bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3557: Stage-restricted osteoblasts specify signatures of osteosarcoma molecular subtypes
Authors: Tao Jianning , Fan g , Torres Haydee 
Published: April 2023

Abstract
A challenging question in osteosarcoma research is the identity of the cell of origin, and its contribution to the molecular subtypes and signatures. We examine the potential of stage restricted osteoblasts to induce fully penetrant osteosarcoma using osteoblast stage specific Cre mice to mutate Trp53. We identified three molecularly distinct subtypes of osteosarcoma induced by the same driver mutation. Our results suggest that the three subtypes arise from different subpopulations of osteoblasts. Despite histologic identity as one entry osteosarcoma, these subtypes are separable based on molecular signatures and specific signaling pathways. These studies point to the cell of origin as a determinant of osteosarcoma molecular subtypes. Our studies may provide insights for understanding osteosarcoma heterogeneity and improving treatment of the disease.
Citation Format: Jianning Tao, g Fan, Haydee Torres. Stage-restricted osteoblasts specify signatures of osteosarcoma molecular subtypes. [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 3557.
Abstract 3596: EMG1 is an rRNA-modifying protein that contributes to breast cancer progression
Authors: Elhamamsy Amr R. , Alsheikh Heba A. , Samant Rajeev S. , Shevde Lalita A. 
Published: April 2023

Abstract
The ribosome, a multi-subunit RNA-protein complex, is essential for translation in all cells. Variation in ribosome composition and characteristics has been observed between cell types and under different metabolic conditions; this phenomenon is referred to as "ribosome heterogeneity." Ribosome heterogeneity has been linked to carcinogenesis and cancer progression. One of the major layers of ribosome heterogeneity is the diverse rRNA modifications. To study the impact of rRNA modifications on cancer, we performed a systematic literature search and identified 22 rRNA modifying proteins (RRMPs) that are involved in mediating different modifications of rRNA. We next examined the RRMPs' expression levels and frequency of mutation in different cancer types, with a focus on breast cancer. We see that most malignancies show alterations in RRMPs' expression levels and frequent mutations. Our analysis of gene expression patterns and clinical outcomes in breast cancer has shown that several RRPMs are strongly linked to an aggressive phenotype and a poor prognosis. Our analysis also revealed that EMG1, a N1-specific psuedouridine methyltransferase, is a RRMP with potential roles in cancer progression and metastasis. Our findings pave the way for further research into the role of RRMPs in different cancers as well as the development of therapies that specifically target RRMPs involved in cancer progression.
Citation Format: Amr R. Elhamamsy, Heba A. Alsheikh, Rajeev S. Samant, Lalita A. Shevde. EMG1 is an rRNA-modifying protein that contributes to breast cancer progression. [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 3596.
Abstract 3689: Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma
Authors: Singh Satishkumar , Choueiry Fouad , Sircar Anuvrat , Epperla Narendranath , Zhu Jiangjiang , Sehgal Lalit 
Published: April 2023

Abstract
DLBCL is the most common B cell malignancy in adults accounting for 30-40% of non-Hodgkin lymphoma. Only 60% of these cases are curable, with activated B cell DLBCL (ABC-DLBCL) having inferior outcomes than the germinal center (GCB) DLBCL. The use of ibrutinib to treat non-responsive/relapsed ABC-DLBCL cases has significantly improved the treatment of this disease. However, in more than 40% of ABC-DLBCL cases, the disease progresses or develops resistance to ibrutinib. Thus, there is an urgent unmet need to understand the molecular basis of resistance mechanisms and identify novel therapeutic regimens to treat IR DLBCL. Utilizing high throughput metabolomics, we identified cysteine-methionine metabolism and alanine, aspartate, and glutamate metabolism to be deregulated in IR cells. We further identified interleukin four induced 1 (IL4I1), an L-amino acid oxidase that partakes in cysteine and methionine metabolism by contributing to the methionine salvage pathway. The amino acid cysteine contributes to cancer metabolic remodeling by a), in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, b), as a substrate for the production of hydrogen sulfide (H2S), which feeds the mitochondrial electron transfer chain and mediates persulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, c), as a carbon source for epigenetic regulation, biomass production, and energy production. Consistent with this, we show that loss of IL4I1 expression induced aberrant cysteine and methionine metabolism accompanied by metabolic reprogramming to OXPHOS, which collectively enabled increased drug tolerance of DLBCL. This adaptive metabolic mechanism exhibited increased cysteine and cystathionine intracellular levels in IR-DLBCL lacking IL4I1 expression. As cysteine and glutathione are scavengers of free radicals (mainly reactive oxygen species (ROS)), they can nullify the effects of the majority of oxidative or alkylating drugs used in cancer therapy, affording a vital resistance mechanism and disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death and provide therapeutic approaches to treat Ibrutinib-resistant-ABC- DLBCL for improved patient care.
Citation Format: Satishkumar Singh, Fouad Choueiry, Anuvrat Sircar, Narendranath Epperla, Jiangjiang Zhu, Lalit Sehgal. Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma. [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 3689.
Abstract 3930: MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma
Authors: Wong Ethan J. , Khammanivong Ali , Maisuria Ravi , Dickerson Erin B. , Gopalakrishnan Raj 
Published: April 2023

