bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-257: Immunoadjuvant ISG15 enhances human papillomavirus 16 antigen-specific cell-mediated antitumor immunity
Authors: Villarreal Daniel , Wise Megan C. , Yang Jian , Weiner David B. 
Published: May 2015

Abstract
Adjuvants are critical components of most clinically used vaccines and act as substances to enhance adaptive immune responses to an antigen. Here we examine a new immunoadjuvant, interferon stimulated gene 15 (ISG15), for its adjuvant effects in an HPV-associated cancer immune therapy model where cell-mediated immunity is crucial for protection. ISG15 is an ubiquitin-like protein induced by type I interferon and associated with antiviral activity. Recent studies of ISG15 have re-established that ISG15 is also a secreted molecule with cytokine-like properties. However, the potential ability of ISG15 to influence the Th1 and CD8 T cell immune responses and act a vaccine adjuvant, has not been well defined. To this end, we developed a highly optimized DNA-vector encoding the ISG15 protein and evaluated its immunogenicity to increase the cellular immune responses in combination with a DNA consensus-based fusion HPV16 E6/E7 construct. We demonstrate that ISG15 can enhance Ag-specific Th1 memory responses to HPV16 E6/E7 antigen by IFN-γ ELISpot analysis. Moreover, ISG15 elicited strong HPV16 Ag-specific polyfunctional CD8+ T cells that secrete both anti-viral IFN-γ and/or TNF-α cytokines. Vaccination conferred remarkable 100% protection against challenge with HPV E6 and E7-expressing tumors. Overall, these findings lay the groundwork of ISG15 as a new immunoadjuvant candidate in the context of cancer immunotherapy.
Citation Format: Daniel Villarreal, Megan C. Wise, Jian Yang, David B. Weiner. Immunoadjuvant ISG15 enhances human papillomavirus 16 antigen-specific cell-mediated antitumor immunity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-257. doi:10.1158/1538-7445.AM2014-LB-257
Abstract LB-266: Generation of antagonistic anti-TIM-3 and anti-LAG-3 monoclonal antibodies for potential novel immunotherapy combinations
Authors: Jun H. Toni , McNeeley Patricia A. , Lassen Andrew , Hynes Brandon , Altobell Larry , Chhoa Mark , Olvera Jesus , MacLaren Josh , Do Minjee , Brown Michael , Correia Jean da Silva , King David 
Published: May 2015

Abstract
Among the most promising approaches in the treatment of cancer is the activation of antitumor immunity by blockade of immune checkpoints. These inhibitory immune checkpoints are crucial for maintaining self-tolerance in the normal immune system but can be co-opted in cancer to allow tumor escape from immune surveillance. Therapeutic validation has been provided using antibodies that inhibit the CTLA-4 and PD-1 signaling pathways, which have shown significant clinical activity. Interestingly, blockade of other T-cell inhibitory signaling molecules TIM-3 and LAG-3 has also been shown to be effective in mouse models of cancer. Potential therapeutic molecules that inhibit the negative signaling of TIM-3 or LAG-3 were identified by screening the AnaptysBio Evolvable Library (ABEL) of fully human germline antibodies. The initial ABEL screens used the soluble extra cellular domains (ECD) of either TIM-3 or LAG-3, followed by screening on cell-surface expressed antigens. The resulting panels of human antibodies were matured to high affinity and potency using SHM-XEL™ which uses mammalian cell display of human IgG followed by in vitro somatic hypermutation (SHM). We have explored the activity of these antibodies both as single agents as well as simultaneous blockade of multiple pathways in in vitro cell-based assays. Inhibition of each pathway in isolation demonstrated immune stimulatory activity as evidenced by increased secretion of IL-2 in a mixed lymphocyte reaction or an activated T-cell assay. Combination of an anti LAG-3 or an anti TIM-3 antibody with an anti-PD-1 inhibitory antibody could increase IL-2 secretion over that seen with blockade of a single checkpoint alone. The magnitude of this effect was donor cell dependent. These data are suggestive that combination immunotherapy towards these targets is worthy of clinical evaluation and may lead to increased efficacy.
Citation Format: H. Toni Jun, Patricia A. McNeeley, Andrew Lassen, Brandon Hynes, Larry Altobell, Mark Chhoa, Jesus Olvera, Josh MacLaren, Minjee Do, Michael Brown, Jean da Silva Correia, David King. Generation of antagonistic anti-TIM-3 and anti-LAG-3 monoclonal antibodies for potential novel immunotherapy combinations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-266. doi:10.1158/1538-7445.AM2014-LB-266
Abstract LB-27: Develop mutant isocitrate dehydrogenase 1 (IDH1)-expressing gliomas using RCAS/tv-a technology
Authors: Kim Youngmi , Lindberg Nanna , Bolouri Hamid , Delrow Jeffrey , Ozawa Tatsuya , Holland Eric 
Published: May 2015

