bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 7378: Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions
Authors: Van Egeren Debra , Chen Andrew , Stoddard Madison , Yuan Lin , Chakravarty Arijit
Published: March 2024

Cancer is a complex disease involving the interplay of several types of malignant and nonmalignant cells. The growth of tumors and surrounding stromal cells can be modeled as an ecosystem, where populations of cancerous and healthy cells interact and compete for resources. In this work, we have explored the application of game theoretic models of cancer to the design of novel anticancer therapies. Notably, a game theoretic-model of tumor-stromal interactions can capture the impact of interactions between cell types and can be used to investigate frequency-dependent parameters describing the impact of drug action during the initiation and growth of metastatic cancers. Previous studies using game theoretic models to describe cancer have focused on explaining progression patterns of specific tumors with known tumor-stromal interactions. This study takes a more general approach to cancer growth dynamics, modeling cancer as a simple game between healthy and cancer cells. This simplified model is used to make general predictions about cancer progression and the efficacy of treatment strategies. Our work suggests that disruption of beneficial interactions between healthy and cancer cells may be a viable treatment strategy for small tumors and preventing metastasis by ensuring that the healthy cell strategy is evolutionarily stable. The efficacy of treatment strategies that disrupt cancer cell cooperation or tumor-stromal dynamics changes as the cancer cell frequency changes. Our work suggests that drugs that target tumor-stromal cell interactions would need to be combined with other types of treatments to be effective against large tumors. Although based on a simplistic model of cancer initiation and progression, the framework derived here can be extended to the real-world design of experimental anticancer therapeutics, and fundamental analyses of this nature can be of practical utility in setting strategy for Target Product Profile design.

Citation Format: Debra Van Egeren, Andrew Chen, Madison Stoddard, Lin Yuan, Arijit Chakravarty. Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7378.
Abstract 743: Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates
Authors: Wang Jing , Chen Jian , Frey Gerhard , Liu Haizhen , Xing Charles , Woodard Kathryn , Chang Hwai , Boyle William J. , Short Jay M.
Published: March 2024

Antibody-drug conjugates (ADCs) are a promising treatment for various forms of cancer. The treatment efficacy is often limited by on-target/off-tumor toxicity caused by the antigen expression in healthy tissue and by unwanted payload release outside the tumor caused by cleavage of the linker via circulating proteases. Our conditionally active biologics (CAB) technology addresses the on-target/off-tumor toxicity and assists in reducing the off-target/off-tumor toxicity by reducing binding to the target under normal physiological conditions (1). To eliminate the remaining off-target/off-tumor toxicity, we developed a novel linker with superior serum stability, solubility, and tumor-specific payload release. Conjugation can be accomplished using regular IgG backbones without the need for sequence modification. Here we report the in vitro and in vivo characterization of a NextGen linker system to generate a CAB anti-Nectin4-ADC that combines the advantages of CAB antibody pH selectivity with the new linker technology. In vivo efficacy data demonstrated complete tumor regression in several cell line derived xenograft models as well as superior efficacy to an enfortumab vedotin analogue in a patient derived pancreatic cancer model. PK and tox data from a toxicology study in non-human primates will be presented. In addition, data demonstrating the influence of linker technology on specific cancer models will also be presented. In conclusion, the NextGen Nectin4 CAB ADC represents a potentially more effective treatment with increased safety in the clinic.

(1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ,and Short JM Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118

Citation Format: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Charles Xing, Kathryn Woodard, Hwai Chang, William J. Boyle, Jay M. Short. Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 743.
Abstract 7464: Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor immunity
Authors: Khanal Shrijan , Harder Olivia , Kirschstein Elijah , Mack Morgan , Ware Carl , Gough Michael , Young Kristina , Gunderson Andrew J.
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is a cancer with low survival rates and currently no immunotherapy options. However, many tumors from PDAC patients can be heavily infiltrated with T and B cells associated with favorable survival outcomes indicating anti-tumor immunity is functional in certain patients. In some of these lymphocyte-inflamed PDAC tumors, spontaneous organization of tertiary lymphoid structures (TLS) is evident upon surgical resection and these patients have a clear survival advantage. TLS are predictive of immune checkpoint blockade response in some cancer types, yet PDAC patients, with or without TLS, are still insensitive to these strategies. To address this paradox, we evaluated surgically resected PDAC tumors from previously untreated patients and discovered that tumors with TLS (TLS+) recruited T and B cells with specific anti-tumor and memory phenotypes suggesting immunosurveillance of disease was enhanced. Furthermore, a subset of TLS+ patients contained germinal centers and improved humoral immune function corresponding to an increased neoantigen burden and long-term survival. When assessing gene expression differences between TLS+ and TLS- patients, operable inflammatory and immunosuppressive pathways emerged that could be therapeutically exploited to activate TLS neogenesis. To address these mechanistic questions, we have developed a method for inducing TLS formation in implantable mouse PDAC tumors in the orthotopic setting utilizing an antibody that agonizes the lymphotoxin beta receptor (LTBR) in mice bearing established PDAC tumors. These TLS are complexed with T cells, B cells, CXCL13+ cells, and PNAd+ HEV associated with reduced tumor growth, presence of lymphocyte-recruiting cancer associated fibroblasts and increases in anti-tumor T and B cell phenotypes. Interestingly, some mouse PDAC cell lines are resistant to TLS formation by LTBR agonism while others are susceptible offering a model to study patient heterogeneity. We will use this TLS+ PDAC mouse model to address how TLS may directly improve antigen-specific T cell and B cell immunity and elucidate the pathways that regulate TLS formation. These data will offer new strategies to overcome immunotherapy resistance in cancer patients.