Abstract
Introduction: Most oral squamous cell carcinomas (OSCC) progress through clinically identifiable stages, starting from premalignant epithelial dysplasia to early invasive OSCC. How cells transform from premalignant dysplasia to early invasive OSCC is unknown. High monocarboxylate transporter 1 (MCT1; SLC16A1) expression is correlated with poor outcomes in OSCC patients, where it is thought to promote tumor growth by supporting metabolic coupling between cancer cells and tumor stroma. Because expression of MCT1 is markedly increased in OSCC patients, we sought to determine if MCT1 played a role in the progression of oral dysplasia in early invasive OSCC.
Methods: Immunohistochemistry (IHC) was used to evaluate changes in the levels of MCT1 expression across adjacent normal, dysplasia, and OSCC tissues to identify expression patterns during cancer progression. Genetic knockout (KO) of SLC16A1 via CRISPR/Cas9 and pharmacological blockade by the MCT1 inhibitor AZD3965 were used on OSCC (TR146) and dysplastic (DOK) cell lines. KO was confirmed by qRT-PCR and immunoblotting. MCT1-KO and AZD3965-treated cells were assayed for changes in cell invasion using Matrigel-coated transwell assays. Correlative changes in gene expression based on MCT1 staining and disease progression were also observed in adjacent normal, dysplasia, and OSCC regions in each tissue section using Nanostring GeoMx Digital Spatial Profiler.
Results: Expression of MCT1 was directly correlated to the progression of disease from dysplasia to early superficially invasive OSCC relative to normal adjacent epithelium. KO of MCT1 significantly decreased the invasion of dysplastic and OSCC cell lines compared to the wild-type (parental) controls. AZD3965 also decreased invasion in the parental dysplastic and OSCC lines. To identify progressive changes in gene expression across normal, dysplasia, and early invasive OSCC, transcripts for cancer-related genes were quantified in the epithelial and stromal compartments from patient samples. Compared to the normal epithelium, upregulation in gene expression, including SLC16A1, was observed in the cell cycle and metabolic pathways in OSCC tissues.
Conclusions: Our data suggest that MCT1 plays a key role in breaching of the basement membrane and facilitating tumor cell migration and invasion. Targeting MCT1 in oral dysplasia may prevent progression to OSCC in oral cancer patients.
Citation Format: Ethan J. Wong, Ali Khammanivong, Ravi Maisuria, Erin B. Dickerson, Raj Gopalakrishnan. MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma. [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 3930.
Abstract 3989: EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer
Authors: Gulla Surendra , Bard Jonathan E. , VanderWeele David J. , Kelly Kathleen , Adelaiye-Ogala Remi 
Published: April 2023

Abstract
Background: Androgen receptor (AR) remains active in castration-resistant prostate cancer (CRPC), and AR cistrome can become extensively reprogrammed with disease progression. Recent findings from our group and others have shown an association with non-canonical AR signature with resistance to enzalutamide. However, the complete mechanism is not fully revealed. EVI1 belongs to the zinc-finger transcription factor family, and overexpression of EVI1 is associated with poor patient outcomes. However, its role in the context of resistance to AR-targeted therapy remains unclear. Our preliminary data from ChIP-seq and GSEA analysis shows a significant enrichment of EVI1 target gene-set captured from annotated enzalutamide-resistant AR binding sites.
Hypothesis: EVI1 cooperates in regulating the non-canonical AR activity associated with resistance to AR targeted therapy and blocking EVI1 may overcome resistance to target therapy.
Methods: Using a PDX model of advanced enzalutamide-resistant CRPC, we performed single-cell ATAC-seq + gene expression multi-omic assay. Next, we determined the enrichment of canonical vs. non-canonical AR signatures across cell populations. Using motif analysis and transcription factor foot printing, we determine EVI1 (MECOM) motif z score and enrichment.
Results: Our findings demonstrate enrichment of non-canonical AR signatures in distinct population of cells following exposure to enzalutamide. In addition, the subpopulation of cells enriched for non-canonical AR cistrome also exhibited high EVI1 (MECOM) motif z-scores.
Conclusion: Our data suggests a potential link between EVI1 and non-canonical AR signaling. Ongoing mechanistic studies will provide insight mechanism by which EVI1 controls non canonical AR activity and its vulnerabilities.
Citation Format: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala. EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer. [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 3989.
Abstract 3992: Elucidating reciprocal interactions between bone marrow stromal cells and a novel γδ CAR T cell therapy in the context of bone metastatic prostate cancer
Authors: Frieling Jeremy S. , Bustos Xiomar , Bishop Ryan T. , Tordesillas Leticia , Abate-Daga Daniel , Lynch Conor C. 
Published: April 2023