Abstract
Malignant brain tumors are the second leading cause of cancer deaths in people under the age of 35, and median survival for glioblastomas, the most aggressive brain tumor, is only 12-14 months. A recent genomewide mutational analysis of glioblastomas discovered that somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) most frequently occur in young glioma patients. A point mutation at codon 132 of IDH1 synthesizes 2-Hydroxyglutarate (2-HG), which results in the disruption of many enzymatic reactions and alters epigenetics. Although many independent research groups have explored brain tumors expressing mutant IDH1 (muIDH1) and worked toward developing inhibitors for this particular target, the lack of suitable brain tumor models for muIDH1 hinders research progress. Thus, we utilize RCAS/tv-a technology to create muIDH1-expressing murine brain tumors. The preliminary data demonstrates that our murine gliomas express muIDH1, and their molecular profiling is similar to human muIDH1-expressing glioma. We believe that our muIDH1-expressing murine glioma model may benefit many aspects of research: from studying gliomagenesis of muIDH1-expressing gliomas to developing specific targets and performing clinical trials for this glioma subtype.
Citation Format: Youngmi Kim, Nanna Lindberg, Hamid Bolouri, Jeffrey Delrow, Tatsuya Ozawa, Eric Holland. Develop mutant isocitrate dehydrogenase 1 (IDH1)-expressing gliomas using RCAS/tv-a technology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-27. doi:10.1158/1538-7445.AM2014-LB-27
Abstract LB-279: Nonsteroidal anti-inflammatory drug (NSAID) use and risk of lethal renal cell carcinoma
Authors: Preston Mark A. , Cheng Jed-sian , Barrisford Glen , Sanchez Alex , Feldman Adam S. , Rodriguez Dayron , Choueiri Toni K. , Stampfer Meir , Willett Walter C. , Cho Eunyoung 
Published: May 2015

Abstract
Background: Studies suggest that non-steroidal anti-inflammatory drug (NSAID) use may increase risk of renal cell cancer (RCC), but the relationship to the lethal form of RCC remains unknown.
Methods: We examined the relationship between NSAID use and RCC risk in two large prospective cohorts: the Nurses’ Health Study and the Health Professionals Follow-up Study. Use of aspirin and other NSAIDs was ascertained in 1990 in the Nurses’ Health Study and in 1986 in the Health Professionals Follow-up Study, and every 2 years thereafter. We evaluated baseline use and duration of NSAID use. We defined the lethal form of RCC as RCC that resulted in death due to the disease.
Results: During follow-up of 18 years among 77,524 women and 20 years among 49,403 men, we documented 364 cases of RCC, of which 102 were fatal. Regular use of non-aspirin NSAIDs was associated with an increased overall RCC risk; there was a dose-response relationship between duration of non-aspirin NSAID use and RCC risk; compared with non-regular use, the pooled multivariable relative risks (RRs) were 0.78 (95% CI, 0.58-1.06) for use of less than 4 years, 1.29 (95% CI, 0.95-1.74)) for 4 to less than 10 years, and 2.21 (95% CI 1.39-3.49) for use for 10 or more years (P for trend, 0.0006). Furthermore, non-aspirin NSAID users of 4-10 years (pooled multivariable RR 3.13, 95% CI 1.70-5.77) and more than 10 years (pooled multivariable RR 7.23, 95% CI 2.51-20.83) had a significantly increased risk of lethal RCC. Aspirin use was not associated with increased risk of overall (pooled multivariable RR 1.07, 95% CI 0.84-1.34) or lethal RCC (pooled multivariable RR 1.59, 95% CI 0.85-2.96).
Conclusion: Our prospective data suggest that non-aspirin NSAID use is associated with an increased incidence of RCC, especially the lethal form of RCC.
Citation Format: Mark A. Preston, Jed-sian Cheng, Glen Barrisford, Alex Sanchez, Adam S. Feldman, Dayron Rodriguez, Toni K. Choueiri, Meir Stampfer, Walter C. Willett, Eunyoung Cho. Nonsteroidal anti-inflammatory drug (NSAID) use and risk of lethal renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-279. doi:10.1158/1538-7445.AM2014-LB-279
Abstract LB-295: The roles of genetic polymorphisms for susceptibility of colorectal cancer in Chinese Lynch syndrome families
Authors: Yeh Chih-Ching , Tang Reiping , Chien Huei-Tzu , Lai Chih-Hsiung , Chiu Li-Ling , Lo Tsai-Ping , Hung Kuan-Yi , Wang Chun-Yi , You Jeng-Fu , Hsiung Chao A. , Hsieh Ling-Ling 
Published: May 2015

