bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-233: Blockade of TGF-beta1 and 2 without TGF-beta3 blockade is sufficient to facilitate tumor vaccine efficacy
Authors: Terabe Masaki , Robertson Faith , Kato Shingo , De Ravin Emma , Clark Katharine , Mizra Amer M. , Berzofsky Jay A. 
Published: August 2015

Abstract
TGF-beta is one of the most potent immunosuppressive cytokines involved in the regulation of tumor immunity. TGF-beta has three isoforms, TGF-beta1, 2 and 3. It has been demonstrated in multiple mouse tumor models that blockade of all three isoforms of TGF-beta facilitates natural tumor immunosurveillance as well as tumor vaccine efficacy. Most studies on the roles of TGF-beta in immunology are on TGF-beta1, which has been demonstrated to induce Treg cells, IL-17-producing T cells and MDSCs. Although some studies reported immunosuppressive activities of TGF-beta2, the role of TGF-beta3 in immune regulation is not well understood. In this study we asked whether it is necessary to inhibit TGF-beta3 to enhance tumor immunity induced by a tumor vaccine in a syngeneic TC1 tumor model. When the tumor reached at least 5 mm in diameter, the mice were given a peptide-based vaccine targeting HPV16 E7, which is an oncogene expressed in TC1 cells. Although the vaccine alone had minimal effects on tumor growth, combination with an anti-TGF-beta antibody that neutralizes all three isoforms significantly delayed tumor growth. A similar effect was obtained with an antibody that neutralizes only TGF-beta1 and 2 but not TGF-beta3. Thus, it is not necessary to block TGF-beta3 to overcome immune suppression. Flow cytometric analysis of immune cells in tumor draining lymph nodes and tumors showed that there was no difference in the number of Treg and MDSCs between mice with/without treatment. The vaccine significantly increased the number of tumor antigen-specific CD8+ T cells and IFN-gamma producing T cells in both lymph nodes and tumors, but there was no further increase in combination with anti-TGF-beta. The vaccine also induced a significant number of T-bet-expressing T cells (both CD4 and CD8) in both tumor draining lymph nodes and tumors, and anti-TGF-beta, regardless of TGF-beta3 blockade, further increased the number of these cells. Together the results suggested that blockade of TGF-beta1 and 2 alone is sufficient to enhance therapeutic tumor vaccine efficacy by facilitating the induction of Th1 type T cells. With the notion that TGF-beta3 might be beneficial for patients in some cancers, developing TGF-beta antagonists that do not inhibit TGF-beta3 may be lead to better outcomes.
Citation Format: Masaki Terabe, Faith Robertson, Shingo Kato, Emma De Ravin, Katharine Clark, Amer M. Mizra, Jay A. Berzofsky. Blockade of TGF-beta1 and 2 without TGF-beta3 blockade is sufficient to facilitate tumor vaccine efficacy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-233. doi:10.1158/1538-7445.AM2015-LB-233
Abstract LB-237: Vaccination increases the breadth and diversity of melanoma neoantigen-specific T cells in humans
Authors: Carreno Beatriz M. , Magrini Vincent , Becker-Hapak Michelle , Kaabinejadian Saghar , Hundal Jasreet , Petti Allegra A. , Ly Amy , Lie Wen-Rong , Hildebrand William H. , Mardis Elaine R. , Linette Gerald P. 
Published: August 2015

Abstract
Melanoma genomes harbor somatic mutations that are caused by exposure to mutagens such as UV light. Tumor missense mutations (MM), translated into amino acid substitutions (AAS), may provide a form of non-self that elicits tumor specific T cell immunity. Indeed, T cell immunity directed against tumor encoded AAS has been reported in humans with cutaneous melanoma, thus implicating MM as a source of patient specific (private) neoantigens. However, a systematic evaluation of these putative neoantigens as validated targets is lacking and it is unknown whether the immune response directed against tumor encoded AAS can be augmented by vaccination. Here we show that vaccination against melanoma AAS-encoding peptides augments naturally occurring T cell immunity and reveals new HLA class I restricted private neoantigens in patients with advanced melanoma. Neoantigen specific T cells recognized naturally processed and presented antigen but failed to recognize wild type (non-mutated) antigen. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. As determined by TCRβ CDR3 DNA sequencing, vaccination promotes a repertoire of neoantigen-specific T cells that is highly diverse in terms of both TCRβ usage and clonal composition. No evidence of autoimmunity was apparent after vaccination. Our results demonstrate that tumor MM can be targeted as neoantigens and vaccination directed at tumor AAS somatic mutations broadens the antigenic breadth and clonal diversity of anti-tumor immunity. These findings provide a new paradigm for private neoantigen identification in neoplasia and may form the basis of personalized cancer immunotherapies targeting somatic mutations.
Citation Format: Beatriz M. Carreno, Vincent Magrini, Michelle Becker-Hapak, Saghar Kaabinejadian, Jasreet Hundal, Allegra A. Petti, Amy Ly, Wen-Rong Lie, William H. Hildebrand, Elaine R. Mardis, Gerald P. Linette. Vaccination increases the breadth and diversity of melanoma neoantigen-specific T cells in humans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2015-LB-237
Abstract LB-247: Querying the RAS genomic network with siRNAs and and flow cytometry: Automatic, multidimensional phenotyping of 135 cancer cell lines by Gaussian mixture fitting and expectation maximization
Authors: Amzallag Arnaud , Yuan Tina L. , Bagni Rachel , Yi Ming , Stephens Robert , Ramawamy Sridhar , McCormick Frank , Benes Cyril H. 
Published: August 2015

