bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1019: Altona regression model: a new prognostic model for breast cancer patients after neoadjuvant treatment
Authors: Wegscheider Anne-Sophie , Lotfy-Eckmann Katharina , Ulm Bernhard , Lindner Christoph , Friedrichs Kay , Niendorf Axel 
Published: April 2023

Abstract
The purpose of the study was to create a new prognostic model for breast cancer (BC) patients that had been treated with a preoperative neoadjuvant chemotherapy, considering different parameters of regressive changes in the residual tumor (RT) respectively the tumor bed (TB).
HE-stained whole-slide images of 518 patients, treated between 2001-2019 in Hamburg, Germany following current therapy standards, were analyzed regarding different variables of regressive changes in the pretherapeutic diagnosed BC. First, size of RT and TB was measured, lymph node metastasis and residual intraductal carcinoma in situ were noted. Additional parameters that were examined were cell density and cell shape of RT, heterogeneity of residual tumor cells spreading within the TB and size of the biggest cell clusters as well as changes of the stroma and inflammation within the TB.
Data were used pseudo-anonymized after consent was given by the patients and a positive vote of the ethics committee.
In the univariate observation of above-mentioned variables it was shown that heterogeneity, cell density and cell shape of residual tumor cells, stroma changes and the presence of lymph node metastases as well as largest diameter and largest cluster of RT have an impact on progression free survival. Using decision tree analysis, the patient cohort could be divided in three risk groups with significant different outcome regarding progression free survival with low, intermediate and high risk for an event (local recurrence of disease, metastasis, death). Our multivariate "Altona regression model", that was constructed using Cox regression, showed significantly better prognostic value concerning progression free survival for BC patients after neoadjuvant therapy and following surgery, compared to two well-known regression gradings by Sinn et al. and MD Anderson (RCB).
Comparison of regression models Altona Sinn et al. RCB Altona vs. Sinn Altona vs. RCB Sinn vs. RCB iAUC 0.607 0.350 0.380 &lt; 0.001 &lt; 0.001 &lt; 0.001 Concordance 0.788 0.378 0.478 &lt; 0.001 &lt; 0.001 &lt; 0.001
Citation Format: Anne-Sophie Wegscheider, Katharina Lotfy-Eckmann, Bernhard Ulm, Christoph Lindner, Kay Friedrichs, Axel Niendorf. Altona regression model: a new prognostic model for breast cancer patients after neoadjuvant treatment [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 1019.
Abstract 1064: Cancer-specific molecular subtypes of pancreatic cancer reveal clinically relevant molecular dependency
Authors: Lee Sung Hwan , Park Jiyeon , Lee Sunyoung , Lee Ju-Seog 
Published: April 2023

Abstract
Introduction: Pancreatic cancer is lethal, showing dismal prognosis and therapeutic resistance. Previous molecular subtypes from genome or transcriptome did not show clinical relevance regarding precision strategy for optimal therapeutic options followed by precise patient classification. This study aims to uncover consensus molecular subtypes from cancer-specific multi-omics data showing clinically relevant therapeutic opportunities.
Methods: We performed comprehensive analyses using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, genome-wide loss-of-function screening using the CRISPR-Cas9 system, and cancer drug sensitivity. The subtype-specific molecular signatures were validated in independent translational cohorts (TCGA-PAAD; n=150, ICGC-PACA-AU; n=461, ICGC-PACA-CA; n=317).
Results: Integrative profiling of multi-omics molecular layers (Mutational signature, Copy number alteration, Transcriptome, MicroRNA, Chromatic profile, Proteome, and Metabolome) from pancreatic cancer cell lines (n=59) from the Cancer Cell Line Encyclopedia (CCLE) revealed a total of three cancer-specific molecular subtypes showing distinct tumor biology through all omics layer as well as clinical relevance with unique molecular dependency. Major molecular features of each subtype were reproducible in the validation cohorts. Subtype-specific molecular biomarkers, including mutational signatures and metabolites, were identified. Finally, the target drug with subtype-specific genetic dependency was analyzed to provide a precision strategy according to distinct subtypes’ molecular characterization.
Conclusions: Integrative profiling from multi-omics molecular layers revealed precision strategies based on cancer-specific molecular subtypes of pancreatic cancer in terms of tumor classification and discriminative therapeutic opportunities. Prospective translational studies companion with clinical trials based on cancer-specific molecular subtypes is mandatory to establish the precision strategy for managing pancreatic cancer.
Citation Format: Sung Hwan Lee, Jiyeon Park, Sunyoung Lee, Ju-Seog Lee. Cancer-specific molecular subtypes of pancreatic cancer reveal clinically relevant molecular dependency [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 1064.
Abstract 1137: Identification of a high selective SMARCA2 degrader which effectively suppresses the SMARCA4-deficient tumors in vitro and in vivo
Authors: Zhou Feng , Yu Zhiyong , Chen Ruonan , Tang Feng , Gu Peng , Yang Wenqing , Xue Liting , Chen Ping , Tang Renhong 
Published: April 2023

