bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3959: Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53
Authors: Sun Yanmei , Xu Mingjing , Wan Ho Lee , Wong Alissa M. , Ng Kelvin K. , Wong Nathalie 
Published: April 2023

Abstract
The Ubiquitin-Proteasome System (UPS) is the major pathway in eukaryotic cells that regulates intracellular protein degradation and turnover. Cumulative evidence has suggested that defects in the UPS machinery are involved in the pathogenesis of human diseases, including cancer. The proteasome-associated polyubiquitin receptor ADRM1 (also known as Rpn13) orchestrates the process of substrate recruitment with deubiquitination in the proteasome through its N-terminal ubiquitin-binding domain and C-terminal activation of deubiquitinating enzyme. Using long-read SMRT-seq to profile the RNA splicing landscape in hepatocellular carcinoma (HCC), we previously reported on an unannotated alternative spliced variant of ADRM1 in human hepatocellular carcinoma (HCC) (Hepatology 2019). This novel isoform exhibits an exon 9 skipping (ADRM1-ΔEx9) that resulted in an altered C-terminus of the protein. In this study, we undertook further investigations to characterize the detailed functional effects of ADRM1-ΔEx9 in HCC biology and the underlying mechanism. Initial study by junction-specific Taqman PCR assay showed that ADRM1-ΔEx9 is more frequently upregulated in HCC tumors than the canonical full-length counterpart (ADRM1-FL). There is an interchange between the two isoforms as tumor develops which underscores an isoform-switch in favor of HCC development. Indeed, our result showed that ADRM1-ΔEx9, but not ADRM1-FL, correlated significantly with inferior patient survival. Functionally, ADRM1-ΔEx9 knockdown profoundly suppressed proliferation by inducing spontaneous apoptosis in HCC cell lines and patient-derived HCC organoids. The corresponding effects were less apparent from ADRM1-FL knockdown. Consistently, overexpression of ADRM1-ΔEx9 in normal human liver organoids promoted pre-malignant features alongside increased in-vitro propagation time. Ubiquitin Proteome profiling revealed that ADRM1-ΔEx9 led to a reduced expression of the pivotal tumor suppressor p53. A parallel transcriptome also substantiated that ADRM1-ΔEx9 modulated genes involved in the p53 and apoptosis pathways. Collectively, our study demonstrated that the non-canonical spliced isoform ADRM1-ΔEx9 confers growth and pro-survival advantages in HCC through mediating selective degradation of tumor suppressor p53 protein.
Citation Format: Yanmei Sun, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Kelvin K. Ng, Nathalie Wong. Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3959.
Abstract 4006: TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC
Authors: Lim Sumin , Choi Seulgi , Lee Ju-Kyung , Choi Eunhyun , Lee Sungwon , Chun Kwangwoo , Baek Myoungki , Park Jiyeon , Kim Jihyun , Kang Areum , Kim Younghoon , Kim Namkyoung , Cho Byoungchul , Sim Taebo , Lee Koo 
Published: April 2023

Abstract
Targeting mutated EGFR is a clinically validated approach for tackling non-small cell lung cancer (NSCLC). Approximately 20% of patients with advanced NSCLC harbor an EGFR mutation. Osimertinib is a 3rd-generation oral EGFR-TKI targeting the EGFR sensitizing mutations Del19 and L858R, as well as an acquired mutation, T790M. Despite osimertinib's efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. Development of another mutation, C797S is the most common mechanism of acquired resistance following osimertinib treatment. This mutation occurs with about 12% frequency after a 1L therapy of osimertinib, and with approximately 17% frequency after a 2L therapy. Here, we report TRX-221 as a novel 4th-generation EGFR-TKI that can overcome C797S-mediated acquired resistance in NSCLC models in vitro and in vivo. TRX-221 exhibited potent inhibitory activity against multiple EGFR mutant kinases, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, L858R/C797S, Del19/T790M, L858R/T790M, Del19, and L858R. Likewise, TRX-221 potently inhibited the proliferation of Ba/F3 cells stably overexpressing these eight EGFR mutants. TRX-221 however showed sparing activity against EGFR wild-type kinase and cell lines. TRX-221 also demonstrated marked anti-proliferative activity against osimertinib-resistant patient-derived cancer cell lines (PDCs). With favorable DMPK profiles, once-daily oral dosing of TRX-221 induced strong anti-tumor effects in a dose-dependent manner in a variety of osimertinib-resistant CDX and PDX models. As a reversible, selective, and broad-spectrum 4th-generation EGFR-TKI, TRX-221 is currently undergoing IND-enabling studies and shows strong potential as a therapeutic solution to treat advanced NSCLC patients harboring EGFR mutations.
Citation Format: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee. TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4006.
Abstract 4068: Ganglioside SSEA4 in Ewing sarcoma: A marker of tumor cells with highly aggressive features and a potential immune target
Authors: Jamitzky Silke , Altvater Bianca , Krekeler Carolin , Hoen Laura , Brandes Caroline , Richter Lisa , Ebbinghaus Julia , Ochs Laurin , Farwick Nicole , Urban Katja , Görlich Dennis , Johnston Ian , Pfeifer Rita , Rossig Claudia , Hartmann Wolfgang , Kailayangiri Sareetha 
Published: April 2023