Abstract
To discover novel therapeutic modalities and genomic predictors of response, large screen utilizing small molecules or sh/siRNA are performed on increasingly large collections of cancer cell lines. However these screens suffer from two main limitations: 1) the off-target effects of the probes 2) the coarse measurement of the cellular response that cannot distinguish between different outcomes such as proliferation block and apoptosis.
Here we profile 50 lung cancer cell lines using highly specific combinations of siRNAs against effector nodes of KRAS, and measured several characteristics of phenotypic response by flow cytometry including viability, level of reactive oxygen species and cell membrane integrity.
For each assay [node-cell line], typically 25,000 events were measured. We often observed multi modal distributions following node silencing. We used the expectation maximization algorithm to fit the different cell populations induced by the gene silencing. This allows us to automatically extract the proportion of dying cells, and also provides estimates of the cell growth impairment. Assessment of replicates shows that our results are highly reproducible, provide an accurate estimate of the proportion of dying cells, and reveal the complexity of multi-modal response of KRAS cancer cell lines to perturbation of key signaling nodes. Using the genomic profiling and pharmaceutical screen of the same cell lines, we reveal the association of specific node silencing with 1) the basal genomic state of the cell lines 2) the activity of a panel of drugs with the goal of identifying new targeting modalities and patient selection strategies for KRAS mutant cancers.
Citation Format: Arnaud Amzallag, Tina L. Yuan, Rachel Bagni, Ming Yi, Robert Stephens, Sridhar Ramawamy, Frank McCormick, Cyril H. Benes. Querying the RAS genomic network with siRNAs and and flow cytometry: Automatic, multidimensional phenotyping of 135 cancer cell lines by Gaussian mixture fitting and expectation maximization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2015-LB-247
Abstract LB-256: Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor
Authors: Byun Jooyun , Song Taehun , Kim Donghyun , Son Junhyeng , Lee Kwang-Ok , Lee Jaeho , Kim Yong Hoon , Lee Young-Mi , Suh Kwee Hyun 
Published: August 2015

Abstract
The first-generation of EGFR1 inhibitors (Gefitinib and Erlotinib) has significant clinical benefits in NSCLC caused by activating mutations, but the efficacy of these agents is often limited due to the emergence of drug resistance conferred by a gatekeeper residue, T790M. HM61713 is a third-generation EGFR tyrosine kinase inhibitor that has been evaluated as a novel therapeutic agent for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations.
HM61713 is an orally active and a novel EGFR mutant selective inhibitor which is potent on resistance mutation (T790M) without affecting EGFR wild type at efficacious dose level. HM61713 showed an anti-cancer activity in several EGFR mutant lung cancer cell lines including T790M mutation harboring cell line.
Integrated pharmacokinetic - pharmacodynamic - xenograft tumor model (PK-PD-XTG) was used to characterize the relationship between HM61713 plasma concentration and tumor growth inhibition (TGI) in H1975 (T790M mutation) xenograft model. Simple one-compartment model applied re-absorption compartment with first-order absorption/elimination was used to describe HM61713 plasma concentration-time profiles. Biophase distribution model with baseline inhibition Emax equation was applied to characterize the PD marker (p-EGFR) and tumor volume shrinkage was explained by michaelis-menten kinetics of p-EGFR. Estimated in vivo IC50 value of p-EGFR inhibition (%) based on plasma free concentration in xenograft mice was 1.14 ng/mL. The human PD marker response curve and the tumor growth inhibition plot were obtained by replacing the mice PK to human PK in our developed model based on the hypothesis thattranslation providesa good relationship of surrogate mice tumor PD to human tumor regression corresponding human PK. According to our simulated curves, we predicted appropriate human active dose from 300 to 800 mg/man and it would be an efficacious dose in patients with NSCLC harboring the EGFR activating and also with T790M resistant mutation. Currently, HM61713 is undergoing in clinical trial phase I/II in NSCLC (ClinicalTrials.gov, NCT01588145).
Citation Format: Jooyun Byun, Taehun Song, Donghyun Kim, Junhyeng Son, Kwang-Ok Lee, Jaeho Lee, Yong Hoon Kim, Young-Mi Lee, Kwee Hyun Suh. Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2015-LB-256
Abstract LB-269: Nutritional effect on CD44 in head and neck cancer
Authors: Almuhaimid Turki M. , Alotaibi Faisal F. , Rearegue Erika , Goodwin William , Franzmann Elizabeth 
Published: August 2015

