bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-086: CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity
Authors: Yacov Niva , Propheta-Meiran Oshrat , Kafri Pinhas , Salem Yaniv , Mendel Itzhak , BREITBART EYAL 
Published: September 2020

Abstract
Introduction: We have previously showed that motile sperm domain-containing protein 2 (MOSPD2), is highly expressed in multiple solid tumors and cancer cell lines but has low/undetectable levels in healthy tissues, implying that MOSPD2 can be an effective target for directed killing of tumor cells. We developed CD3xMOSPD2 bi-specific IgG antibodies (BsAb) that induced T-cell activation and yielded profound death of target tumor cells in-vitro.
Experimental procedure: NSG mice were injected subcutaneously with the metastatic cervical cancer HeLa cell line (day 0). Freshly isolated human PBMC were transferred I.P when tumors volume reached an average of 150mm3 (day 29). Subsequently, mice were treated I.V with control IgG antibody or CD3xMOSPD2 BsAb and monitored for survival. To assess in-vivo T-cell activation, serum collected 6hr after first antibody treatment was analyzed for cytokines level.
Results: Treatment with CD3xMOSPD2 BsAb, significantly increased serum concentration of IFN-γ, IL-6 and TNF-α compared with control IgG-treatment. Strikingly, by day 65, survival rate of CD3xMOSPD2 BsAb treated mice was 90% compared with only 10% in the control IgG-treated group (n=9-10; p=0.00106). No evidence of toxicity or off target activity was detected.
Conclusions: Our data show that CD3xMOSPD2 bi-specific antibody induces T-cell activation in-vivo and significantly extends the survival of mice carrying established metastatic cervical cancer. These results highlight the potential of bi-specific mediated immuno-oncology therapy for the treatment of MOSPD2-positive metastatic solid tumors.
Citation Format: Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Yaniv Salem, Itzhak Mendel, EYAL BREITBART. CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-086.
Abstract LB-098: The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models
Authors: Hallin Jill , Calinisan Andrew , Hargis Lauren , Aranda Ruth , Engstrom Lars D. , Briere David M. , Marx Matthew A. , Olson Peter , Christensen James G. 
Published: September 2020

Abstract
The ability to develop effective therapies for KRAS mutant cancers has remained elusive despite decades of research. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor presently under evaluation in clinical trials. MRTX849 inhibits only inactive GDP-bound KRASG12C, a mutation known to be dependent on nucleotide cycling and extrinsic factors which regulate the activation state of KRAS. Preclinical and early clinical data suggest KRASG12C inhibitors induce tumor regression/response in a subset of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models and patients. Previous work in tumor xenograft models demonstrated activation of pathways upstream or downstream of KRAS through additional mutations or relief of feedback inhibition can limit the single agent activity of MRTX849 in the less responsive tumors. These data indicated that activation of receptor tyrosine kinases (RTKs) through relief of feedback inhibition was one mechanism implicated in modulating the response to MRTX849. As KRAS G12C mutations are present in ~4% of colon cancer, MRTX849 was further evaluated in CRC models to identify combination strategies that might optimize anti-tumor activity. A range of responses to single agent MRTX849 were observed across cell line and patient-derived xenograft (PDX) models. The combination of MRTX849 plus cetuximab demonstrated the best anti-tumor activity in multiple models. The combination of MRTX849 and cetuximab demonstrated increased KRASG12C modification and MAPK pathway inhibition suggesting these therapies converge to more fully inhibit KRASG12C. Despite the fact that cetuximab-based therapy is contra-indicated for KRAS-mutant CRC, these data suggest co-targeting EGFR and KRAS may more comprehensively inhibit KRAS mediated signaling and more effectively treat a subset of CRC patients with KRASG12C-mutant cancers.
Citation Format: Jill Hallin, Andrew Calinisan, Lauren Hargis, Ruth Aranda, Lars D. Engstrom, David M. Briere, Matthew A. Marx, Peter Olson, James G. Christensen. The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-098.
Abstract LB-149: Serum thymidine kinase 1 levels predict prostate cancer-specific survival
Authors: Murtola Teemu J. , Raittinen Paavo , Tammela Teuvo 
Published: September 2020