Abstract
Cancers can aberrantly express carbohydrate antigens restricted to immature cells during prenatal human development, and these may be exploited for selective immune targeting. We studied expression and functional associations of the globo-series ganglioside stage-specific embryonic antigen 4 (SSEA4), a cell surface marker of human embryonic stem cells, in Ewing sarcoma (EwS). Flow cytometry revealed SSEA4 expression on the cell surface of each of 13 EwS cell lines, with moderate to high expression densities in 6 of 13 (46%) cell lines. Of 31 primary EwS tumor biopsies, 21 (68%) were SSEA4 positive by immunofluorescence staining. No associations of SSEA4 positivity with molecular or clinical disease parameters were found. Comparisons of paired tumor cell subpopulations with high and low/negative SSEA4 expression selected by cell sorting from 8 EwS cell lines revealed increased cell proliferation and colony formation of SSEA4high tumor cells, along with higher doxocrubicin chemoresistance and a higher propensity to migrate in transwell assays. SSEA4 negative cells selected from bulk populations of EwS cells regained SSEA4 expression during continued in vitro culture as well as after in vivo xenografting into immunodeficient mice. SSEA4high expression in EwS cells was not dependent on expression levels of the EWSR1-FLI1 fusion transcript or its direct targets, nor associated with markers of epithelial/mesenchymal plasticity. To retarget human T cells to SSEA4, we generated a second-generation, 41BBζ CAR using the antigen-binding domains of a murine anti-SSEA4 monoclonal antibody. SSEA4-specific CAR T cells specifically interacted with SSEA4 positive EwS cells in a strictly antigen-dependent manner, resulting in effective tumor cell lysis in vitro. We conclude that targeting of SSEA4 with CAR T cells or alternative immune therapeutics could be an attractive strategy to eliminate tumor cell subsets with high propensity to drive disease progression in EwS and therefore deserves further evaluation towards clinical translation.
Citation Format: Silke Jamitzky, Bianca Altvater, Carolin Krekeler, Laura Hoen, Caroline Brandes, Lisa Richter, Julia Ebbinghaus, Laurin Ochs, Nicole Farwick, Katja Urban, Dennis Görlich, Ian Johnston, Rita Pfeifer, Claudia Rossig, Wolfgang Hartmann, Sareetha Kailayangiri. Ganglioside SSEA4 in Ewing sarcoma: A marker of tumor cells with highly aggressive features and a potential immune target. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4068.
Abstract 4097: Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas
Authors: Kelsey Lauren , Latta Karin , Kolb Joey , John Bincy , Aylott Ilona , Rocca Daniel , Bacita Alexandru , Kirkham Christopher , Walters Patrick , Humphery Charlotte , Ballesteros Lorena Sueiro , Self-Fordham Jezrom , Brackenbury Louise , Hall Chassidy , David Harris , Schueler Julia , Nunan Robert 
Published: April 2023