Abstract
Head and neck (HN) cancer incidence accounts for more than 550,000 cases annually worldwide, with an estimated of 55,000 Americans developing head and neck cancer each year. There are multiple risk factors associated with HN cancer including smoking, alcohol consumption, human papillomavirus (HPV) infection, genetic predisposition, poor oral hygiene, periodontal disease and poor diet. According to World Health Organization (WHO), 35 - 55% of human cancers and approximately 15% of oropharyngeal cancers can be attributed to dietary deficiencies or imbalances. There is convincing evidence that we can reduce the risk of cancer, including that of oral cancer through improved nutrition. CD44 is a cancer stem cell marker associated with HN cancer and poor prognosis. Protein levels in saliva are also associated with HN cancer risk. This study will investigate the relationship between nutritional effect of a balanced diet which includes fruits and vegetables and levels of CD44 and salivary protein. 150 participants diagnosed with HN cancer and 150 controls were frequency matched for tobacco use, alcohol, age, gender, race and socioeconomic status. Participants completed a lifestyle questionnaire which included questions about fruit and vegetable consumption. Oral rinse CD44 and protein levels were measured in both groups. We did a preliminary investigation on the number of servings of juice, salad, fruits, carrots, potato and other vegetables within the cancer case and control groups to determine whether there was an association between these dietary variables and CD44 and protein levels. HN cancer cases who ate salad one or more times per week were found to have significantly lower CD44 levels than those who ate salad less frequently (4.22ng/ml verses 7.09 ng/ml p = 0. 004). Since high CD44 levels are associated with worse prognosis, these findings suggest that dietary factors such as greater salad intake may be associated with better HN cancer prognosis.
Citation Format: Turki M. Almuhaimid, Faisal F. Alotaibi, Erika Rearegue, William Goodwin, Elizabeth Franzmann. Nutritional effect on CD44 in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-269. doi:10.1158/1538-7445.AM2015-LB-269
Abstract LB-273: Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer
Authors: Szewczuk Myron R. , Haxho Fiona , Allison Stephanie , Alghamdi Farah , Brodhagen Lacey , Kuta Victoria , Abdulkhalek Samar , Neufeld Ronald 
Published: August 2015

Abstract
Patients with triple-negative breast cancers (TNBCs) lacking the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors have typical high grading, frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes. No current targeted therapies are effective for TNBC. Here, preclinical studies on the antitumor activity of oseltamivir phosphate (OP) monotherapy was investigated to identify its role in tumor neovascularization, growth, invasiveness, and long-term survival in RAGxCγ double mutant mouse model of human TNBC. Sialidase, WST-1, and immunohistochemistry assays were used to evaluate sialidase activity, cell viability, and expression levels of E-, and N-cadherins, and host CD31+/PECAM-1 cells in paraffin-embedded TNBC MDA-MB-231 tumors grown in these mice. OP, anti-Neu1, and matrix metalloproteinase-9-specific inhibitor blocked Neu1 activity associated with EGF-stimulated MDA-MB-231 cells. OP treatment of MDA-MB-231 and MCF-7 cells and their stable tamoxifen-resistant clones reproducibly and dose-dependently reduced the sialidase activity associated with EGF-stimulated live cells and the cell viability after 72 hours of incubation. Combination of 1 μM cisplatin, 5-fluorouracil, paclitaxel, gemcitabine, or tamoxifen with OP in a dose-dependent manner significantly reduced cell viability at 24, 48, and 72 hrs when compared to the chemotherapeutic alone. Heterotopic xenografts of MDA-MB-231 tumors developed bloody tumor vascularization in these mice. OP treatment at 30 mg/kg daily I.P. treatment reduced tumor vascularization and growth rate with significant reduction in tumor weight and spread to the lungs compared with the untreated cohorts. OP treatment at 50 mg/kg completely ablated tumor vascularization, growth and spread to the lungs, with significant long-term survival for 180 days post-implantation, tumor shrinking, and no relapses after 56 days off-drug. OP 30 mg/kg cohort tumors had significantly reduced levels of human N-cadherins and host CD31+ endothelial cells with concomitant significant expression of E-cadherins compared to the untreated cohorts. These findings signify a novel treatment therapy for TNBC.
Citation Format: Myron R. Szewczuk, Fiona Haxho, Stephanie Allison, Farah Alghamdi, Lacey Brodhagen, Victoria Kuta, Samar Abdulkhalek, Ronald Neufeld. Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2015-LB-273
Abstract LB-274: Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
Authors: Szewczuk Myron R. , Abdulkhalek Samar , Geen Olivia , Brodhagen Lacey , Haxho Fiona , Alghamdi Farah , Allison Stephanie , Simmons Duncan , O'Shea Leah , Neufeld Ronald 
Published: August 2015