Abstract
The SWI/SNF chromatin-remodeling complex plays essential roles in a variety of cellular processes including differentiation, proliferation and DNA repair. Mammalian SWI/SNF complexes always contain one of two mutually exclusive and structurally highly related ATPases: SMARCA2/BRM or SMARCA4/BRG1, as its catalytic subunit, which hydrolyze ATP to drive nucleosome movement. It is reported that absence of SMARCA4 are present in several cancers and these SMARCA4 deficient cells highly depend on its paralog SMARCA2 for survival. Furthermore, concurrent inhibition of SMARCA2 and SMARCA4 is fatal to normal cells. Therefore, it holds great therapeutic promise to treat SMARCA4 deficient cancers with selective SMARCA2 degraders while leaving SMARCA4 wild type cells unaffected. Here, we report that SCR-9140 is a high selective SMARCA2 degrader which demonstrates superior anti-tumor activity and low cytotoxicity against non-malignant cells. SCR-9140 strongly degrades SMARCA2 with DC50 of &lt;1 nM and achieves the complete protein degradation (Dmax of &gt;95%) and also shows 100-fold degradation selectivity over SMARCA4 with DC50 of around 100 nM and Dmax of &lt;60% in HiBiT knock-in SW1573 cells. Across a panel of SMARCA4 deficient tumor cell lines, SCR-9140 potently inhibits proliferation with IC50 values ranging from 1 to 50 nM. Due to the high selectivity over SMARCA4, SCR-9140 neither inhibits proliferation of SW1573 (SMARCA2-WT SMARCA4-WT) cells nor NCI-H1581 (SMARCA2-DEL SMARCA4-DEL) cells with IC50s of over 2000 nM. The degraders with poor selectivity of SMARCA2/4 (DC50 ratio: &lt; 10 folds, Dmax of SMARCA4 &gt; 80%) strongly inhibit the SW1573 cells proliferation with IC50s &lt; 100nM, while there are no significant effects on the NCI-H1581 cells ascribing to the absence of targets. Furthermore, SCR-9140 demonstrates weak cytotoxicity on non-malignant cells, such as WI-38 (human lung fibroblast cells), THLE-2 (human liver cells), and human PBMC, rendering it the greater therapeutic window. In a CDX model of NSCLC, SCR-9140 effectively inhibits tumor growth and TGI correlates well with SMARCA2 degradation in tumors. In conclusion, our potent and selective SMARCA2 degrader, SCR-9140 induces strong synthetic lethality in SMARCA4 deficient cells in vitro and in vivo and shows great safety margin in normal cells.
Citation Format: Feng Zhou, Zhiyong Yu, Ruonan Chen, Feng Tang, Peng Gu, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Identification of a high selective SMARCA2 degrader which effectively suppresses the SMARCA4-deficient tumors in vitro and in vivo [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 1137.
Abstract 1212: Horizontal transfer of functional human papillomavirus genes in head and neck squamous cell carcinoma
Authors: Tasoulas Jason , Yarbrough Wendell Gray , Issaeva Natalia 
Published: April 2023