Citation Format: Shrijan Khanal, Olivia Harder, Elijah Kirschstein, Morgan Mack, Carl Ware, Michael Gough, Kristina Young, Andrew J. Gunderson. Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7464.
Abstract 7491: ctDNA liquid biopsy result among gynecologic cancer patients: Does it give additional information
Authors: Kim Min Kyu
Published: March 2024

Objectives: There are many target molecules for precisional cancer therapy Precision diagnosis-based target treatment is believed to be better survival approach compared than conventional treatment. Predictive markers are variant and vast. This study evaluated the initial experience of ctDNA liquid biopsy as a precision tumor marker for gynecologic cancer patients?

Methods: we retrospectively identified ovary/endometrial and cervical cancer patients who approved ctDNA test for various purpose. Two methods were used. Guardant 360 and Foundation One Liquid CDx.

Results: There were 31 cases. Median age was 60(46-84). Half of cases were ovarian cancer(17/31 55%).Cervix and endometrial cancer are 12(39%) and 2(6%).We found about ten percentages of actional genetic mutation patients(3/31).Two BRCA1 mutation(each patients have variant allele frequency(VAF) percentages are 50.4,49.6).One high bTMB(blood tumor mutational burden)was 21.There was no mutation in 6/31(19 %).

Conclusions: It seems additional supportive information may be acquired through well-established ctDNA liquid biopsy test among this population. Role of ctDNA liquid biopsy test for precision tumor marker should be investigated for future study.

Keywords: Liquid biopsy; Precision medicine; Tumor marker

Citation Format: Min Kyu Kim. ctDNA liquid biopsy result among gynecologic cancer patients: Does it give additional information [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7491.
Abstract 7588: Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor
Authors: Chen Qin , Huang Qionglin , Zhang Ke , Hao Yuli , Wang Zixuan , Li Bing
Published: March 2024

PARP7 is a mono-ADP-ribosyl transferase that catalyzes the transfer of single units of ADP-ribose onto substrate proteins to regulate their functions. One of its substrates is TANK binding kinases 1 (TBK1), whose MARylation by PARP7 inhibits its activation and thereby represses the type I IFN response to cytosolic nucleic acid. PARP7 is upregulated in many kinds of cancers and acts as a brake in cytosolic nucleic acid sensing, which leads to the suppression of type I IFN signaling and immune response. Therefore, PARP7 is a novel and promising target in cancer immunotherapy. Herein, we describe the discovery of a novel small molecule NSP-5033 as a dual PARP7/PARP12 inhibitor, which potently inhibits PARP7 and PARP12 enzymes with sub-nanomolar and low nanomolar activities, respectively. It displayed potent anti-proliferative activities against a number of cancer cell lines in vitro. NSP-5033 also increased the mRNA level of IFNβ and CXCL10 and stimulated STAT1 phosphorylation, suggesting that it restored the type I IFN response in tumor cells. With excellent ADME and pharmacokinetic properties, NSP-5033 demonstrated potent in vivo efficacy in human lung cancer xenografts with tumor regression and induced antitumor immunity in tumor-bearing immunocompetent mice. NSP-5033 has been nominated as a preclinival candidate for treatment of solid tumors and is undergoing IND-enabling studies.

Citation Format: Qin Chen, Qionglin Huang, Ke Zhang, Yuli Hao, Zixuan Wang, Bing Li. Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7588.
Abstract 7589: The novel complex delivery system of C-phycocyanin-loaded klebsiella pneumoniabacterial ghost induces apoptosis and sensitizes non-small cell lung cancer cell lines to doxorubicin
Authors: Abdelaziz Basma Adel Elsayed , Mahmoud Hoda Eid , Sadek Omayma Mohamed , Sultan Ahmed Samir
Published: March 2024

