bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sudden shock waves in modified gravity
Authors: Antoniadis Ignatios , Cotsakis Spiros , Trachilis Dimitrios 
Published: June 2023

AbstractWe construct a generic asymptotic solution for modified gravity near a sudden singularity. This solution contains a fluid source with no equation of state and is function-counting stable, that is it has eleven independent arbitrary functions of the spatial coordinates as dictated by the Cauchy problem of the theory. We further show that near the sudden singularity the solution has a shock wave character with the same number of free functions in the Jordan and Einstein frame.
Trackways in the New Red Sandstone of the Connecticut River Valley, USA, the cradle of ichnology
Authors: Bourgeois Joanne 
Published: June 2023

Abstract
Fossil trackways in the Jura-Triassic rift basin of the Connecticut River Valley are important to geoheritage for their quality, preservation, and role in the history of geology, especially of ichnology. Discovered in the early 1800s, these trackways of small to large, bipedal, three-toed animals came to the attention of Edward Hitchcock, a prolific geologist and natural theologian. His first publication on the subject was in January 1836 and, in the same year, William Buckland included parts of the report, with illustrations, in his Bridgewater Treatise. Hitchcock and Buckland are credited with establishing the field of ichnology, the study of track and trails. Within the first decade, other traces documented include four-footed tracks, fish fossils, invertebrate burrows, plant impressions, ripple marks and raindrop impressions; few bones have ever been discovered in the valley. Early fossil-track collectors included Hitchcock, James Deane, Dexter Marsh and Roswell Field. Specimens quickly made their way to Europe, and publications brought the tracks to international attention, in both science and literature. In nineteenth-century discussions, the three-toed trackway makers – birds or dinosaurs? – were particular subjects of interest and debate. These fossil trackways remain well known and studied today, with several preserved field sites and museum collections.
ABBV-184: A Novel Survivin-specific TCR/CD3 Bispecific T-cell Engager is Active against Both Solid Tumor and Hematologic Malignancies
Authors: Chervin Adam S. , Stone Jennifer D. , Konieczna Iwona , Calabrese Kelly M. , Wang Ningyan , Haribhai Dipica , Dong Feng , White Michael K. , Rodriguez Luis E. , Bukofzer Gail T. , Ellis Paul A. , Cosgrove Cormac , Hecquet Claudie , Clarin Jerry D. , Palma Joann P. , Reilly Edward B. 
Published: June 2023

AbstractCD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell–mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematologic and solid tumors, treatment of acute myeloid leukemia (AML) and non–small cell lung cancer (NSCLC) cell lines with ABBV-184 results in T-cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2–positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.
Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer
Authors: Toader Dorin , Fessler Shawn P. , Collins Scott D. , Conlon Patrick R. , Bollu Reddy , Catcott Kalli C. , Chin Chen-Ni , Dirksen Anouk , Du Bingfan , Duvall Jeremy R. , Higgins Stacy , Kozytska Mariya V. , Bellovoda Kamela , Faircloth Chelsey , Lee David , Li Fu , Qin Liuliang , Routhier Caitlin , Shaw Pamela , Stevenson Cheri A. , Wang Jason , Wongthida Phonphimon , Ter-Ovanesyan Elena , Ditty Elizabeth , Bradley Stephen P. , Xu Ling , Yin Mao , Yurkovetskiy Alexandr V. , Mosher Rebecca , Damelin Marc , Lowinger Timothy B. 
Published: June 2023

Abstract
Antibody–drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.
Abstract 1125: Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab
Authors: Alban Tyler Joseph , Riaz Nadeem , Parthasarathy Prerana , Makarov Vlad , Kendall Slav , Yoo Seong-Keun , Shah Rachna , Weinhold Nils , Srivastava Raghvendra , Ma Xiaoxiao , Krishna Chirag , Garon Edward , Akerley Wallace , Creelan Ben , Aanuren Nivedita , Chowell Diego , Geese William , Rizvi Naiyer , Chan Timothy 
Published: June 2023