Abstract
Background: Lynch syndrome is associated with germ-line mutations in DNA mismatch repair (MMR) genes. Polymorphisms in candidate genes that have been implicated in sporadic colorectal cancer (CRC) risk may also play roles in hereditary CRC risk. In this retrospective analysis, we examined multiple polymorphisms (including MSH2 IVS10+12A&gt;G, MLH1 A-93G, NAT1, GSTM1, GSTP1 Iel105Val, GSTA1 C-69T, TP53 Arg72Pro, CYP17A1 T-34C, CYP1A1*2C, CYP1A1*1F, TGFBR1 IVS7+24G&gt;A, and TGFBR2 G-875A) to assess the genetic effect on the CRC risk in MLH1 and MSH2 mutation carriers.
Material and Methods: DNA samples from 284 mutation-positive Lynch syndrome participants were genotyped by Sequenom iPLEX MassArray. Univariate and multivariate analysis was used to analyze the association between the genetic polymorphisms and CRC risk.
Results: We found significant associations between the presence of variant alleles in TP53 Arg72Pro (G&gt;C) and TGFBR2 G-875A genes and the risk of developing CRC among MLH1 and MSH2 mutation carriers. The TP53 Arg72Pro GC+CC genotypes were associated with decreased risk of CRC (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.42-0.94). However, the TGFBR2 G-875A GA+AA genotypes were associated with increased risk of CRC (HR = 1.60, 95% CI = 1.06-2.42). None of the other gene polymorphisms examined were associated with CRC risk.
Conclusion: To our best knowledge, our study is the first and largest study investigating multiple genetic modifiers that may influence CRC risk in Chinese Lynch syndrome families. Our results suggested that TP53 and TGFBR2 polymorphisms may associate with CRC risk among MLH1 and MSH2 mutation carriers. Such knowledge may be helpful in identifying high-risk individuals who require more intensive surveillance.
Citation Format: Chih-Ching Yeh, Reiping Tang, Huei-Tzu Chien, Chih-Hsiung Lai, Li-Ling Chiu, Tsai-Ping Lo, Kuan-Yi Hung, Chun-Yi Wang, Jeng-Fu You, Chao A. Hsiung, Ling-Ling Hsieh. The roles of genetic polymorphisms for susceptibility of colorectal cancer in Chinese Lynch syndrome families. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-295. doi:10.1158/1538-7445.AM2014-LB-295
Abstract LB-297: Mortality trends from lung and bronchus cancer in Boone County, W.V., USA before and after mountaintop removal mining practices
Authors: Crosby Lynn M. , DeVera Christina , Charles Kaylene , Orem William 
Published: May 2015