Abstract
Bone metastatic castrate resistant prostate cancer (CRPC) generates tumors hallmarked by extensive bone formation due to enhanced mesenchymal stem cell (MSC)-osteoblast differentiation. These lesions are at present incurable and substantially diminish patient quality of life, but exciting preclinical studies by our group have shown that these metastases are highly sensitive to gamma delta (γδ) T cell-based CAR-T therapies. However, the impacts of CAR-T cell therapies on the bone microenvironment are presently unknown. Because MSCs are an important stromal component of the cancer-bone microenvironment with emerging immunoregulatory activities, we have recently focused on characterizing the interactions between γδ CAR-T cells and the MSC compartment and their implications for bone metastatic CRPC. Our data show that: 1) γδ CAR-T cells or conditioned media (CM) did not significantly alter MSC viability, 2) MSCs were robustly chemotactic to CM derived from tumor-activated γδ CAR-T cells, 3) MSCs treated with tumor-activated γδ CAR-T CM showed a significant induction of ICAM-1 (9.12-fold, P=0.00640) compared to controls, 4) ICAM-1 silencing significantly reduced γδ CAR-T educated MSC migratory ability, 5) tumor-activated γδ CAR-T CM differentially regulated key genes involved in MSC-osteoblast differentiation, a finding supported by Alizarin red S staining and alkaline phosphatase functional assays, and 6) tri-cultures of MSCs, CRPC cells, and γδ CAR-T cells demonstrate that MSCs significantly enhanced γδ CAR-T mediated CRPC killing. Taken together, we have shown that γδ CAR-T cells promote MSC recruitment in an ICAM-1 dependent manner, and MSCs enhance γδ CAR-T targeted CRPC killing. Reciprocally, γδ CAR-T can promote MSC commitment to osteoblast lineage without impacting their viability. These data are the first to interrogate how bone stromal components regulate γδ CAR-T mediated killing in the context of bone metastatic CRPC. We are currently investigating the mechanisms underpinning the bi-directional interplay between these cell populations.
Citation Format: Jeremy S. Frieling, Xiomar Bustos, Ryan T. Bishop, Leticia Tordesillas, Daniel Abate-Daga, Conor C. Lynch. Elucidating reciprocal interactions between bone marrow stromal cells and a novel γδ CAR T cell therapy in the context of bone metastatic prostate cancer. [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 3992.
Abstract 4035: Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer
Authors: Siegel Franziska , Karsli-Uzunbas Gizem , Kotynkova Kristyna , McVeigh Quinn , Siegel Stephan , Korr Daniel , Schulze Volker , Berger Markus , Beckmann Georg , Cherniack Andrew , Meyerson Matthew , Greulich Heidi 
Published: April 2023

Abstract
HER2 mutations are potent oncogenic drivers in various cancer indications. In NSCLC, about 2% of patients carry either a HER2 exon20 insertion mutation or a HER2 point mutation. With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. However, there remains a high unmet need for more effective and better tolerated therapies with the potential to improve response rates and response durability.
BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, phase I clinical trial in patients with EGFR mutant NSCLC (NCT05099172).
Here, we present the preclinical activity profile of BAY 2927088 in HER2 mutant NSCLC. BAY 2927088 shows strong antiproliferative activity in an isogenic Ba/F3 cell line panel of HER2 exon20 insertion mutations as well as HER2 point mutations. BAY 2927088 is highly potent on the most frequent HER2 exon20 insertion mutations A775insYVMA and G776del insVC, as well as in the HER2 point mutations S310F, S335C, and L755S, among others. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA.
The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations.
Citation Format: Franziska Siegel, Gizem Karsli-Uzunbas, Kristyna Kotynkova, Quinn McVeigh, Stephan Siegel, Daniel Korr, Volker Schulze, Markus Berger, Georg Beckmann, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer. [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 4035.
Abstract 4112: Evaluating the survival outcomes of an anti-isoaspELAVL4 response in a small cell lung cancer mouse model
Authors: Velarde Diego A. , Elmalh Sarah A. , Lee Hannah , Valdes Joseph , Gladstone Matthew , Dinigle Ryan E. , Kast Martin , Offringa Ite A. 
Published: April 2023

