tbuckley/cabot-search huggingface dataset:
Abstract 1157: Molecular signatures associated with the progression from DCIS to IDC
Authors: Siqi Chen, Alla Karpova, Preet Lal, Erik Storrs, Reyka Jayasinghe, Michael Iglesia, Andrew Houston, Yanyan Zhao, Andrew Shinkle, Chia-Kuei Mo, John Herndon, Feng Chen, William Gillanders, Li Ding
Journal: Cancer Research (2024)

Abstract Patients with ductal carcinoma in situ (DCIS) are frequently overtreated. Identifying markers that accurately predict which cases of ductal carcinoma in situ (DCIS) would progress to invasive ductal carcinoma (IDC) is crucial to personalized medicine but remains a challenge. Deciphering the process of DCIS progression at cellular, molecular and genetic levels helps identify biomarkers, allowing for better informed clinical decision-making. To study molecular signatures associated with the progression from DCIS to IDC, we collected samples from breast cancer patients with co-occurring DCIS and IDC, and performed Visium spatial transcriptomics (ST), single-nucleus RNA sequencing and multiplex imaging on these samples. We identified MGP, SLC39A6, PLAT, MLPH, AZGP1, TFF1 and TFF3 as showing significant differential expression levels in DCIS compared to IDC from ST analysis, which was confirmed with snRNA analysis. Notably, in multiplex imaging, MGP and PLAT showed consistently higher expression in DCIS compared to IDC at the protein level. Moreover, we evaluated these molecular signatures using MMTV-PyMT genetic mouse models at various breast cancer progression stages (3, 6, 12, 15, and 20 weeks) with snRNA-seq and multiplex imaging platforms. Collectively, our findings highlight the importance of identifying biomarkers at the molecular level, and provide potential predictive biomarkers for DCIS progression. Citation Format: Siqi Chen, Alla Karpova, Preet Lal, Erik Storrs, Reyka Jayasinghe, Michael Iglesia, Andrew Houston, Yanyan Zhao, Andrew Shinkle, Chia-Kuei Mo, John Herndon, Feng Chen, William Gillanders, Li Ding. Molecular signatures associated with the progression from DCIS to IDC [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 1157.
Abstract 1028: Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma
Authors: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles J. Rosser, Hideki Furuya
Journal: Cancer Research (2024)

Abstract Introduction and Objective: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with upper tract urothelial carcinoma (UTUC). The application of a robust urine-based multiplex assay, Oncuria-Detect®, to aid in the detection of UTUC has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis. Methods: To evaluate the performance of Oncuria-Detect®, a multiplex immunoassay capable of querying a voided urine sample for 10 protein biomarkers associated with urothelial carcinoma (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA). Its application to UTUC was evaluated in a multi-institutional cohort of 35 prospectively collected subjects presenting for evaluation of upper tract mass along with 46 prospective collected matched controls (i.e., non-tumor bearing). The ability of the test to identify patients harboring UTUC was assessed. UTCU status was confirmed by endoscopy and tissue biopsy or definitive surgery. Diagnostic performance was assessed using ROC curves. Results: Oncuria-Detect® provided an AUC of 0.886 (95% CI: 0.807-0.964) with an overall sensitivity of 91.4%, specificity of 73.9%, NPV 91.9% and PPV 72.7%. Sensitivity values of the diagnostic panel for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 86.7%, 90.9%, 88.9% and 94.1%, respectively. Urinary cytology or selective ureteral washing/cytology was associated with an overall sensitivity of 54.2%, specificity of 100%, NPV 63.3% and PPV 100%. Sensitivity values of cytology for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 100%, 100%, 100%, and 77.8%, respectively. Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of UTUC and controls non-tumor bearing individuals. The multiplex Oncuria-Detect® test can achieve the efficient and accurate detection of UTUC in a non-invasive patient setting. Citation Format: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles J. Rosser, Hideki Furuya. Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma [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 1028.
Abstract 1435: Utilization of CLDN18.2 syngeneic mouse models to study chimeric antigen receptor T cells in immunocompetent mice
Authors: Shannon Breen, Rosa Carrasco, Kelly McGlinchey, Brianna Janocha, Peter Zanvit, Lorenzo Ortiz, Benjamin Clark, Aleksandra Toloczko, Mark Cobbold, Gordon Moody, Emily Bosco, Allison Barrett
Journal: Cancer Research (2024)