Abstract
Publically-available databases (CDC/NCI) report causes of mortality at the national, state and recently, county level. However, county or sub-county-wide health in West Virginia is difficult to assess due to the rural, sparse and isolated nature of many counties. In Boone County, WV, villages are arranged in a narrow, winding valley or ‘hollow’ lying between mountain peaks and situated along a creek or river. This region, rich with subterranean coal seams, has been mined for over 100 years; however, mountaintop removal mining (MTR), which began in the 1980s, now allows for the removal of previously-inaccessible seams by surface mining techniques in the top third of a mountain. Mountaintop removal mining has increased dramatically and current estimates suggest greater than 30 percent of West Virginia’s coal is produced using this technique. For people residing near MTR sites, dust particulates or other mobilized constituents (minerals, metals, coal, or excipients) may present a health hazard by entering the food chain via vegetables or fruit grown in a home garden, through drinking water, or by breathing or ingestion. To evaluate whether the rate of lung and bronchus cancer deaths have changed over the past fifty years, mortality records were examined from 1962 and 1972-3 (before mountaintop mining removal was widely used) and compared with those from 2006-12. The Chi-squared statistic was used to compare the frequency distributions for the rate of lung and bronchus cancer deaths in eight age categories between 1962, 1972-3, and 2006-12. We found the three time periods were significantly different from one another (α=0.005), and that the number of lung and bronchus cancer deaths had increased in those aged 45 years or older. Smoking rates and socioeconomic status within the county have remained relatively constant during the past decade. Taken together societal and environmental changes and medical advances have influenced causes of mortality in this coal-rich Appalachian county.
Citation Format: Lynn M. Crosby, Christina DeVera, Kaylene Charles, William Orem. Mortality trends from lung and bronchus cancer in Boone County, W.V., USA before and after mountaintop removal mining practices. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-297. doi:10.1158/1538-7445.AM2014-LB-297
Abstract LB-3: Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism
Authors: Elbahrawy Ali I. , Tarhuni Abdelmetalab , Naura Amarjit S. , Errami Youssef , Alwan Mohamed , Hammad Samar , Trillo-Tinoco Jimena , Hemeida Ramadan , Brim Hassan , Ashktorab Hassan , Valle Luis Del , Boulares Hamid A. 
Published: May 2015

Abstract
Colorectal cancer is a leading cause of cancer-related mortality. Apolipoprotein E (ApoE) is a major player in cholesterol metabolism and has been suggested, through association studies, to play a role in colon homoeostasis and cancer. Genetic studies suggested that polymorphisms in the ApoE alleles constitute a risk factor for the development of colon cancer. Collectively, these studies explored the role of ApoE in colon cancer by narrowly focusing on its established function in lipid metabolism. In the current study, we utilized a genetic mouse model (ApcMin mouse) of colon cancer to test the hypothesis that ApoE is a determinant in the disease progression. We show that ApoE gene heterozygosity, which reduces the protein (∼50%) and minimally affects the lipid profile, significantly increased tumor burden in ApcMin mice both in the small intestine and the colon. Surprisingly, ApoE gene knockout, which completely eliminates the protein and drastically elevates the lipid profile, did not aggravate the tumor burden in ApcMin mice compared to that caused by gene heterozygosity, suggesting a novel and cholesterol-metabolism-independent function for ApoE in colon homeostasis. In vitro studies with primary colon epithelial cells, isolated using a novel technique developed by our laboratory, show that ApoE-deficiency achieved by ApoE heterozygosity, knockout, or knockdown increased the level of active β-catenin in the absence of any stimulation. It appears that such increase in β-catenin may be at an mRNA level. ApoE deficiency was also associated with an increase in inflammatory factors including VCAM-1, MCP-1, and COX-2 in TNF-treated colon epithelial cells. Altogether, our preliminary results suggest a major role of ApoE in colon homeostasis and that deficiency in ApoE levels may constitute a risk factor for colon cancer progression.
Citation Format: Ali I. Elbahrawy, Abdelmetalab Tarhuni, Amarjit S. Naura, Youssef Errami, Mohamed Alwan, Samar Hammad, Jimena Trillo-Tinoco, Ramadan Hemeida, Hassan Brim, Hassan Ashktorab, Luis Del Valle, Hamid A. Boulares. Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-3. doi:10.1158/1538-7445.AM2014-LB-3
Abstract LB-306: The Ras exchange factor RasGRP1 opposes proliferative EGFR-SOS1 Ras signals and restricts intestinal epithelial cell growth
Authors: Depeille Philippe , Henricks Linda M. , Ven Robert van de , Lemmens Ed , Matli Mary , Haigis Kevin M. , Donner David , Warren Robert , Roose Jeroen P. 
Published: May 2015