Abstract
Background: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis. Thymidine kinases phosphorylate thymidine as part of the DNA synthetic pathway. TK1 expression is a marker of active cellular proliferation; intracellular concentrations are low during the G0/G1 phases of the cell cycle, increasing during the S/G2 phases. Previous studies have suggested that serum TK1 levels could be used as marker for presence of prostate cancer (PCa). Here, we evaluated whether serum TK1 levels could predict risk of PCa prognosis. Materials and Methods: The study population included 40 men with clinically defined T1/T2NxM0 PCa and 43 men with de novo metastatic cancer (M1) at diagnosis confirmed by bone scan imaging. All men were diagnosed and treated at the Tampere University Hospital between 2000-2010. All men provided a serum sample at the time of diagnosis. Information on deaths and causes of death were obtained from national causes of death registry. Serum TK1 concentrations were determined using the AroCell TK210 ELISA kit. Cox regression and Kaplan-Meier Curves with adjustment for tumor risk group (Gleason-grade, TNM stage and PSA level) were used to evaluate the risk of PCa death in relation to TK1 levels (median or below vs. above median). ROC analyses were used to evaluate the predictive accuracy of PSA, TK1 and their combination. Results: M1 cases were older than M0 cases; median age 72 vs 62 years, respectively. M1 cases were mainly managed with androgen deprivation therapy, whereas M0 cases were most often managed with radical prostatectomy. Median serum TK1 levels were significantly higher among M1 cases compared to M0 cases (p for difference 0.001). In the combined study population, serum TK1 levels were a significant predictor of PCa-specific (HR 8.33, 95% CI 2.05-33.88) and overall mortality (HR 5.53, 95% CI 1.93-15.85) after adjustment for established prognostic factors including tumor risk group. Kaplan-Meier survival curves defined by TK1 level started to differ within 24 months from PCa diagnosis. In ROC analyses TK1 alone or in combination with PSA was no more accurate than PSA alone in predicting PCa death. Conclusion: The proliferation biomarker TK1 in serum predicted survival after PCa diagnosis, demonstrating independent predictive value over established clinical risk factors. If confirmed in further and larger studies, this biomarker could be incorporated in PCa risk stratification when selecting optimal treatment and surveillance schedule.
Citation Format: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela. Serum thymidine kinase 1 levels predict prostate cancer-specific survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-149.
Abstract LB-159: The association of alveolar lipid laden macrophages with inflammatory cytokines in electronic cigarette users
Authors: Song Min-Ae , Shields Peter G. , Freudenheim Jo L. , Brasky Theodore M. , McElroy Joseph P. , McElroy Joseph P. , Reisinger Sarah A. , Weng Daniel Y. , Ren Rongqin , Eissenberg Thomas , Wewers Mark D. , Shilo Konstantin 
Published: September 2020

Abstract
Introduction: Lipid laden macrophages (LLM) from lung bronchoscopies have been identified as characteristic for some patients with e-cigarette (e-cig) or vaping product use associated lung injury (EVALI). While vaping with THC oils containing vitamin E acetate is thought to have caused the outbreak, there is a subset of the EVALI cases who reported vaping only with nicotine-containing e-cigs. A recent animal study showed that propylene glycol (PG) and vegetable glycerin altered lipid homeostasis and induced LLM. In addition to the associations with EVALI, understanding the health effects of vaping with e-cigs in general needs additional investigation. Objective: We examined alterations in alveolar lipid homeostasis comparing e-cig users to cigarette smokers and never-smokers. Further, we determined the association of LLM with inflammatory cytokines. Methods: LLMs, inflammatory cell counts, and cytokines were determined in bronchial alveolar fluids (BAL) from a cross-sectional study of 62 volunteer subjects, age 21-45. Participants who were e-cig users were either never-smokers or former smokers. Cigarette smoking and e-cig use were confirmed by biomarkers of exposure, including lung and urine cotinine and 3-hydroxycotinine and urine anatabine, nicotelline, and PG. Results: High LLM counts were found in the lungs of almost all smokers and about half of the e-cig users, but not in any never-smokers (P&lt;0.001). LLMs were significantly correlated with the inflammatory cytokines IL-4 and IL-10 in e-cig users (P=0.01). Smoking history, including cigarettes per day and biomarkers of exposure, e-cig use history, and gender were not associated with LLMs (all P&gt;0.05). LLMs were not related to THC exposure. Discussion: This is the first report comparing LLMs in the lungs of e-cig users with smokers and never-smokers. LLMs were found in lungs of both smokers and a portion of e-cig users. Given their presence among smokers, they are not likely to be useful as a marker identifying those with EVALI. However, LLMs may be one of the markers for specific disease risks associated with e-cig usage, but not smoking.
Citation Format: Min-Ae Song, Peter G. Shields, Jo L. Freudenheim, Theodore M. Brasky, Joseph P. McElroy, Joseph P. McElroy, Sarah A. Reisinger, Daniel Y. Weng, Rongqin Ren, Thomas Eissenberg, Mark D. Wewers, Konstantin Shilo. The association of alveolar lipid laden macrophages with inflammatory cytokines in electronic cigarette users [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-159.
Abstract LB-210: Chemotherapy promotes metastasis through extracellular vesicle secretion
Authors: Wills Carson A. , Sundstrom Jeffrey , Wang Hong-Gang 
Published: September 2020