Abstract CLDN18.2 expression has been observed in pancreatic, gastric and esophageal cancers, whereas normal tissue expression of CLDN18.2 is mostly restricted to differentiated gastric mucosal epithelial cells. This expression profile renders CLDN18.2 an ideal tumor associated antigen (TAA) for CAR-T targeting and an armored targeted CAR-T, AZD6422, is in clinical development. While CAR-T are beginning to show clinical promise in solid tumors, a consistent challenge is to overcome the immunosuppressive tumor microenvironment (TME) where immune and stromal cells secrete high levels of TGFb. Since the majority of pre-clinical CAR-T efficacy data is generated utilizing immunocompromised mouse models, which lack a proper TME, the team utilized syngeneic xenograft models to circumvent this challenge. ​ In vitro studies showed that CLDN18.2 targeted murine CAR-T cells generated by retroviral transduction induced efficient cytolysis of target positive mouse tumor cells accompanied by cytokine release. To model the clinical scenario, tumor-bearing mice were lymphodepleted with total body irradiation (TBI) to enhance CAR-T engraftment. The dosage of TBI used in these studies was predetermined to have caused leukopenia and minimal impact on tumor growth. We observed substantial tumor control and extended tumor efficacy in mice treated with mCAR-T cells compared to those infused with untransduced T cells or in non-target bearing control tumors in the absence of gross toxicities. ​ This syngeneic mouse model platform will additionally allow us to investigate how mCAR-T cells perform within a fully competent TME in combination with other therapeutic agents targeting cancer cells via altered mechanism of action. ​ Citation Format: Shannon Breen, Rosa Carrasco, Kelly McGlinchey, Brianna Janocha, Peter Zanvit, Lorenzo Ortiz, Benjamin Clark, Aleksandra Toloczko, Mark Cobbold, Gordon Moody, Emily Bosco, Allison Barrett. Utilization of CLDN18.2 syngeneic mouse models to study chimeric antigen receptor T cells in immunocompetent mice [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 1435.
Abstract 7340: Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities
Authors: Madeleine Ndahayo, Vera Mukhina, Ishita Gupta, Daria A. Gaykalova
Journal: Cancer Research (2024)

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the top cancers with significant cancer health disparities among racial and ethnic groups. African Americans (AAs) with HNSCC demonstrate worse overall survival compared to European Americans (EAs). While the reasons behind this disparity are multifaceted, recent findings suggest that biological features in HNSCC may contribute to differences in disease progression. However, race-related biological factors in HNSCC have been relatively little explored. We have identified the gene UBASH3B, a protein tyrosine phosphatase that plays a role in the stabilization of the Epidermal Growth Factor Receptor (EGFR). High expression of UBASH3B in AAs is associated with significantly worse overall survival compared to high expression in EAs and low expression in AAs. This study seeks to examine the role of UBASH3B in HNSCC and determine its impact on tumorigenesis. We hypothesize that the upregulation of UBASH3B in AAs contributes to the survival disparity by promoting tumor progression through EGFR signaling. Preliminary data using The Cancer Genome Atlas (TCGA) shows overexpression of UBASH3B in tumor samples of both AAs and EAs HNSCC samples. Plus, the overexpression of UBASH3B is associated with perineural invasion. Additionally, among AA-HNSCC patients, advanced T-stage is associated with increased UBASH3B expression. Elucidating the role UBASH3B plays in tumorigenesis will give us a further understanding of HNSCC in African Americans and can serve as a potential therapeutic target for new treatment options, as well as the biomarkers for the detection of the high-risk group. Citation Format: Madeleine Ndahayo, Vera Mukhina, Ishita Gupta, Daria A. Gaykalova. Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities [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 7340.
Abstract 6035: Fluoride effects on thermal properties of irradiated dentin and enamel
Authors: Rachel J. Kulchar, Yusuke Kakiuchi, Vania Sanchez-Gamarra, Jie Deng, Francis Mante
Journal: Cancer Research (2024)

Abstract Aim: Radiation therapy to treat oral cancer introduces various harms, including decreased hardness of dentin and enamel. Fluoride treatments, including silver diamine fluoride (SDF), have been used as a tool to combat these harms, but its influences on the thermal properties of dentin and enamel prior to and after radiation therapy are not well understood. Thus, this study analyzed how SDF influences the thermal stability of dentin and enamel that has been exposed to radiation therapy intended for head and neck cancer patients. Methods: Forty human posterior teeth were collected, cleaned of debris and soft tissue, and then mounted into acrylic resin molds. The teeth were divided into two equal groups, with one group being the control (no treatment) and the other group receiving SDF treatment. Using an X-Rad 320ix biological irradiator, all teeth were subjected to two grays of radiation therapy every day for six weeks. Afterwards, the dentin and enamel were pulverized a SPEX freezer mill. Samples were heated in a NETZSCH Thermal Analysis instrument, and the amount of carbon dioxide and water released was determined. All teeth were heated to 1429 °C from room temperature. Results: The SDF-treated dentin released the most carbon dioxide (49,611.82 ppm/mg), followed by irradiated dentin (47,672.76 ppm/mg) and untreated dentin (45,249.66 ppm/mg). In contrast, the SDF-treated enamel released less carbon dioxide (7,367.62 ppm/mg) than the control enamel (8,172.01 ppm/mg). The pattern of release of water was different from that of carbon dioxide. The control dentin group released the most water (45.56 ppt/mg), followed by the SDF-treated (39.72 ppt/mg) and irradiated dentin (23.51 ppt/mg). Similarly, the control enamel also released the highest amount of water (0.83 ppt/mg), as well as the highest amount of carbon dioxide. The SDF-treated enamel released around 65% of the water compared to the control enamel group (0.54 ppt/mg). Furthermore, the irradiated dentin had the largest heat reversal temperatures for carbon dioxide (85.19 °C) and water (86.57 °C). Conclusions: The impacts of SDF treatment and radiation vary between dentin and enamel. Comparatively, dentin has a higher content of combustible material than enamel. Radiation treatment reduces the water content of both enamel and dentin, which may make teeth more susceptible to fracture. Therefore, regular dental check-ups and frequent fluoride treatment to increase the strength of the teeth are recommended for patients undergoing radiation therapy. Citation Format: Rachel J. Kulchar, Yusuke Kakiuchi, Vania Sanchez-Gamarra, Jie Deng, Francis Mante. Fluoride effects on thermal properties of irradiated dentin and enamel [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 6035.
Abstract 6955: Activation of ERK pathway by mutant Ras oncoproteins derived from THP-1 cell exosomes
Authors: Joseph B. Hwang, Laura Marquardt, Osama Sait, Brooke Gilliam, Qiang Xiao
Journal: Cancer Research (2024)