Abstract
Human papillomavirus (HPV) infections are currently associated with more than 70% of oropharyngeal squamous cell carcinomas (OPSCCs). HPV-positive OPSCCs display a distinct biologic behavior and treatment response and thus are now considered a distinct entity than HPV-negative OPSCCs. However, the underlying process of HPV-related OPSCC carcinogenesis is not entirely clear. HPV as a driver of cervical carcinogenesis is well-characterized with identification of a canonical mechanism dependent on HPV DNA integration, loss of HPV E2 gene expression, and increased expression of HPV E6 and E7 oncogenes with no active infection present in malignant lesions. However, whole genome sequencing found no HPV DNA integration in ~25% of HPV-associated OPSCC, suggesting an alternative mechanism of HPV carcinogenesis. Expression of all HPV genes, including self-assembling capsid proteins, in a substantial portion of HPV+ OPSCC, led us to hypothesize that tumors with episomal HPV are capable of transferring HPV genes to surrounding cells and that HPV gene transfer contributes to carcinogenesis in this subset of OPSCC. Our data support this hypothesis, showing that growth media from HPV+ OPSCC cell lines, as well as isolates from HPV+ tumors or nodal metastases, effectively transferred functional HPV genes to cells lacking HPV. The HPV DNA Transferring Agent (HDTA) derived from HPV+ OPSCC contained HPV L1 capsid protein and intact HPV genome protected from DNAase degradation. Initial characterization revealed that anti-L1 antibody blocked gene transfer and that exposure of cells to the HDTA initiated a robust innate immune response in recipient cells. Negative staining of HDTA isolate from metastatic lymph nodes revealed many pleomorphic, electron-dense particles with diameter ranging between 20 and 80nM, with approximately 40% of particles being between 50 and 60nM, consistent with the size of HPV. We propose that development and/or maintenance of OPSCCs depend on continuous production of HDTA capable of transferring HPV genes into neighboring cells. This paradigm of tumorigenesis/maintenance in OPSCC is most likely to apply to cancers lacking HPV integration, but may also apply to tumors with integration, since recent data suggested that integrated HPV may excise from the genome to recreate a transient episomal like structure, even containing cellular DNA. Our findings offer novel insights into oropharyngeal carcinogenesis and suggest targeting HDTA as a new therapeutic strategy for HPV-positive OPSCCs.
Citation Format: Jason Tasoulas, Wendell Gray Yarbrough, Natalia Issaeva. Horizontal transfer of functional human papillomavirus genes in head and neck 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 1212.
Abstract 122: The subclonal dynamics of gross ploidy alterations in TNBC cells under chemotherapeutic pressure
Authors: Gardner Andrea L. , Zheng Lan , Parker Patrik , Howland Kennedy , Morgan Daylin , Brock Amy 
Published: April 2023

Abstract
Solid tumors such as triple-negative breast cancer (TNBC) have characteristically high rates of aneuploidy and polyploidy. Chromosome-level aneuploidies are known to arise through errors in cytokinesis, but many of the mechanisms which drive large-scale ploidy alterations such as whole genome doubling (WGD) are still under investigation. WGD and subsequent ploidy reduction has been implicated as a key event in cancer evolution across patient samples. Further, in vitro studies have suggested that cells may undergo polyploidization to survive certain chemotherapies. Here, we apply lineage tracing technologies to test the hypotheses that some cells are primed to undergo WGD through endocycling or cell-cell fusion and that active polyploidization is a mechanism to resist chemotherapy. To deconvolve WGD by endocycling from WGD by cell-cell fusion, we transduced the TNBC cell line HCC1806 to create parallel populations with transcribed DNA barcodes on H2B-GFP or H2B-mCherry. All experiments were performed with homotypic cocultures containing equal proportion of cells from each fluorescent barcode population. With this method, ploidy alterations due to endoreplication were identifiable as monofluorescent single-barcoded cells with increased ploidy, while ploidy changes due to fusion were identifiable as double positive (GFP+mCherry+) double-barcoded cells with increased ploidy. The cell population was treated with an LD75 dose of doxorubicin and parallel plates were monitored by live-cell imaging. At each timepoint (pre-treatment, then 3, 5, and 14 days post-treatment), triplicate plates were stained with Hoechst and sorted into two fractions for lysis and DNA extraction: Near diploid (~2N) and ii) Hyperploid (&gt; 4N). Barcode composition of cells from each fraction and each timepoint was determined through Illumina sequencing of barcode amplicons. Here, we will present preliminary results revealing the subclonal dynamics of gross ploidy alterations through normal culture conditions and chemotherapeutic perturbation. This study will elucidate whether pre-existing or de novo polyploidy promotes cell survival during chemotherapy, and determine if gross ploidy alterations occur randomly or through deterministic selection.
Citation Format: Andrea L. Gardner, Lan Zheng, Patrik Parker, Kennedy Howland, Daylin Morgan, Amy Brock. The subclonal dynamics of gross ploidy alterations in TNBC cells under chemotherapeutic pressure [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 122.
Abstract 1259: Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment
Authors: Wieboldt Ronja , Zingg Andreas , Carlini Emanuele , Börsch Anastasiya , Läubli Heinz , Manutano Natalia Rodrigues 
Published: April 2023