Abstract
Small cell lung cancer (SCLC) has a 95% mortality rate and a 5-year survival of 8%, resulting in the death of over 20,000 Americans each year. There has been marginal improvement in therapy over the past 30 years, with the recent addition of immune checkpoint inhibition therapy modestly increasing overall SCLC patient survival from 10.3 to 12.3 months [PMID 30280641]. This highlights the need for additional SCLC therapies. Previous studies have identified a subset of SCLC patients (10-20%) exhibiting a naturally occurring immune response called ‘anti-HuD’. It is associated with improved response to therapy and improved survival [PMID 9256130; 26606748]. Previous work identified the anti-HuD antigen to be ELAVL4. The Offringa lab and collaborators determined that the antigenic epitope consists of isoaspartylated ELAVL4 (isoAspELAVL4) [PMID 27725125]; the protein carries isoaspartylated residues in the N-terminal region (amino acids 1-36). All tested Anti-Hu-positive SCLC patient serum samples reacted with isoAspELAVL4, and all examined SCLC tissue samples stained positive for isoAspELAVL4 [PMID 27725125]. Here we used the Trp53fl/fl; Rb1fl/fl inducible SCLC mouse model [PMID 14522252] to examine 1) whether immunization with isoAspELAVL4 prior to SCLC induction is protective, and 2) whether immunization with isoAspELAVL4 following completion of 3 rounds of cisplatin+etoposide therapy increases survival. In both cases, mice were immunized with recombinant N-terminal fragment of ELAVL4 (amino acids 1-117) generated in Clear Coli and emulsified in incomplete Freund’s adjuvant (IFA) or control (phosphate-buffered saline in IFA). The trajectories of mice have been monitored with a detailed body metric score and blood has been drawn every 2 weeks to monitor the anti-ELAVL4 antibody response. Kaplan-Meier analysis will be used to assess survival differences between the immunized and control groups and will be presented. The study will provide insight into interplay between SCLC and the immune response to isoAspELAVL4.
Citation Format: Diego A. Velarde, Sarah A. Elmalh, Hannah Lee, Joseph Valdes, Matthew Gladstone, Ryan E. Dinigle, Martin Kast, Ite A. Offringa. Evaluating the survival outcomes of an anti-isoaspELAVL4 response in a small cell lung cancer mouse model. [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 4112.
Abstract 4296: Fast de novo antibody structure prediction with atomic accuracy
Authors: Wang Yining , Gong Xumeng , Li Shaochuan , Yang Bing , Sun Yiwu , Luo Yujie , Li Hui , Song Le 
Published: April 2023

Abstract
Background: In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2 (AF2), a breakthrough in the field of structural biology, provides a solution to this protein structure prediction problem by learning a deep learning model. However, the computational efficiency and undesirable prediction accuracy on antibody, especially on the complementarity-determining regions limit its applications in de novo antibody design.
Methods: To learn informative representation of antibodies, we trained a deep antibody language model (ALM) on curated sequences from observed antibody space database via a well-designed transformer model. We also developed a novel model named xTrimoABFold++ to predict antibody structure from antibody sequence only based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame aligned point loss.
Results: xTrimoABFold++ outperforms AF2 and OmegaFold, HelixFold-Single with 30+% improvement on RMSD. Also, it is 151 times faster than AF2 and predicts antibody structure in atomic accuracy within 20 seconds. In recently released antibodies, for example, cemiplimab of PD-1 (PDB: 7WVM) and cross-neutralizing antibody 6D6 of SARS-CoV-2 (PDB: 7EAN), the RMSD of xTrimoABFold++ are 0.344 and 0.389 respectively.
Conclusion: To the best of our knowledge, xTrimoABFold++ achieved the state-of-the-art in antibody structure prediction. Its improvement on both accuracy and efficiency makes it a valuable tool for de novo antibody design, and could make further improvement in immuno-theory.
Experimental results on immune antibody dataset with 95% confidence interval. Method RMSD TMScore GDTTS GDTHA AlphaFold2 3.1254 ± 0.1410 0.8385 ± 0.0055 0.7948 ± 0.0057 0.6548 ± 0.0063 OmegaFold 3.2610 ± 0.1463 0.8384 ± 0.0057 0.7925 ± 0.0059 0.6586 ± 0.0063 HelixFold-Single 2.9648 ± 0.0997 0.8328 ± 0.0055 0.7805 ± 0.0057 0.6225 ± 0.0060 ESMFold 3.1549 ± 0.0067 0.8390 ± 0.0003 0.7952 ± 0.0003 0.6551 ± 0.0003 xTrimoABFold++ 1.9594 ± 0.0805 0.8986 ± 0.0052 0.8694 ± 0.0057 0.7456 ± 0.0066
Citation Format: Yining Wang, Xumeng Gong, Shaochuan Li, Bing Yang, Yiwu Sun, Yujie Luo, Hui Li, Le Song. Fast de novo antibody structure prediction with atomic accuracy. [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 4296.