Abstract
Chimeric Antigen Receptor (CAR)-T cell therapy has achieved great success in treating a variety of liquid tumors, in particular CD19+ lymphomas. CAR technology is advancing rapidly, with notable improvements in efficacy, safety and complexity as human ingenuity seeks solid tumor applicability. Here we describe how to efficiently generate, expand and validate in-vitro and in-vivo efficacy of a clinically tested CD19-specific CAR. HLA-A*02:01+ CD3+ T-cells were transduced to express a CD19-CAR to &gt;80% efficiency (in 5 donors) and reproducibly expanded to &gt;68 fold over a 19 day period. In-vitro studies were used to assess tumor killing ability, utilizing a HLA-A*02:01+ patient derived xenograft (PDX) CD19+ cell line, alongside human cancer cell lines RAJI (CD19+) and K562 (CD19-). Analysis revealed the potent ability of CD19-CAR-T cells to specifically target CD19+ cells in a dose dependent manner. Supernatant analysis showed highly elevated IFNγ concentrations, identifying enhanced activation of CAR-T cells in the presence of CD19+ target cells only. In-vivo survival studies were completed to identify translatability & efficacy in both systems. Mice were inoculated with CD19+ cells to produce multiple tumor burdened models (RAJI, JEKO-1 & PDX4009). This demonstrated high efficacy of CAR-T at targeting both tumor cell line RAJI or PDX in vivo, with almost complete tumor regression seen in both models. JEKO-1 tumors saw progression slowed in comparison to non-transduced or no treatment controls however due to the nature of this cell line (highly tumorigenic) the level of tumor regression was not matched to the other models. Cell bio-distribution was assessed with CAR-T cells tracking successfully to the tumors as well as the highly vascularized tissues, which was expected and consistent with previous data. These assays can be translated to any CAR construct aimed at targeting either solid or hematological tumors and demonstrates an integrated platform for translating CAR research that can be utilized end to end.
Citation Format: Lauren Kelsey, Karin Latta, Joey Kolb, Bincy John, Ilona Aylott, Daniel Rocca, Alexandru Bacita, Christopher Kirkham, Patrick Walters, Charlotte Humphery, Lorena Sueiro Ballesteros, Jezrom Self-Fordham, Louise Brackenbury, Chassidy Hall, Harris David, Julia Schueler, Robert Nunan. Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4097.
Abstract 4209: Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System
Authors: Bytnar Julie A. , Lin Jie , Moncur Joel T. , Shriver Craig D. , Zhu Kangmin 
Published: April 2023

Abstract
Background: Cancers of unknown primary (CUP), a group of heterogenous metastatic cancers lacking a known primary site, have poor prognosis. This study compared survival by histologic type, patient characteristics, and treatment in the U.S. Military Health System (MHS), which provides universal care to its members.
Methods: Patients diagnosed with CUP were identified from the U.S. Department of Defense’s Automated Central Tumor Registry. Median survival with 95% confidence intervals was calculated for demographic and treatment variables by histologic type. A multivariable accelerated failure time model estimated time ratios and 95% confidence intervals.
Results: The study included 3,358 CUP patients. The most prevalent CUP in this study was well and moderately differentiated adenocarcinomas. Median survival varied by histologic type with squamous cell carcinoma having the longest at 25.1 months and poorly differentiated carcinomas having the shortest at 3.0 months. For each histologic type, survival was generally similar by sex and active-duty status. Younger patients tended to have longer survival than those aged 65 years or older. Women with well and moderately differentiated adenocarcinoma had longer survival than their male counterparts. Generally, there were no racial differences in survival except poorer survival for Blacks than Whites with other histologic types. Patents with chemotherapy and radiation treatment generally had improved survival whereas patients with squamous cell carcinoma who received chemotherapy had shorter survival than those without.
Conclusion: Survival generally did not differ between racial groups, which may be related to equal healthcare access despite racial background. Further studies are warranted to better understand how survival in the MHS compares with that in the general U.S. population.
Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of USUHS, HJF, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products or organizations does not imply endorsement by the US Government.
Citation Format: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu. Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4209.
Abstract 4266: Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation
Authors: Arigbede Olumide , Buxbaum Sarah G. , Falzarano Sara , Rhie Suhn K. 
Published: April 2023

