFR expression on cell membrane was measured by flow cytometry and transcription levels were measured by Real-Time PCR. EGFR half-life was shorter in H1975 compared to HCC827 cells after cycloheximide inhibition of protein synthesis. EGFR phosphorylation levels were not affected by erlotinib in H1975 while in HCC827 they were significantly reduced (p &lt; 0.001). EGFR expression on cell membrane decreased similarly in both H1975 and HCC827 cell lines. Also the transcription levels of EGFR remained unaffected by erlotinib treatment in both cell lines. However, there was more apoptosis in HCC827 compared to H1975 with 64% vs. 22%. Our results suggest that H1975 cells present more EGFR degradation however, they show less cell death by apoptosis and this could represent a resistance mechanism to EGFR-TKIs.
Citation Format: Hernandez-Pedro Y. Norma, Soca-Chafre Giovanny, Orozco-Morales Mario, Barrios-Bernal Pedro, Arrieta Oscar. Evaluation of EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells compared to EGFR-TKI sensitive 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 LB-186.
Abstract LB-188: POH1 knockdown induces cancer cell apoptosis via p53 and Bim
Authors: Chen Shi-Lu 
Published: August 2018

Abstract
The ubiquitin-proteasome system is implicated in cell apoptosis that is frequently dysregulated in human cancers. POH1/rpn11/PSMD14, as a part of the 19S proteasomal subunit, contributes to the progression of malignancy, but its role in apoptosis remains unclear. Here, we showed that POH1 expression was increased and associated with poor outcomes in three independent cohorts of patients with hepatocellular carcinoma (HCC), esophageal cancer (EC), and colorectal cancer (CRC). The knockdown of POH1 significantly inhibited tumor cell proliferation and induced apoptosis mediated by the mitochondrial pathway in vitro. Intratumoral injection of POH1 small interfering RNA (siRNA) significantly reduced the progression of tumor growth and induced apoptosis in vivo. Furthermore, p53 or Bim siRNA markedly attenuated the apoptosis induced by POH1 depletion. POH1 depletion resulted in cell apoptosis by increasing the stability of p53 and Bim and inhibiting their ubiquitination. Overall, POH1 knockdown induced cell apoptosis through increased expression of p53 and Bim via enhanced protein stability and attenuated degradation. Thus, POH1 may serve as a potential prognostic marker and therapeutic target in human cancers.
Citation Format: Shi-Lu Chen. POH1 knockdown induces cancer cell apoptosis via p53 and Bim [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 LB-188.
Abstract LB-193: TRAIL promotes entosis through Caspase-8
Authors: Bozkurt Emir , Dussmann Heiko , Prehn Jochen H. 
Published: August 2018

Abstract
Despite its apoptosis-inducing activity, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also activates survival signaling pathways. Survival signaling not only interferes with apoptosis and causes resistance, but can also lead to gain of several tumor-promoting functions such as proliferation, invasion and metastasis. Here we demonstrate that colorectal cancer cells surviving from TRAIL treatment can initiate a cell-in-cell invasion process known as entosis. Entosis refers to a unique cell-in-cell phenomenon, in which one or more viable cells are actively internalized into another cell of the same type. After formation of cell-in-cell structures (CICs), internalized cells can divide inside the host cell or they can escape, however, the vast majority of cells undergo cell death inside their hosts, through a lysosome-dependent mechanism. Although the clinical relevance of entosis is highly context-dependent, the frequency of entosis has been shown associated with tumor grade and poor outcome in several malignancies. While monitoring single-cell response upon TRAIL stimulation, we noted that some cells internalized into their neighboring cells and died inside a vacuole. We confirmed CICs by fluorescence staining of cytoplasm, nucleus, lysosome and cell membrane, in addition to TEM. Further quantification revealed that TRAIL indeed increased the number of CICs in colorectal cancer cell lines (HCT116 and LS180) and spheroids. Moreover, both pre-treatment with ROCK inhibitor (Y-27632) and knockout of Caspase-8 resulted in a significant reduction in the number of TRAIL-induced CICs. After forming cell-in-cell structures, the majority of internalized cells appeared positive for lysotracker staining and underwent cell death inside their hosts. These cells showed an increase in IETD FRET probe cleavage, additionally, we observed increased levels of cleaved caspase-8, cleaved caspase-9 and cleaved caspase-3 in these cells in presence of TRAIL. Pre-treatment with z-VAD-fmk reduced the number of internalized cells undergoing cell death and Bax/Bak double knockout cells escaped from their hosts without undergoing cell death in response to TRAIL. Our findings demonstrate that entosis can be induced by TRAIL in a caspase-8-dependent manner, and may give new insights in understanding the death, survival and escape mechanisms in internalized cells.
Citation Format: Emir Bozkurt, Heiko Dussmann, Jochen H. Prehn. TRAIL promotes entosis through Caspase-8 [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 LB-193.
Abstract LB-200: A pan-cancer analysis of stage-dependent gene expression program
Authors: Kim Man-Sun , Kim Dongsan , Kim Jeong-Rae , Lim Yong Pyo 
Published: August 2018

Abstract
Cancer cells undergo diverse gene expression alterations according to their development and progression due to the accumulation of mutations. Understanding these phenomena not only provide us an insight into the underlying mechanisms of cancer development, but also offer useful information on the prediction of patient's prognosis. For some cancer types, previous studies attempted to identify key genes that change with the development of cancer. However, identification of cancer stage-dependent gene expression dysregulations based on pan-cancer dataset have not been addressed. Here, based on gene expression profiles and clinical data from 20 major cancer types and ~6,000 individual patients, we identified both gene expression programs that specifically change from each cancer-type and across all cancer types. Based on the pan-cancer analysis, we found that cell cycle and p53 dependent pathways are the most commonly dysregulated pathways across all cancer types according to cancer development. Next, we investigated whether the identified the stage-dependent gene expression programs from the pan-cancer analysis also hold from each cancer-type analysis. Interestingly, we identified that only about half cancer types also showed consistent gene expression alterations. These results suggest that although most cancer share common dysregulation mechanisms as cancer progress, also show that some cancer type have quite unique cancer development programs depending on the cancer type.
Keywords: stage-dependent gene expression, systems biology, PANCANCER
Citation Format: Man-Sun Kim, Dongsan Kim, Jeong-Rae Kim, Yong Pyo Lim. A pan-cancer analysis of stage-dependent gene expression program [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 LB-200.