Abstract
Snail is a transcriptional factor and repressor of E-cadherin. It is well known for its role in cellular invasion, epithelial to mesenchymal transition (EMT), tumor progression and metastases. shRNA lentiviral knockdown (KD) of Snail and its associated member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. Live cell sialidase, WST-1 and immunohistochemistry assays were used to evaluate sialidase activity, cell proliferation and the expression levels of tumor E-, N- and VE-cadherins, and host endothelial CD31+(PECAM-1) cells in A2780, A2780 Snail KD and A2780 Slug KD tumors grown in RAGxCγ double mutant mice. Oseltamivir phosphate (OP), anti-Neu1and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 cells. Silencing Snail and Slug in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to parental cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD50 of 7 and 4μM, respectively. Heterotopic xenografts of A2780 tumors developed abnormal bloody tumor vasculature in these mice. Anti-tumor activity of OP treatment at 50 mg/kg daily I.P. did not significantly impede A2780 tumor growth rate in a time-to-progression, but significantly cause a reduction of lung metastases compared with the untreated and OP 30 mg/kg cohorts. Silencing Snail in A2780 cells, but not the Slug KD member completely abrogated the tumor vascularization, growth and spread to the lungs in these mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells. These findings uncover a novel organizational signaling platform connecting the Snail-MMP-9 signaling axis in amplifying the Neu1-MMP-9 cross-talk in regulating EGF receptors, tumor neovascularization, growth and invasiveness.
Citation Format: Myron R. Szewczuk, Samar Abdulkhalek, Olivia Geen, Lacey Brodhagen, Fiona Haxho, Farah Alghamdi, Stephanie Allison, Duncan Simmons, Leah O'Shea, Ronald Neufeld. Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2015-LB-274
Abstract LB-284: Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families
Authors: Kuusisto Kirsi M. , Rantapero Tommi , Kankuri-Tammilehto Minna , Nykter Matti , Laasanen Satu-Leena , Schleutker Johanna 
Published: August 2015

Abstract
Background: Breast cancer has a well-established genetic component. However, genetic predisposition factors remain mostly unresolved in high-risk hereditary breast cancer families that do not carry mutations in two major susceptibility genes, BRCA1 and BRCA2. In this study, we aimed to identify rare variants contributing to disease susceptibility in the high-risk Finnish BRCA1/2-negative hereditary breast or breast-ovarian cancer families by using family-based exome sequencing approach.
Methods: Germline DNA of 37 individuals from 13 high-risk hereditary breast or breast-ovarian cancer families was analyzed using targeted exome capture and massively parallel sequencing. Priority was given for rare (minor allele frequency&lt;0.05) coding functional variants including nonsynonymous single nucleotide variants (SNVs), frameshift indels as well as stoploss/stopgain and splice-site variants. Candidate variants were selected based on the computational pathogenicity predictions by several tools and gene pathway analyses. Moreover, segregation of the variants with the disease was studied in the families. Candidate variants were confirmed by Sanger sequencing and genotyped in additional cohorts of breast cancer patients and healthy controls.
Results: Altogether 21,530 rare coding functional variants (97.0% nonsynonymous SNVs, 1.6% frameshift indels, 1.4% stoploss/stopgains variants) as well as 5 splice site variants were observed in 37 individuals. Of these, 93 novel variants, that harbor genes participating in the DNA damage response pathway, were prioritized. Furthermore, only variants that were predicted to be pathogenic, were considered and they were manually studied through literature. Altogether 20 candidate variants were selected for further segregation, validation, and genotyping experiments, which are currently ongoing.
Conclusions: Identified rare functional variants especially in the DNA damage response pathway genes can explain a fraction of the genetic predisposition to breast and ovarian cancer in the high-risk Finnish families.
Citation Format: Kirsi M. Kuusisto, Tommi Rantapero, Minna Kankuri-Tammilehto, Matti Nykter, Satu-Leena Laasanen, Johanna Schleutker. Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-284. doi:10.1158/1538-7445.AM2015-LB-284