Abstract
Issue: Prostate cancer (Pca) is still among the most frequently diagnosed cancers in adults. The most often mutated gene in PCa is PTEN (Phosphatase and Tensin Homolog), making it a possible biomarker for prospective customized therapy. The root causes of health inequalities in PCa have not received much attention. Numerous online databases, like The Cancer Genome Atlas (TCGA), provide gene expression data and other data, allowing researchers to further investigate new processes or therapy options. However, there hasn't been much study on tailored therapy up to this point since there may have been difficulties with access to genomic information and bioinformatic tools.
Methods: The PCa data in cBioPortal comprises 494 samples. We selected 154 samples comprising 7 Blacks and 147 Whites. We used the TCGA database to obtain the PCa gene expression and DNA methylation data for study. In order to examine the data by race/ethnicity, gene expression, DNA methylation, and genomic changes, we evaluated at the differentially expressed and methylated genes using online tools (cBioPortal). To evaluate gene methylation, expression, and alterations, log ratios of means in Blacks to means in Whites were computed across the data. Additionally, Kaplan-Meier survival analysis, protein interaction analysis, and multivariable data analysis were carried out.
Results: PCa data in the TCGA database showed PTEN mutation in 20% patients. The median age of participants was 63 years (range: 42-78). For every category of data assessed, there were significant differences by race/ethnicity (q &lt; 0.05). In the survival analysis, SLC2A1, NUDT12, CUTALP, and other genes were associated with survival.
Conclusion: Genetic alteration, expression, and DNA methylation are each significantly different by the two race groups compared. According to our research, PTEN mutation in PCa may influence several genes and biological processes.
Citation Format: Olumide Arigbede, Sarah G. Buxbaum, Sara Falzarano, Suhn K. Rhie. Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4266.
Abstract 4439: Negative impact of the GABA pathway on aPD(L)1 immunotherapy
Authors: Lyalina Svetlana , Ortiz-Munoz Guadalupe , Yuen Kobe , Mellman Ira , Mariathasan Sanjeev , Albert Matthew , Nagarkar Deepti , Moussion Christine 
Published: April 2023

Abstract
Although gamma-amino butyric acid (GABA) is well characterized as the primary inhibitory neurotransmitter of the central nervous system, its role in the periphery as an immunomodulatory agent is not well understood. Given the widespread use of GABA-A receptor agonists as palliative care in clinical practice, we examined here the impact of GABA on response to immunotherapy in preclinical tumor models and the association of GABA-A receptor agonist usage with outcomes in patients receiving immunotherapy.We show that important genes controlling the GABA pathway are enriched in human tumors versus normal tissue across indications, and tumor cells themselves are able to produce GABA. We found that several key genes of the GABA pathway are upregulated in non-responders to atezolizumab and we derived a 5-gene signature associated with poor outcomes in 2L urothelial cancer patients receiving atezolizumab. Preclinical models further indicated that GABA at the tumor site promotes tumor growth and dampens adaptive immunity preventing response to immunotherapy. Finally, we noted that 45% of urothelial cancer patients received concomitant GABA-A positive allosteric modulators, given as palliative therapy in atezolizumab trials IMvigor-210 and -211. This group exhibited significantly lower OS and PFS as compared to atezolizumab treated patients who did not receive GABA-A positive modulators. A similar negative impact was seen in patients receiving standard of care anti-PD(L)1 immunotherapy in 2L NSCLC using EHR derived deidentified Flatiron Health - Komodo Health claims linked data. These findings highlight the need for further evaluation of concomitant GABA modulators to understand potential risk associated with palliative care in the setting of cancer immunotherapy.
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Citation Format: Svetlana Lyalina, Guadalupe Ortiz-Munoz, Kobe Yuen, Ira Mellman, Sanjeev Mariathasan, Matthew Albert, Deepti Nagarkar, Christine Moussion. Negative impact of the GABA pathway on aPD(L)1 immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4439.
Abstract 4502: Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and therapy
Authors: Rady Islam , Bakry Sayed , El-Azm Fatma Abou , Mukhtar Hasan 
Published: April 2023

Abstract
Melittin (MEL), a major peptide component of bee venom (BV), has shown chemopreventive as well as chemotherapeutic effects against many cancers in preclinical model systems. However, its applicability to humans has met with limited success due to several issues including its toxicity, nonspecificity, degradation, inefficient systemic delivery and limited bioavailability. Earlier, the concept of "nanochemoprevention" i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention is introduced. Then, "non-targeted nanobees" i.e. nanoformulated mellitin is developed to exhibit excellent anti-prostate cancer efficacy in vitro and in animal models coining the concept as ‘Nanobee- Chemoprevention’. Here, we are extending this work and developed nanobees targeted with small molecular entities (A10 2′-fluoropyrimidine RNA aptamers (Apt)), able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa) and evaluated their efficacy in preclinical studies. The Apt-Nanobees led to an enhanced anti-proliferative activity in PCa cell lines compared to the free melittin. The behavior of Apt-Nanobees in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor using nanobees with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of targeted nanobees enhanced the bioavailability and limited unwanted toxicity of melittin, thus leading to a significant potential for probable clinical outcome.
Citation Format: Islam Rady, Sayed Bakry, Fatma Abou El-Azm, Hasan Mukhtar. Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4502.