Abstract
Background: Overexpression of sialic acids on glycans, called hypersialylation is a common alteration in cancer that drives immune evasion via interaction with Sialic acid-binding immunoglobulin-like lectin (Siglec) immunoregulatory receptors on tumor-infiltrating immune cells. Myeloid derived suppressor cells (MDSCs) generated by cancer-induced aberrant myelopoiesis are highly immunosuppressive cells inhibiting immune cells via direct interaction or secretion of suppressive cytokines. Targeting the complex suppressive tumor microenvironment (TME) remains a challenge.
Methods: Siglec expression of murine and human MDSCs in healthy conditions and tumor setting was assessed by flow cytometry. Functional analysis of Siglec-E knockout on MDSCs in mice was evaluated using SigE-LysMCre mice and suppressive capacity was tested in vitro in combination with SiglecE blocking and cleavage of Sialoglycans using Sialidase. Results were confirmed in the human setting using an in vitro assay to generate MDSC-like cells including RNA-Sequencing and a MDSC suppression assay with cancer-derived MDSCs.
Results: MDSCs express multiple inhibitory Siglec receptors in humans and mice. Knockout of SiglecE in the myeloid compartment in vivo resulted in prolonged survival and increased T cell infiltration compared to litter mates expressing Siglec-E. Of note, desialylation of MDSCs and Siglec-E blocking in vitro reduced MDSCs suppressive function against T cells. Similarly, reducing Sialoglycans by Sialidase in human MDSC generated in vitro resulted in increased suppressive capacity and downregulation of functional MDSC markers on RNA level. Findings were validated with lung cancer patient derived MDSCs.
Conclusion: Our results provide first insights into the importance of the Siglec-Sialoglycans axis to modulate MDSCs in the TME. Targeting glycosylation of MDSCs with Sialidase reduces their suppressive capacity making it a powerful approach to improve cancer immunotherapy. Further studies are needed to reveal the underlying mechanisms.
Citation Format: Ronja Wieboldt, Andreas Zingg, Emanuele Carlini, Anastasiya Börsch, Heinz Läubli, Natalia Rodrigues Manutano. Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment [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 1259.
Abstract 1348: Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma
Authors: Sturgeon Reegan , Goel Paran , Molczyk Caitlin , Batra Surindar K. , Singh Rakesh 
Published: April 2023