Abstract
Neoadjuvant chemotherapy treatment is the gold standard for children and adults with intermediate- to high-risk tumors. However, a subset of patients develop distant metastases following treatment, and evidence suggests that chemotherapy itself may promote metastasis in some patients. Indeed, utilizing xenograft mouse model of human triple-negative breast cancer, we confirm that treatment with the chemotherapeutic agent Doxorubicin decreases primary tumor growth while promoting pulmonary metastasis. The purpose of this research is to understand how chemotherapy treatment regulates tumor-derived exosomes, extracellular vesicles that are secreted by all cells and that function in cellular communication through the horizontal transfer of biologically-active molecules. Specifically, our goal is to determine how exosomes derived from chemotherapy-treated tumor cells, or ‘chemoexosomes,' regulate tumor metastasis in order to develop more effective chemotherapeutic options for cancer patients. Utilizing models of both breast cancer and pediatric neuroblastoma, we demonstrate that sublethal doses of DNA-damaging chemotherapeutic agents significantly enhance exosome secretion compared to vehicle control. Xenografted mice treated with exosomes derived from chemotherapy-treated cells demonstrate a significant acceleration in metastasis with no increase in primary breast tumor growth compared to mice treated with exosomes derived from control-treated cells or saline. Although chemoexosomes do not enhance tumor cell migration or invasion in vitro, they demonstrate tumor type-specific preferential organotropic localization to the most common sites of tumor metastasis in vivo. Mice treated with chemoexosomes prior to tail-vein injection of either neuroblastoma or breast tumor cells demonstrate a significant increase in metastatic tumor burden compared to mice pre-treated with control exosomes or saline. Through proteomic analysis, we identified differentially-expressed exosomal proteins upregulated by chemotherapy treatment. Utilizing CRISPR-Cas9-mediated gene knockout, we identified a component of the complement pathway upregulated in chemoexosomes that is critically involved in exosome-mediated metastasis. Taken together, this research proposes a novel mechanism of chemotherapy-induced metastasis by which organ-specific uptake of exosomes derived from chemotherapy-treated cells primes the pre-metastatic niche in order to create a favorable environment for metastatic tumor growth.
Citation Format: Carson A. Wills, Jeffrey Sundstrom, Hong-Gang Wang. Chemotherapy promotes metastasis through extracellular vesicle secretion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-210.
Abstract LB-220: Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes
Authors: AbouRaya Dina Hesham , El-Naggar Shahenda 
Published: September 2020

Abstract
Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare variant of embryonal brain tumors. Amplification of C19MC microRNA cluster and expression LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR is not thoroughly investigated. In the current study a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue- matched ETMR (SRP032476), and fetal controls from the Human Developmental Biology Resource (HDBR) (E-MTAB-4840) datasets. Gene expression was quantified in samples using kallisto/sleuth pipeline. For the alternative splicing analysis, reads were mapped to the genome (hg38) using STAR. Identification and quantification of alternative splicing events (skipped exon, alternative 5′ and 3′splice sites, mutually exclusive exons, multi Exons Skip and retained intron) were carried out using SplAdder. Functional enrichment analysis for the differentially expressed and the differentially spliced genes was subsequently performed using Metascape. All statistical values reported were corrected for multiple hypothesis testing by Benjamini-Hochberg false discovery rate (q-values).The expression analysis revealed a total of 2205 differentially expressed genes (DEGs) between ETMR and fetal controls while 2446 showed differential alternative splicing patterns. DEGs with significant alternative splicing events were identified to be involved in ubiquitin mediated proteolysis, endocytosis, RNA transport, regulation of actin cytoskeleton pathways as well as histone modification. Interestingly, DEGs with intron retention events were involved in various signaling pathways including TGF-beta signaling pathway, MAPK signaling pathway and ErbB signaling pathway. These findings highlight the role of defective alternative splicing in shaping ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets.
Citation Format: Dina Hesham AbouRaya, Shahenda El-Naggar. Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-220.
Abstract LB-221: Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors
Authors: Amer Nada , Taha Hala , Hesham Dina , Mahmoud Noura , Elayadi Moatasem , Mossab Amal , Youssef Ayda , Elbeltagy Mohamed , Zaghloul Mohamed Saad , Azziz Ahmad Abdel , El-Naggar Shahenda 
Published: September 2020