Lung cancer is a significant cause of cancer-related deaths worldwide, with a high incidence rate, poor prognosis, aggressiveness, and a lack of effective treatment options. The present study has brought together two FDA-approved drugs with antineoplastic properties to create a complex that promises to revolutionize the treatment of Non-Small Cell Lung Cancer (NSCLC). By combining C-Phycocyanin extract (PCE), a pigment-protein complex synthesized by blue-green microalgae platensis, with the immunostimulatory doxorubicin (DOX) loaded Bacterial Ghosts (BGs), the present study aims to achieve enhanced dual-chemotherapy and remarkable inhibition of DOX-chemoresistance. The BG delivery system uses purified bacterial cell evacuation and safe confirmed Klebsiella pneumoniae BGs (KPBG) for safe and effective delivery, overcoming issues with resistance and poor delivery. The complex delivery system of KPBG-PCE/DOX was tested on two NSCLC cell lines, wild-P53, A549, and mutant-P53, NCI/H358, respectively. Our data showed that the loaded combined treatment significantly induced morphological changes with signs of apoptosis induction in the tested cell lines compared with the control. The WST-1 assay was used to evaluate cell proliferation. Data indicates that PCE and DOX have a synergistic effect at low concentrations when loaded on KPBGs for a constant count of BGs CFU/ml after 48 h of treatment. The viability inhibition and apoptosis induction of A549 and NCI/H358 cells were amplified in the combined treatment of 48 h compared to the control or either each drug alone. At the protein levels, our data showed activation of caspase-3, upregulation of BAX, and downregulation of Bcl-2, Bcl-XL, m-TOR, S6k, oncogenic β-catenin, and cyclin-D1 protein expression levels after treatment with (KPBG-PCE/DOX) for 48 h, indicating apoptotic induction and modulating oncogenic signaling pathways. In conclusion, the current study presents a promising outcome of a synergistic delivery system of KPBG-PCE/DOX that can inhibit lung cancer cell line proliferation, induce apoptosis, and increase cell sensitivity to DOX. The KPBG delivery system offers an appealing approach for a successful combination of targeted therapy for lung cancer.

Citation Format: Basma Adel Elsayed Abdelaziz, Hoda Eid Mahmoud, Omayma Mohamed Sadek, Ahmed Samir Sultan. The novel complex delivery system of C-phycocyanin-loaded klebsiella pneumoniabacterial ghost induces apoptosis and sensitizes non-small cell lung cancer cell lines to doxorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7589.
Abstract 7595: PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells
Authors: Suresh Samyuktha , McPherson Lisa A. , Ford James M.
Published: March 2024

Background: Treating triple-negative breast cancer (TNBC) patients, an aggressive subtype of breast cancer, is an ongoing clinical challenge. Small-molecule inhibitors targeting the poly ADP-ribose polymerase (PARP) DNA repair enzymes, have been approved for treating only a subset of TNBC patients with a specific genetic landscape (BRCA1 mutation). However, TNBC patients with wildtype BRCA1 (BRCA1WT) are still lacking targeted therapy and chemotherapy remains their main treatment strategy. High expression of protein arginine methyltransferase 5 (PRMT5) is linked to poor prognosis in breast cancer and PRMT5 alone or via its interacting proteins plays an oncogenic role in breast cancer. Recent evidence suggests that PRMT5 is a key player in regulating the repair of DNA double strand breaks (DSBs) either through homologous recombination (HR) or non-homologous end joining (NHEJ) depending on the PRMT5 expression level within the cell. This dependency of cancer cells on PRMT5 expression levels in deciding the repair pathway of choice can be exploited for developing therapies. We hypothesize that in BRCA1 wildtype TNBC cells, inhibiting PRMT5 activity will force the cells to rely on NHEJ rather than HR to repair DNA DSBs, and introducing PARP inhibitors in this setting will inactivate NHEJ as well, causing synthetic lethality and cell death. In this study, we evaluated the pre-clinical benefit of combining PARP inhibitors with a PRMT5 inhibitor in TNBC cells.

Methods: Human TNBC cell lines with wildtype BRCA1 (MDA-MB-468, HCC1806) and mutant BRCA1 (MDA-MB-436, SUM149-PT) were treated with varying doses of two PARP inhibitors (Olaparib, Talazoparib) and a PRMT5 inhibitor (GSK3326595) as single agents or in combination. MTT-based cell viability assay was used to determine cytotoxicity of the treatments. mRNA expression was determined by RT-qPCR after drug treatment.

Results and Conclusion: We report that PRMT5 inhibition synergizes with both Olaparib and Talazoparib, to potentiate cell death in two BRCA1WT but not in BRCA1mut TNBC cell lines. Furthermore, we show that inhibiting PRMT5 in BRCA1WT cells upregulates the mRNA expression of RAD50, a DNA damage sensing gene in the HR pathway. Our ongoing study is to delineate the molecular mechanism of action for the observed synergy and whether PRMT5 inhibition can overcome resistance to PARP inhibitors. Through this study, we will identify a novel treatment strategy for the majority of TNBC patients (BRCA1WT) who currently lack targeted therapies.

Citation Format: Samyuktha Suresh, Lisa A. McPherson, James M. Ford. PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7595.
Abstract 7602: Discovery of GH1581, a potent and selective WRN inhibitor as a cancer therapy
Authors: Li Jiapeng , Zhang Guiping , Li Jie Jack
Published: March 2024