Abstract
Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet how tumor evolution and neoantigen immunogenicity shape treatment response remains poorly understood. To address these questions, we conducted a prospective clinical trial of NSCLC patients treated with nivolumab. We assessed genomic alterations in tumors from 58 patients and performed large-scale immune epitope analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy was associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenic and recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic mutations compared to non-immunogenic mutations. We used this large collection of neoantigens to build ImmunoSEEK, a machine learning-based neoantigen prediction model and validated it using an orthogonal set of neoantigens. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the genomic and neoantigen landscapes underlying nivolumab’s mechanism of action.
Citation Format: Tyler Joseph Alban, Nadeem Riaz, Prerana Parthasarathy, Vlad Makarov, Slav Kendall, Seong-Keun Yoo, Rachna Shah, Nils Weinhold, Raghvendra Srivastava, Xiaoxiao Ma, Chirag Krishna, Edward Garon, Wallace Akerley, Ben Creelan, Nivedita Aanuren, Diego Chowell, William Geese, Naiyer Rizvi, Timothy Chan. Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab [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 1125.
Abstract 1188: IL-17/IL-17RA signaling in the pancreatic epithelium upregulates B7-H4 to promote tumorigenesis
Authors: Pando Susana Castro , Li Le , Howel Rian Morgan , Mascaro Marilina , Le Roux Olivereen , Romanin David , Riquelme Erick , Zhang Yu , Kolls Jay , Moghaddam Seyed Javad , McAllister Florencia 
Published: June 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to overtake other cancers as the second leading cause of death from cancer. PDAC is distinguished by the early formation of a highly immunosuppressive fibro-cellular tumor microenvironment (TME). Our group has demonstrated that IL-17 is necessary for the development and spread of pancreatic cancer, but we have not yet identified the cellular compartment responsible for IL-17-mediated tumor promotion. We propose that early pancreatic carcinogenesis is mediated by modification of an immunosuppressive program and is dependent on pancreatic epithelial IL-17/IL-17RA signaling. We created mice with Kras activated and IL-17RA selectively deleted from the pancreatic compartment (KC; IL-17RAfl/fl). In order to specifically remove IL-17RA from hematopoietic cells, we implanted IL-17RA deficient (IL17-RA−/−) bone marrow cells into KC animals. While deletion of IL-17RA in the hematological compartment had no effect on the progression of pancreatic carcinogenesis, deletion of IL-17RA from the epithelial compartment delayed the development of premalignant lesions, indicating that the pancreatic epithelium is the compartment required for IL-17/IL-17RA signaling during tumorigenesis. Deletion of IL-17RA from the oncogenic epithelium resulted in increased cytotoxic CD8+T cells infiltration in the TME. To learn more about the transcriptional alterations brought on by the lack of IL-17RA in the pancreatic compartment we performed single cell sequencing of pancreas tissue of KC and KC; IL-17RAfl/fl. We found that the absence of IL-17RA in the pancreatic compartment had an impact on epithelial cells transcriptional profiles, with modulation of several immune pathways including regulation of B7-H4, a negative regulator of T cells through Eomes activation. We have generated pancreatic cancer transgenic animals that lack B7-H4 and found that KC; B7-H4−/− mice have delayed tumorigenesis and decreased immunosuppression. In sum, we describe a novel IL-17-mediated regulation of B7-H4 and unravel its function in pancreatic tumorigenesis.
Citation Format: Susana Castro Pando, Le Li, Rian Morgan Howel, Marilina Mascaro, Olivereen Le Roux, David Romanin, Erick Riquelme, Yu Zhang, Jay Kolls, Seyed Javad Moghaddam, Florencia McAllister. IL-17/IL-17RA signaling in the pancreatic epithelium upregulates B7-H4 to promote tumorigenesis [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 1188.
Abstract 1301: Evolution of heterogenous BRAFi/MEKi+CDK4/6i resistance mechanisms and targeting site-specific resistant populations in metastatic cutaneous melanoma
Authors: Wilson Haley P. , Purwin Timothy J. , Capparelli Claudia , Cheng Phil F. , Levesque Mitch P. , Dummer Reinhard , Teh Jessica , Aplin Andrew E. 
Published: June 2023