Abstract
Pancreatic cancer (PC) continues to be a challenge for today’s therapeutics, with a meager 5-year survival rate of 11%. Due to the pancreas’ location, patients often receive diagnosis late, leaving them with limited treatment options. Often, they fail to respond to chemotherapy regimens or develop resistance to those therapies. Tumor-promoting inflammation is a hallmark of cancer that contributes to tumor cells’ survival and proliferation. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation. Previously we have determined that inflammation and CXCR2 ligand expression increases with pancreatic ductal adenocarcinoma (PDAC) progression. In the present study, we examined the role of neutrophil recruitment in PDAC progression using Kras-dependent KC and KPC murine models. Our data suggest a positive association between tumor-associated neutrophils (TANs) and PDAC progression. Furthermore, the frequency of neutrophil extracellular traps (NETs) also increased as the disease progressed. In vitro, we observed PDAC cell condition-media enhanced survival of neutrophils in a concentration-dependent manner. Moreover, increased survival was associated with disease aggressiveness and therapy resistance. Additionally, we observed that PDAC-conditioned media modulated the expression of immunoregulatory cytokines and chemokines in neutrophils. Together, our data suggest that increased recruitment of TANs supports PDAC progression, and PDAC cell-neutrophil interaction modulates neutrophil survival and immunoregulatory phenotype.
Citation Format: Reegan Sturgeon, Paran Goel, Caitlin Molczyk, Surindar K. Batra, Rakesh Singh. Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma [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 1348.
Abstract 1363: Breast pericytes: A newly identified driver of tumor cell proliferation
Authors: Toro Katelyn Del , Licon-Munoz Yamhilette , Hines William C. 
Published: April 2023

Abstract
A crucial problem limiting our progress to a cure for breast cancer is understanding what drives tumor growth. While we are aware that potent regulators of tumor development include non-malignant cells coexisting in tumors, not all cell types are easily recognized—nor have they been examined rigorously as potential contributors to malignancy. An obstacle in approaching this problem has been an inability to isolate and purify each cell type from the tissue. Recently our laboratory developed models of each cell type in the breast, allowing us the opportunity to investigate the contributions of primary cell types to tumor cell growth through co-culture. We have discovered that pericytes secrete a potent factor that drives tumor cell expansion directly— and dramatically more than controls (isogenic fibroblasts). The effects of this factor are dose-dependent, and we find that it is protease- and heat-inactivated. Furthermore, tissue immunostaining reveals that pericytes expand into tumor stroma, where they may interact directly with tumor cells. Single-cell RNA sequencing uncovers the heterogeneity of pericytes, which exist on a perivascular spectrum.
Citation Format: Katelyn Del Toro, Yamhilette Licon-Munoz, William C. Hines. Breast pericytes: A newly identified driver of tumor cell proliferation [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 1363.
Abstract 1366: HMGB1 localization and its effect on the immune response in the lung tumor microenvironment
Authors: Jafri Kisa , Andre Nicole M. , Simmons Glenn E. 
Published: April 2023

Abstract
Lung adenocarcinoma is the leading cause of cancer mortality. High Mobility Group Box 1 (HMGB1) is a master regulator of innate immunity that is elevated in lung cancer tissues. Furthermore, HMGB1 has been previously demonstrated to suppress functional anti-tumor immune responses in this context. However, beyond demonstrating that HMGB1 is elevated and modulates inflammation, studies to date have not comprehensively investigated the influence of HMGB1 on the immune response to lung cancer. HMGB1 contributes to PD-L1 expression in melanoma and promotes secretion of inhibitory cytokines TGF-α and IL-10, which have roles in the differentiation of regulatory T cells. Therefore, HMGB1 sits atop an immunomodulatory signaling cascade in the tumor microenvironment. While treatment of lung cancers with immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1) has had success, there are limitations. One major limitation is the failure of patients with advanced or refractory disease to generate a strong anti-tumor immune response. Recently, we have identified HMGB1 as a protein that is functionally dependent on monounsaturated fatty acid (MUFA) availability. Utilizing a combination of molecular assays and 3-dimensional cultures, we now show that HMGB1 is sequestered intracellularly, rather than being secreted extracellularly in a MUFA-dependent fashion. We hypothesized that MUFAs promote an anti-tumor immune response via modulating HMGB1 release from cancer cells. Thus, by restricting extracellular HMGB1 levels, HMGB1-responsive proinflammatory/tumor signaling pathways (e.g., NF-kB) are suppressed. Taken together, these observations suggest a novel approach to decreasing maladaptive immune and inflammatory signaling from innate immune cells. Exploiting the MUFA/HMGB1 signaling axis could be a novel approach to improve the efficacy of therapies in populations that are not currently benefiting from current strategies for eliminating tumors.
Citation Format: Kisa Jafri, Nicole M. Andre, Glenn E. Simmons. HMGB1 localization and its effect on the immune response in the lung tumor microenvironment [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 1366.