Defects in DNA mismatch repair (MMR) proteins could induce damage of genome, resulting microsatellite instability (MSI). MSI is highly correlated with the occurrence of several types of cancers, mainly in colon, gastric, endometrial, and ovarian cancers. Despite advances in the treatment of MSI-high cancers, tumor evolution and drug resistance remain the leading causes of treatment failure and death in cancer patients. About 50% MSI cancers have no response to immune checkpoint inhibitors. There is still unmet needs to be fulfilled for MSI-high patients. WRN is a RecQ family helicase involves in genome stability maintenance, DNA repair, replication, transcription, and telomere maintenance. Recent studies have identified WRN as a synthetic lethal target of MSI-high cancers. Employing structure-based drug design strategy, we have discovered a potent and selective WRN inhibitor, GH1581. In vitro, GH1581 displayed specific < 10 nM potency in ADP-Glo assay and < 10 nM potency in cell proliferation assay using MSI cancer cell lines. In vivo, GH1581 demonstrated favorable pharmacokinetic properties in different species. In SW48 xenograft model, it inhibited the tumor growth with 100% TGI at QD dosing of 10 mg/kg without severe adverse effect on body weight. In summary, we discovered GH1581 as a novel inhibitor of WRN with high in vitro and in vivo efficacy.

Citation Format: Jiapeng Li, Guiping Zhang, Jie Jack Li. Discovery of GH1581, a potent and selective WRN inhibitor as a cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7602.
Abstract 7636: Quantitative analysis of colorectal adenocarcinoma images obtained by single-shot 17-plex staining followed by imaging with the Orion™ spatial biology platform
Authors: Lo Edward , George Tad , Larkin Selena
Published: March 2024

Background To understand the tumor microenvironment (TME), high resolution imaging of multiple biomarkers with whole slide context can be used as a basis for downstream biomarker quantitation and predicting patient outcomes1. Here we investigate a sample of invasive colorectal adenocarcinoma using whole slide, single-step high-plex staining and imaging at single-cell resolution followed by quantitative analysis.

Methods The slide was stained in one round with a 17-plex immune-oncology panel then imaged in one round with the Orion™ spatial biology platform. Quantitative analysis was performed on the resulting TIFF file using the following pipeline:- Manually annotate regions of interest (ROI) on the tissue- Segment whole slide images into cells with UnMICST and S3segmenter - Import mask and clean data in QuPath - Generate primary feature data table with QuPath - Classify cells into populations in QuPath - Generate spatial biomarkers - Compare cell populations and their spatial interactions in the different ROIs.

Results Data revealed a distinction between normal colonic epithelium, well-differentiated adenocarcinoma with immune cell collection, and an infiltrating border of the carcinoma. Differences in immune cell content and spatial organization were measured, and the infiltrating border found to contrast with other tumor regions by showing a lower proliferative fraction (Ki-67, nuclear) and differences in E-cadherin and cytokeratin expression patterns.

Conclusions These data highlight the importance of sufficient plex, resolution and whole slide context to derive reliable spatial biomarkers of potential prognostic value. Further, hours vs. days speed for whole-section multiplexed biomarker quantitation, along with same-section conventional chromogenic analysis, makes this approach suited to multi-patient clinical studies.

1 JR Lin et al., High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers, Nat Cancer, 4, 1036-1052 (2023).

Citation Format: Edward Lo, Tad George, Selena Larkin. Quantitative analysis of colorectal adenocarcinoma images obtained by single-shot 17-plex staining followed by imaging with the Orion™ spatial biology platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7636.
Abstract 779: Functional role of TGF-beta receptor type-2 in breast cancer progression and survival
Authors: Srivastava Meera , Bera Alakesh , Pollard Harvey B. , Hu Hai , Shriver Craig D.
Published: March 2024

Background and Rational: Transforming growth factor β (TGFβ) signaling is pivotal in cellular proliferation and can exhibit either tumor-suppressive or promoting effects depending on cellular context and genetic alterations. TGFβ receptor type-2 (TGFβR2), the ligand-binding receptor, is implicated in various cancers. This study explores the functional role of TGFβR2 in breast cancer (BrCa) progression. Materials and

Method: Genomic alterations in TGFβR2 were assessed in TCGA samples. TGFβR2 mRNA and protein expression were examined in a panel of BrCa cell lines, including MCF7, MCF12A, MDA-MB-231, and MDA-MB-468. Additionally, serum samples from BrCa patients, meticulously categorized into subtypes such as triple-negative (TN), human epidermal growth factor receptor 2-positive (Her2+), Luminal A (LA), Luminal B1 (LB1), and Luminal B2 (LB2), were analyzed. BrCa cell lines were treated with TGFβ ligand to investigate receptor expression modulation.

Results: Analysis of genomic alterations in TGFβR2 from The Cancer Genome Atlas (TCGA, n=1084, BrCa samples) revealed TGFβ copy number amplification in 25% of samples, while less than 1% showed TGFβR2 amplification. Elevated TGFβR2 levels were identified in aggressive triple-negative MDA-MB-231 cells compared to other tested cell lines. Serum samples from BrCa patients (n=240) demonstrated higher TGFβR2 levels, particularly in Luminal B1 subtype and African American patients. Treatment of BrCa cell lines with TGFβ ligand induced TGFβR2 expression, suggesting ligand-induced receptor upregulation.

Discussion: The findings suggest TGFβR2 as a potential biomarker for BrCa, with higher levels associated with aggressiveness and racial disparities. Ligand-induced receptor upregulation implies a potential oncogenic role. These results contribute to understanding TGFβR2's functional significance and its implications in breast cancer progression, offering insights into potential biomarkers and therapeutic targets.