Abstract
Intrapatient heterogeneity among different metastatic sites contributes to targeted therapy resistance. Determining the proteomic profile of metastatic melanoma lesions that develop within the same patient could help elucidate adaptive mechanisms that drive tumor progression during therapy. Tumors that persist through treatment and colonize distant organs adapt to and rely on organ-specific microenvironments. To assess how protein expression is altered in cutaneous melanoma derived from different metastatic sites in a single patient, we utilized patient-derived BRAFi/MEKi and BRAFi/MEKi+CDK4/6i-treated samples from the LOGIC2 clinical trial. Eight cell lines were established from patient biopsies at chronological time points throughout treatment and subsequent post-mortem resection of the bone, ovary, and brain metastatic sites. While the initial metastatic tumor in the breast was BRAFV600E mutant, NRASQ61 mutations were acquired after treatment with CDK4/6i in the bone and ovary tumors. RPPA was performed on six of the cell lines to characterize site-specific differences in protein expression. We detected upregulation of ErbB3 in the brain metastatic tumor. Since neuregulin 1, a ligand for ErbB3, is abundant in brain tissue, we tested its ability to promote resistance to BRAFi/MEKi in melanoma brain metastases. Neuregulin 1 rescued the growth of brain metastasis cells and restored phospho-AKT and phospho-ERK1/2 levels in the presence of BRAFi/MEKi. Therefore, the ErbB3-Neuregulin axis may be targeted, for example by using ErbB3 inhibitors to improve response to MAPK inhibitors in melanoma brain metastases. Further studies aim to investigate the evolution of metastatic cutaneous melanoma longitudinally in response to targeted therapies. Site-specific signaling mechanisms will be functionally examined as possible avenues for metastasis-specific targeted therapies to improve patient outcomes.
Citation Format: Haley P. Wilson, Timothy J. Purwin, Claudia Capparelli, Phil F. Cheng, Mitch P. Levesque, Reinhard Dummer, Jessica Teh, Andrew E. Aplin. Evolution of heterogenous BRAFi/MEKi+CDK4/6i resistance mechanisms and targeting site-specific resistant populations in metastatic cutaneous melanoma [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 1301.
Abstract 1375: Paranuclear retention of c-KIT by Merkel cell polyomavirus large T-antigen suppresses autophagy through interaction with Beclin 1 essential for Merkel cell carcinoma cell survival
Authors: Shi Hao , Yang Yajie , Larsson Catharina , Lui Weng-Onn 
Published: June 2023

Abstract
Merkel cell carcinoma (MCC) is a very aggressive skin cancer most commonly caused by Merkel cell polyomavirus (MCPyV). While the strong expression of the human proto-oncogene c-KIT in MCC is well established, the functional relevance of this expression is unknown. Here, we demonstrate that paranuclear presence of c-KIT suppresses autophagy which is essential for maintenance of MCC cells. Specifically, after its phosphorylation, c-KIT traffics by clathrin-dependent endocytosis to late endosomes where it is sequestered in the paranuclear compartment by the MCPyV-encoded large transforming antigen (LT) via its Vam6p binding site, which also blocks c-KIT's lysosomal degradation. In this paranuclear compartment, c-KIT interacts directly with both the BH3 and the evolutionarily conserved domain (ECD) of Beclin 1, decreasing its binding to VPS34 and increasing its binding to BCL2, resulting in suppression of autophagy. Indeed, silencing of c-KIT induces autophagy and apoptosis in MCPyV-positive MCC cell lines. It is noteworthy that the positive feedback loop of LT and c-KIT also applies in the reverse direction, as LT is degraded via autophagy. This notion explains why an autophagy-inducing peptide efficiently induces apoptosis-independent cell death and inhibits tumor growth of MCC xenografts in mice. In conclusion, we identified a novel mechanism of MCPyV LT to suppress autophagy through sequestering and stabilizing c-KIT in the paranuclear compartment, which is mandatory to maintain the oncogenic phenotype of MCC cells. Autophagy-inducing agents therefore represent a therapeutic strategy for patients with advanced MCPyV-associated MCC.
Citation Format: Hao Shi, Yajie Yang, Catharina Larsson, Weng-Onn Lui. Paranuclear retention of c-KIT by Merkel cell polyomavirus large T-antigen suppresses autophagy through interaction with Beclin 1 essential for Merkel cell carcinoma cell survival [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 1375.
Abstract 1433: Targeting the mitotic kinase NEK2 potentiates CDK4/6 inhibitor efficacy in breast cancer
Authors: Bobbitt Jessica R. , Cuellar-Vite Leslie , Bryson Benjamin , Weber-Bonk Kristen , Keri Ruth 
Published: June 2023