Abstract
Protein misfolding and aggregation result in proteotoxic stress, and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. Aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Our previous work revealed the presence of aggresomes in pediatric choroid plexus tumors (CPT). CPTs are rare neoplasms comprised of three pathological subgroups; choroid plexus carcinoma (CPC), a grade III tumor, atypical choroid plexus papilloma (ACPP), a grade II tumor, and choroid plexus papilloma (CPP), a grade I tumor. In the current study, we aimed to investigate the prognostic value of aggresomes-positivity and if it could be used to improve the disease subclassification. Forty two pediatric CPT tumor samples were stratified into two molecular subgroups; Cluster “A", and “B”, using Illumina Infinium Methylation EPIC BeadChip array. Kaplan Meier analysis showed that “cluster B” is associated with significantly shorter overall survival (OS) and event free survival (EFS) with P= 0.008 and P =0.007 respectively. Aggresomes were detected in 64.2% of samples using immunohistochemistry and they were distributed among different pathological and molecular subgroups. The presence of aggresomes significantly correlated with patient outcome in both OS (P = 0.057) and EFS (P = 0.051). The survival-based cutoff determination was performed using various percentages of aggresomes; ranging from 10% to 50%. Aggresome presence maintained significance at all cutoffs, yet the 25% cutoff had the highest impact in OS and EFS (P = 0.001). Moreover, the classification based on the 25% cutoff concurred with the methylation signature of low-risk “A” and high-risk “B” clusters. Hence, the detection of aggresomes in CPTs provides a new prognostic marker supporting histopathological tumor classification.
Citation Format: Nada Amer, Hala Taha, Dina Hesham, Noura Mahmoud, Moatasem Elayadi, Amal Mossab, Ayda Youssef, Mohamed Elbeltagy, Mohamed Saad Zaghloul, Ahmad Abdel Azziz, Shahenda El-Naggar. Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-221.
Abstract LB-329: Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets
Authors: Elmas Abdulkadir , Molina-Sanchez Pedro , Tharakan Serena , Jaladanki Suraj , Liu Tao , Lujambio Amaia , Huang Kuan-lin 
Published: September 2020

Abstract
Dysregulated oncogenic signaling is a key hallmark of cancer. Protein kinase alterations, including genomic mutations and copy-number amplifications, are known druggable targets in multiple cancer types. Thus, kinase inhibitor drugs act on protein and direct observation of protein/phospho-level overexpression may reveal new treatment opportunities. Herein, we developed and applied a new algorithm, OPPTI, to provide a catalog of overexpressed kinases across 10 cancer types using curated global mass spectrometry proteomic data of 1,071 cases. Aside from overexpressed proteins through genomic mutations, amplifications, or fusions, including ERBB2, AKT2, and EGFR, kinase overexpression also occurred in cancers without genomic-level alterations, such as CDK6 in hepatocellular carcinoma (HCC), FGFR1/2 in ovarian cancer, and PDGFRA in both gastric cancer and lung adenocarcinoma. Integrating cancer-cell dependency data, we further identified 38 new cancer vulnerability targets overexpressed in &gt;10% of the patient cohorts, including TK1 in breast and gastric cancers, NRBP2 in liver and lung cancers, and CKB in ovarian, endometrial, and colorectal cancers. A fraction of overexpressed kinases was validated by immunostainings and correlated with phosphosignaling pathway activities. Finally, we demonstrated that a subset of HCC mouse models that overexpressed PDGFRB -as detected in parallel in human HCC cohorts- could be specifically treated by a receptor tyrosine kinase inhibitor. Overall, our results suggest that proteomic-level alterations not readily observed by genomics represent cancer vulnerabilities that need to be carefully considered as potential targets for personalized treatments.
Citation Format: Abdulkadir Elmas, Pedro Molina-Sanchez, Serena Tharakan, Suraj Jaladanki, Tao Liu, Amaia Lujambio, Kuan-lin Huang. Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-329.