Citation Format: Meera Srivastava, Alakesh Bera, Harvey B. Pollard, Hai Hu, Craig D. Shriver. Functional role of TGF-beta receptor type-2 in breast cancer progression and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 779.
Abstract 896: Predicting metastatic transcriptomes of patient tumors with deep learning
Authors: Li Gang , Béal Evan , Sumner Dean , Galli Giorgio G. , Cremasco Viviana , Korn Joshua M. , Dondelinger Frank , Ruddy David , Kauffmann Audrey , Dimitrieva Slavica
Published: March 2024

Metastases are the primary cause of cancer-related death, and improving the means of predicting and targeting their development is one of the major goals in cancer research. While surgical resection and neo-adjuvant therapy can cure well-confined primary tumors, our ability to effectively treat cancer is largely dependent on our capacity to interdict the process of metastasis. The recent accumulation of ‘omics data from metastatic tumors provides an unprecedented opportunity to develop machine learning models to predict the molecular changes during metastasis and explore the patterns of metastasis formation. With this in mind, we developed MetMapper, a deep learning model trained on primary and metastatic tumors from > 13 000 patients integrating data from 11 published data resources. MetMapper can predict the transcriptomic changes of a primary tumor when it metastasizes to different distant organs. The results were extensively validated using transcriptomics data from matched primary and metastatic tumor biopsies extracted from the same patients. Furthermore, MetMapper’s predictions revealed that the non-random patterns of cancer metastases can be partly explained by the degree of transcriptome reprogramming needed during metastasis: primary tumors tend to metastasize to organs that require minimal changes to their transcriptomes. Using MetMapper, we derived a metastatic potential score for patient tumors and demonstrate that this score can be used to stratify patients into high and low survival groups across different indications. The predicted metastatic potential of patient tumors significantly correlates with experimentally characterized metastatic potential of cancer cell lines. Additionally, by performing in-silico perturbations of genes and oncogenic pathways that can alter the metastatic potential of patient tumors, we identified genomic features that are highly associated with metastases to specific organs, some of which were reported by existing pan-cancer clinical sequencing studies. Our results demonstrate the utility of MetMapper as a novel AI-powered methodology for investigating mechanisms and patterns of metastatic dissemination, as well as forecasting metastatic outcomes of patient tumors.

Citation Format: Gang Li, Evan Béal, Dean Sumner, Giorgio G. Galli, Viviana Cremasco, Joshua M. Korn, Frank Dondelinger, David Ruddy, Audrey Kauffmann, Slavica Dimitrieva. Predicting metastatic transcriptomes of patient tumors with deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 896.
Abstract 928: Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC)
Authors: Yazdanpanah Omid , Dwabe Sami , Harada Garrett , Seyedin Steven , Mar Nataliya
Published: March 2024

Multiple regimens are available for management of mccRCC including either immuno-oncology doublet (IO/IO) or combinations of IO and tyrosine kinase inhibitors (TKI). Clinical trials have compared these regimens to sunitinib, with no direct comparison between them. As such, there is ambiguity among physicians about preferred first-line for mccRCC. We performed a single-institution retrospective study of adults treated in first-line for mccRCC between 1/1/2017 and 1/1/2023. Regimens included IO/IO (ipilimumab/nivolumab [I/N]) or IO/TKI (pembrolizumab/axitinib [P/A], nivolumab/cabozantinib [N/C], or pembrolizumab/lenvatinib [P/L]). We compared efficacy and toxicity endpoints, using Kruskal-Wallis test for medians and Chi-square for categorical variables. 42 patients with median age of 61 (range: 36-95) were included. Patient distribution in IO/IO vs IO/TKI group was 20.0% vs 30.8% in International Metastatic Database Consortium (IMDC) favorable risk, 46.7% vs 38.5% in intermediate-risk, and 33.3% vs 30.8% in poor-risk group. 78.6% vs 66.6% of patients had WHO grade 3/4 ccRCC, 18.8% vs 15.4% had sarcomatoid features in the IO/IO vs IO/TKI, respectively. 38% (16/42) received I/N, 7% (3/42) N/C, 52% (22/42) P/A, and 2% (1/42) P/L. Median follow-up was 109 weeks. Table-1 compares the efficacy of IO/IO vs IO/TKI. IO-related toxicity, TKI-related toxicity, treatment interruptions, dose reductions, and need for steroids were not significantly different between IO/IO and IO/TKI (p= 0.240, p=0.372, p=0.923, p=1.00, and p=0.248, respectively). Genomic characteristics will be reported in poster.

Despite small sample size, our real-world data showed that patients treated with IO/IO had significantly worse outcomes compared to those treated with IO/TKI. While this difference may stem from a more aggressive disease in IO/IO group but further insights needs to be obtained through future prospective studies comparing IO/IO and IO/TKI regimens.