Abstract
Mitotic kinases are essential for cell cycle progression, and several mitotic kinase inhibitors have been developed to target the uncontrolled proliferation of cancer cells. However, despite their efficacy in preclinical models, mitotic kinase inhibitors are generally considered poor therapeutic targets due to their off target effects in other rapidly proliferating tissues and subsequent toxicity. However, preliminary data in our lab shows that relative to non-transformed cells, triple negative breast cancer (TNBC) cells are selectively sensitive to inhibition of the mitotic kinase NEK2 compared to other mitotic kinase inhibitors. Therefore, we hypothesize that NEK2 is a targetable vulnerability of TNBC. To begin to understand the role of NEK2 in TNBC, we performed RNA-sequencing following NEK2 silencing and found increased expression of genes important at the G1/S cell cycle transition. This transition is largely controlled by the RB-E2F signaling axis, where CDK4 and CDK6 are key players. CDK4/6 inhibitors have been FDA approved for the treatment of a subset of breast cancers. We investigated the impact of silencing NEK2 and treating with CDK4/6 inhibitors and found that loss of NEK2 sensitizes TNBC cells to CDK4/6 inhibition. Mechanistically, this combination causes a significant increase in genomic instability phenotypes. We tested the combination of NEK2 inhibition and CDK4/6 inhibition in vivo, and found that the combination significantly decreases mouse tumor volume without inducing toxicity. Mechanistically, the combination altered mitotic spindle genes in vivo, indicating an increase in genomic instability. Together, these data suggest that that NEK2 is a viable therapeutic target that could be used in combination with FDA approved CDK4/6 inhibitors for the treatment of aggressive breast cancers such as TNBC.
Citation Format: Jessica R. Bobbitt, Leslie Cuellar-Vite, Benjamin Bryson, Kristen Weber-Bonk, Ruth Keri. Targeting the mitotic kinase NEK2 potentiates CDK4/6 inhibitor efficacy in breast 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 1433.
Abstract 1713: TRMT6-mediated N1-methyladenosine methylation promotes tumorigenesis in colorectal cancer
Authors: SUI SILEI , XU CAIMING , Qing Ying , Baba Hideo , Goel Ajay 
Published: June 2023

Abstract
Background: N1-methyladenosine (m1A) within tRNAs, an essential and highly conserved RNA modification, has recently emerged as a significant epigenetic modification that plays a pivotal role in tumor progression in some cancers. However, the role of m1A methylation in colorectal cancer (CRC) remains largely unexplored. TRMT6 is the most critical methyltransferase that catalyzes N1-methyladenine modification within tRNA, and early evidence suggests that this TRMT6-mediated m1A methylation is also required for the self-renewal of cancer stem cells (CSCs). Herein, we systematically interrogated the role of TRMT6 in mediating stemness and pathogenesis of CRC.
Methods: We first analyzed the expression levels of all m1A regulators in paired tumor and adjacent-normal samples from TCGA and GEO databases. Subsequently, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting (WB) assays were performed to validate the dysregulation of TRMT6 in CRC tissues and cell lines. m1A dot-blot assays were undertaken to detect methylation levels in CRC tissues and RKO and SW620 CRC cell lines. Cell viability, colony formation, spheroid formation, wound healing, and invasion assays were conducted to investigate the biological functions of TRMT6 in CRC.
Results: Higher m1A methylation levels were detected in CRC than in normal tissues. By analyzing the expression of ten m1A regulators in public datasets, and subsequent qRT-PCR validation in a CRC clinical cohort, we identified that high TRMT6 expression was significantly associated with advanced tumor stages (III&IV vs. I&II, p&lt;0.05) and poor prognosis (5-year relapse-free survival rates in high vs. low expression groups: 50.9% vs. 65.1%, p&lt;0.05). TRMT6 silencing in CRC cell lines inhibited cell growth, colony formation, and metastatic efficiency (p&lt;0.01-0.001). Furthermore, we discovered that the TRMT6 could enhance stem cell-like properties required for CSC self-renewal. Transcriptomic profiling identified that the epidermal growth factor receptor (EGFR) pathway is one of the critical signaling regulators of TRMT6 in CRC. The TRMT6 knockdown resulted in significant inhibition of p-EGFR and p-ERK, but not p-AKT in CRC cell lines (all p&lt;0.05), which suggested that m1A modification exerts its oncogenic effects in CRC by activating EGFR downstream pathway.
Conclusion: Our study elucidates for the first time the oncogenic effects of TRMT6 on catalyzing m1A modification through the EGFR/ERK pathway, which could offer a promising therapeutic strategy in CRC.
Citation Format: SILEI SUI, CAIMING XU, Ying Qing, Hideo Baba, Ajay Goel. TRMT6-mediated N1-methyladenosine methylation promotes tumorigenesis in colorectal 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 1713.