Abstract
The character of EGFR signals can influence cell fate. Anti-EGFR treatment has been successful as cancer therapy but not in colorectal cancer (CRC) where activating somatic KRAS mutations (KRASMUT) are prevalent. While relevant to CRC, intestinal EGFR signaling is poorly understood, particularly in the context of KRASMUT. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of the EGFR but act in functional opposition to one another in the context of KRASMUT. RasGRP1 creates a negative feedback loop that limits EGFR-SOS1-Ras signals and restricts CRC growth. Genetic Rasgrp1 depletion from KRasMUT mice exacerbates intestinal epithelial cell growth and dysplasia, leading to a highly serrated colonic epithelium. Furthermore, low RasGRP1 expression in CRC patient specimens correlates with poor clinical outcome. The unexpected inhibitory role of EGFR-RasGRP1 signals in KRASMUT gastrointestinal malignancies reveals an intricacy of EGFR signaling that should be considered for future molecular therapeutics.
Citation Format: Philippe Depeille, Linda M. Henricks, Robert van de Ven, Ed Lemmens, Mary Matli, Kevin M. Haigis, David Donner, Robert Warren, Jeroen P. Roose. The Ras exchange factor RasGRP1 opposes proliferative EGFR-SOS1 Ras signals and restricts intestinal epithelial cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-306. doi:10.1158/1538-7445.AM2014-LB-306
Abstract LB-307: Giα proteins exhibit functional differences in activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells
Authors: Chu Wen-Ming 
Published: May 2015

Abstract
Background
In a classic model, Giα proteins, Gi1α, Gi2α and G3α, are important for transducing signals from Gi protein-coupled receptors (GPCRs) to their downstream cascades in response to hormones and neurotransmitters. Our previous study has suggested that Giα proteins are also important for activation of the PI3K/Akt/mTORC1 pathway by epidermal growth factor (EGF) and its family members. However, a genetic role of Giα proteins in activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) by EGF is largely unknown. Further, it is not clear whether Giα proteins are also engaged in activation of both the Akt/mTORC1 and ERK1/2 pathways by other growth factor family members. Additionally, a role of Giα proteins in breast cancer remains to be elucidated.
Results
We found that Giα deficient MEFs showed defective ERK1/2 activation by EGFs, IGF-1 and insulin, and Akt and mTORC1 activation by EGFs and FGFs. Giα1/2/3 knockdown breast cancer cells exhibited a similar defect in this activation and a defect in in vitro growth and invasion. Giα proteins associated with RTKs, Gab1, FRS2 and Shp2 in breast cancer cells and their ablation impaired Gab1's interactions with Shp2 in response to EGF and IGF-1, or with FRS2 and Grb2 in response to bFGF.
Conclusions
Giα proteins differentially regulate activation of Akt, mTORC1 and ERK1/2 by different families of growth factors. Giα proteins are important for breast cancer cell growth and invasion.
Citation Format: Wen-Ming Chu. Giα proteins exhibit functional differences in activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-307. doi:10.1158/1538-7445.AM2014-LB-307
Abstract LB-308: Monoubiquitination is critical for Otub1 to suppress UbcH5 and stabilize p53
Authors: Li Yuhunag , Sun Xiao-Xin , Elferich Johannes , Shinde Ujwal , David Larry , Dai Mushui 
Published: May 2015

Abstract
Otub1 regulates p53 stability and activity via non-canonical inhibition of the MDM2 cognate ubiquitin (Ub)-conjugating enzyme (E2) UbcH5. However, it is not clear how this activity of Otub1 is regulated in cells. Here we report that Otub1 is monoubiquitinated by UbcH5 in cells and in vitro, primarily at lysine 59 and 109 residues. This monoubiquitination in turn contributes to the activity of Otub1 to suppress UbcH5. The lysine-free Otub1 mutant (Otub1K0) fails to be monoubiquitinated and is unable to suppress the Ub-conjugating activity of UbcH5 in vitro and the MDM2-mediated p53 ubiquitination in cells. Consistently, this mutant is unable to stabilize p53, induce apoptosis, and suppress cell growth. Overexpression of Otub1K0 inhibits DNA-damage induced apoptosis. Adding either Lys 59 or Lys 109 back to the Otub1K0 mutant restored the monoubiquitination of Otub1 and its function to stabilize and activate p53. We further show that UbcH5 preferentially binds to the monoubiquitinated Otub1 via Ub interaction with its backside donor Ub-interacting surface, suggesting that this binding interferes with the self-assembly of Ub-charged UbcH5 (UbcH5∼Ub) conjugates, which is critical for the Ub transfer. Thus, our data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with and its function to suppress UbcH5.
Citation Format: Yuhunag Li, Xiao-Xin Sun, Johannes Elferich, Ujwal Shinde, Larry David, Mushui Dai. Monoubiquitination is critical for Otub1 to suppress UbcH5 and stabilize p53. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-308. doi:10.1158/1538-7445.AM2014-LB-308