Variable IO/IO IO/TKI p-value Median treatment duration (weeks) 8.3 59.4 <0.001 Disease control rate (complete response + partial response + stable disease) (%) 50.0 91.7 0.024 Time from 1st line to 2nd line therapy (weeks) 14.6 57.1 0.001 Median overall survival (weeks) 63.6 Not reached 0.001

Citation Format: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar. Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 928.
Association between Portal Vein Thrombosis after Umbilical Vein Catheterization and Neonatal Asphyxia
Authors: Colella Marina , Zanin Anna , Toumazi Artemis , Bourmaud Aurélie , Boizeau Priscilla , Guilmin-Crepon Sophie , Leick Noémie , Khat Sophea , Alison Marianne , Baud Olivier , Biran Valerie
Published: March 2024

Introduction: Neonatal portal vein thrombosis (PVT) is frequently related to umbilical venous catheterization (UVC), but risk factors remain unclear. This study aims to analyze the variables associated to PVT in near- to full-term newborns with UVC, with a focus on newborns exposed to controlled therapeutic hypothermia (CTH) for hypoxic ischemic encephalopathy (HIE). Methods: This is retrospective cohort study of infants delivered at or after 36 weeks and with a birthweight over 1,500 g. All infants were assessed for UVC location and PVT using ultrasonography performed between day 5 and day 10 after catheterization. Results: Among 213 eligible patients, PVT was diagnosed in 57 (27%); among them, 54 (95%) were localized in the left portal vein branch. With all significant factors in univariate analysis considered, higher gestational age at birth (adjusted OR 1.35; 95% CI: 1.12–1.64, p = 0.002) and duration of UVC placement (adjusted OR 1.36; 95% CI: 1.11–1.67, p = 0.004) were the main risk factors of PVT. Among 87 infants who were cooled for HIE, 31 (36%) had PVT compared to 26 (21%) in infants without CTH. Using a multivariate model including variables linked to treatment procedures only, an increased PVT incidence was statistically associated with UVC duration (adjusted OR 1.33; 95% CI: 1.08; 1.63, p = 0.01) and CTH (adjusted OR 1.94; 95% CI: 1.04–3.65, p = 0.04). Conclusion: Left PVT was frequently observed in near- to full-term neonates with UVC. Among factors linked to treatment procedures, both duration of UVC and CTH exposure for HIE were found to be independent risk factors of PVT.
Delayed Presenting Gastric Duplication Cyst Mimicking a Left Adrenal Cyst in a Young Female: A Case Report with a Literature Review
Authors: Bapir Rawa , Qader Deedar , Gharib Dana , Tahir Soran , Abdullah Ari , Asaad Hoshmand , Ahmed Shaho , Ali Hemn , Abdullah Hiwa , Ahmed Sasan , Kakamad Fahmi Hussein , Aghaways Ismaeel
Published: March 2024

Introduction: Gastric duplication cyst (GDC) is a rare congenital anomaly of the gastrointestinal tract. Though GDC is often misdiagnosed, misidentification as an adrenal cyst has rarely been reported. Herein, we report a case of GDC in a young female mimicking an adrenal cyst. Case Presentation: A 17-year-old female presented with chronic epigastric pain, nausea, and intermittent vomiting. Physical examinations revealed mild tenderness in the epigastric region. Esophagogastroduodenoscopy showed no abnormality. Ultrasound, contrast-enhanced computed tomography scan, and MRI of the abdomen and pelvis showed an oval-shaped left adrenal cystic lesion measuring 33 × 26 mm. Preoperative blood investigations and hormonal assessments were normal. Laparoscopy showed that the cyst originated from the greater curvature of the stomach. The left adrenal gland was normal. After an intraoperative consultation with a gastrointestinal surgeon, a wedge resection of the cyst was performed. Histopathology confirmed the gastric duplication cyst. Conclusion: GDCs are rare congenital malformations that may become symptomatic during adulthood. They can mimic adrenal cysts and lead to misdiagnosis.
Passio: o projeto
Authors: Usai Paolo Cherchi
Published: March 2024

Por que essa ansiedade para criar imagens em movimento? Haveria sentido falar de arte e da ética da visão? Qual é a diferença entre observar os restos de um antigo manuscrito iluminado e o fragmento de um filme desconhecido, a pista de um aeroporto filmada por uma câmera de vigilância, um home movie de uma família que nunca conhecemos?
Immersive and Interactive 3D Visualization of Large-Scale Geoscientific Data
Authors: Flatken Markus , Schneegans Simon , Fellegara Riccardo , Gerndt Andreas
Published: March 2024

Virtual reality (VR) technology has great potential in supporting planetary scientists and the field of geosciences by offering immersive and interactive experiences for data exploration and analysis. This paper shows the opportunities presented by the use of VR technology in the geosciences domain while also identifying the open challenges associated with this integration. Our focus is on highlighting the several benefits that VR brings, including stereo vision, head tracking, and collaborative capabilities. These features can foster knowledge exchange and interdisciplinary research. Nevertheless, the adoption of VR presents certain challenges that need to be addressed. These include maintaining high refresh rates, handling large heterogeneous datasets, and striking a balance between visualization fidelity and performance. Fortunately, significant advancements have been made in high-performance data analysis, progressive data streaming, and real-time visualization, enabling interactive exploration of large-scale datasets within VR environments. To support a broader adoption among domain experts, we propose a visualization approach that scales both with display and with data size. As such, the system can be used to interactively explore large-scale datasets in immersive environments like CAVEs or powerwalls, on HMDs, or on traditional desktop setups. This approach allows for seamless transitions between desktop and VR experiences, leveraging immersive environments for collaboration and outreach activities. In this paper, we present an architectural framework, hardware environments, use cases, lessons learned, and the future potential of VR in this field. Through this scalable system, we anticipate transformative advancements in scientific exploration, collaboration, and knowledge dissemination.
Newly Found South Slavic Manuscripts of the Fourteenth and Fifteenth Centuries with the Pseudo-Athanasian Questions and Answers to Antiochus the Duke
Authors: Gritsevskaya Irina M. , Lytvynenko Viacheslav V.
Published: March 2024

This paper addresses the problem of an insufficient base of manuscript material for the study of the Slavonic translation of the Pseudo-Athanasian Questions and Answers to Antiochus the Duke (QAD). It begins with a brief survey of the two existing approaches to identifying the main groups of manuscripts and versions of the text (Lara Sels and William R. Veder) and alerts researchers to the fact that the number of examined witnesses today is too small to establish the real textual tradition of QAD. In the second part of the article, the authors present three newly found manuscripts as a way of partly responding to this problem and also suggest a new way of grouping them with those that have been previously studied.
Loanwords in Basic Vocabulary as an Indicator of Borrowing Profiles
Authors: de Heer Mervi , Blokland Rogier , Dunn Michael , Vesakoski Outi
Published: March 2024

Loanwords carry information on linguistic interactions, and can also reveal (pre-)historical population contacts. The contact history of a particular language family is an essential component of historical linguistics, but it is also illuminating for integrative studies of the human past. However, data availability and the time-consuming nature of etymology mean that comprehensive research on loanword layers exists for relatively few languages, forcing us to rely on limited material for others. This paper compares the loanword layers in the basic and total vocabulary of six well-studied Uralic languages, assessing how accurately the borrowing profile in basic vocabulary reflects the full profile of a language. We define “borrowing profile” as the known contact history of a language reflected by its loanword layers. We demonstrate that the loanword layers in basic vocabulary provide an adequate cross-section of the full borrowing profile, although basic vocabulary manifests prehistoric contacts more strongly than more recent contacts.
Consumer Trust and Online Purchase Intention for Sustainable Products
Authors: Rizomyliotis Ioannis
Published: March 2024

With the global market for eco-friendly products expected to reach $2.4 trillion by 2025, the sustainable products industry is poised to play a significant role in the transition to a more sustainable future. Similarly, the industry of sustainable products that are sold online is growing rapidly as consumers become more aware of the environmental and social impacts of their purchases. As a result, e-commerce companies make an effort to investigate the factors that influence consumer intent to purchase sustainable products online. By doing so, they aim to optimize their operations and better meet the needs of their customers. In this article, we will critically evaluate literature on this topic and explore trust as one of the critical factors that have a significant impact on consumer online purchase intention in the context of sustainable products. This research seeks to understand the determinants of consumer trust in relation to sustainable products that are sold online. The research model is empirically tested through the data of 278 participants. The research findings indicate that perceived risk, perceived security, and perceived privacy predict trust on e-commerce which, in turn, predicts online purchase intention for sustainable products. Consumer trust of sustainable products is also found to moderate the latter relationship.
Diabetes in Trauma Patients: A Potential Gateway to a Medical Home
Authors: Hart Kaylee , Thames Margaret A. , Massey Ashley Caroline , Capasso Thomas , Lee Yannlei L. , Mbaka Maryann , Kinnard Christopher M. , Bright Andrew C. , Williams Ashley Y. , Polite Nathan M. , Simmons Jon D. , Butts C. Caleb
Published: March 2024

Background

Diabetes is a major determinant of health outcomes. Trauma patients are disproportionately from lower socioeconomic status, where lack of access to health care prevents timely treatment. Trauma centers could play a role in identifying patients in need of improved glucose management, but the current burden of disease is not known. We assessed the incidence of patients in need of intervention that presented to a level 1 trauma center over a 6-month period.

Methods

A retrospective chart review over 6 months of all trauma patients admitted to a level 1 trauma center was performed. Patients’ past medical history (PMH), medication reconciliation, and hemoglobin A1c (HbA1c) were recorded on initial assessment; patients <18 years old, lacking an HbA1c, or missing PMH were excluded. Patients with PMH of diabetes or antihyperglycemic use were classified by HbA1c: well-controlled ≤8.0% or poorly controlled >8.0%. Patients with no history of diabetes or antihyperglycemic use were classified based on their HbA1c: non-diabetic <5.7%, pre-diabetic 5.7-6.4%, and undiagnosed diabetic ≥6.5%.

Results

Overall, 1377 patients were identified. After exclusion criteria, 903 patients were classified as follows: 593 (66%) non-diabetics, 160 (18%) pre-diabetics, and 150 (17%) diabetics. Fifteen diabetics were undiagnosed; 39 of the diagnosed diabetics were poorly controlled. Including pre-diabetics, a total of 214 (24%) trauma patients were in need of improved glycemic control.

Discussion

One in four trauma patients would benefit from improved outpatient glycemic management, representing a missed opportunity for preventative health care. Trauma centers should develop strategies to meet this need as part of their post-discharge care.
Weight-Based Dosing for Low-Molecular-Weight Heparin (Enoxaparin) Administration to Achieve Optimal VTE Prophylaxis in Trauma Patients
Authors: Thind Tarendeep , Heye Thomas , Henson Curran , Reif Rebecca , Jensen Hanna K. , Kalkwarf Kyle J. , Bhavaraju Avi , Robertson Ronald , Jenkins Allison
Published: March 2024

Introduction

Patients admitted after traumatic injuries are at high risk for developing venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) is commonly used to prevent VTE in this patient population; however, the optimal dosing strategy has yet to be determined. To address this question, a fixed-dosing strategy of LMWH was compared to a weight-based dosing strategy of LMWH for VTE prophylaxis.

Methods

A retrospective, pre-post implementation cohort study compared a fixed vs a weight-based dosing strategy of LMWH for VTE prophylaxis. Patients admitted to our level 1 trauma center were included if they had an estimated glomerular filtration rate >30 mL/min/1.73 m2, received at least 3 doses of LMWH, and had an appropriately drawn anti-Xa level on their initial dosing regimen. Patients in the pre-cohort received 30 mg LMWH subcutaneously twice daily as the initial dosing regimen. Patients in the post-cohort received .5 mg/kg (max 60 mg) LMWH subcutaneously every 12 h as the initial dosing regimen. A goal anti-Xa of .2-.4 IU/mL was targeted for prophylaxis.

Results

There were 817 patients in the fixed-dosing group (FDG) and 874 patients in the weight-based dosing group (WBDG). In the FDG, 42.8% of the patients achieved the goal initial anti-Xa level, with 54.1% and 3.1% reaching sub- and supratherapeutic doses, respectively. In the WBDG, 66.5% of patients reached goal initial anti-Xa levels, with 23.5% and 10.1% at sub- and supratherapeutic levels. The distribution of dose ranges was significantly different between the dosing strategies ( P-value <.001). There was no difference in the number of patients who received blood products (39.1% vs 41.7%. P-value = .299).

Conclusions

In our study, weight-based dosing of LMWH yielded a significantly higher proportion of patients who achieved goal prophylactic anti-Xa levels than fixed-dosing of LMWH. Larger-scale studies are needed to assess the risk of VTE events and bleeding with these dosing strategies.
Opioid Use in Pelvic Fractures: The Impact of Opioid Prescribing Laws in Pennsylvania
Authors: Villa Nicole Ann E. , Shum Kristina , Atkinson Allison , Ong Adrian , Muller Alison , Espiridion Eduardo
Published: March 2024

Pennsylvania’s Prescription Drug Monitoring Program (PDMP) was established in 2016, but its impact on opioid use for pelvic fractures is understudied. We compared opioid use in 277 pelvic fracture cases between two periods: 2015-2017 (T1) and 2018-2020 (T2). Outcomes included daily inpatient morphine milligram equivalents (MME), long-term opioid use (LOU) 60-90 days post-discharge, and intermediate-term opioid use (IOU) 30-60 days post-discharge. T1 and T2 had comparable baseline characteristics. T2 was associated with a decrease in average daily inpatient MME (58.6 vs 78.5, P = .02), particularly in younger patients. Regression analyses showed age and Injury Severity Score (ISS) were significant predictors for daily inpatient MME, while time period was not. Geriatric patients in T2 had significantly decreased IOU (30% vs 9%, P = .05). Pelvic fracture type and daily MME predicted IOU, while pelvic fracture type predicted LOU. This study suggests a modest impact of these laws, but further study is needed.
Urbanisation and Economic Growth: Some Insights from the Himalayan State of Sikkim
Authors: Singha Komol , Sherpa Lakpa Doma , Jaman Md. Samsur
Published: March 2024

Sikkim has experienced rapid urbanisation and industrialisation, particularly since the implementation of the North East Industrial and Investment Promotion Policy in 2007 (NEIIPP 2007). Though urbanisation and economic growth are inextricably linked, previous research findings on their causal relationships appear to be contradictory. Increased urbanisation/industrialisation seemed to enrage the Sikkimese, not because of revenue generation or environmental concerns, but because of their disproportionate share of employment opportunities in comparison to outsiders. Using secondary data, this article investigated two critical research questions: (a) Whether urbanisation is a result of or a cause of economic growth; and (b) Has Sikkim’s industrialisation, largely fuelled by the NEIIPP 2007, benefited locals? The causality test revealed a unidirectional relationship between the two, with urbanisation causing economic growth. Despite attracting migrant labour, Sikkim’s increased industrialisation/urbanisation has significantly reduced poverty and unemployment.

JEL Codes: H20, L59, O10, O15, O25, R23