Abstract The study of exosomes has attracted worldwide research due to its ability to modulate cellular activities, especially in the progression of cancer. Exosomes are membrane vesicles that can deliver lipids, proteins, and nucleic acids from one cell to another through membrane fusion, providing a unique form of cell-to-cell communication. It has been shown that KRAS G12V oncoprotein has been detected inside various pancreatic cancer cell derived exosomes. Our goal for this study was to examine the effect of KRAS G12V oncoprotein, detected inside exosomes isolated from THP-1 cell line supernatant, to activate MAPK pathway in MCF-7 breast cancer and AsPC-1 pancreatic cancer cells. To this end, we developed MILLIPLEX® immunoassays to detect cell signaling proteins as well as the exosome markers (CD9, CD63 and CD81), using Luminex® xMAP® technology which allows multiplex detection of proteins in a small volume of sample. Exosomes were isolated from THP-1 derived cell supernatant, using Qiagen exoEasy Maxi kit according to the kit protocol. KRAS G12V oncoprotein was detected in isolated THP-1 exosomes. As a control, THP-1 exosomes were enriched with exosome markers such as CD9, CD63 and CD81. After 48-hour incubation of AsPC-1 cells with KRAS G12V containing THP-1 exosomes, significant increase in KRAS G12V levels were detected in AsPC-1 cells. More importantly, this increase in KRAS G12V levels corresponded with an increase in phosphorylated ERK signaling, but not JNK, p38, NFκB, Akt, STAT3 and STAT3 pathways. In contrast, 48-hour incubation of MCF-7 cells with KRAS G12V containing THP-1 exosomes had no effect on any signaling pathways. Using MILLIPLEX® multiplex immunoassays, our data supports research findings that exosomes contain mitogenic signaling components that may enhance progression of cancer. Citation Format: Joseph B. Hwang, Laura Marquardt, Osama Sait, Brooke Gilliam, Qiang Xiao. Activation of ERK pathway by mutant Ras oncoproteins derived from THP-1 cell exosomes [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 6955.
Abstract 2327: MADVAR: An algorithm that improves the relevance of computational biology output, while reducing compute time and space requirements
Authors: Gilad Silberberg, Michael Ritchie
Journal: Cancer Research (2024)

Abstract High-throughput methods implemented in biology research produce a continuously growing array of data input that are used to produce data output with an increasing abundance of features. While growth in the volume and diversity of data input can be highly valuable for studying biological systems, it presents the challenge of managing enormous quantities of features, many of which are not relevant to the specific research question being asked. This excess data input burdens storage and computation of downstream clustering and machine learning tasks. A common approach used to manage this data input relies on filters applied to the features by their variance across the sample set, while applying random cutoffs. Our proprietary algorithm (“MADVAR”) enables the prioritization of variable features from high-throughput continuous data, by automatically finding an optimal cutoff for the distribution of the data. Based on the right-skew nature of biological data distribution, MADVAR finds and excludes the "0 variance peak" using the median of the distributions and the median absolute deviation (MAD). MADVAR enables a faster analysis with a reduced memory requirement, and dramatically improves clustering results with minimal loss of relevant features. Citation Format: Gilad Silberberg, Michael Ritchie. MADVAR: An algorithm that improves the relevance of computational biology output, while reducing compute time and space requirements [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 2327.
Abstract 2278: Unraveling immune dynamics of CD4+ in non-small cell lung cancer through single-cell analysis and gene expression profiling
Authors: Hyunmin Woo, JiHye Yang, Siyoung Yang, Seong-il Eyun
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancer (NSCLC) is a type of epithelial lung cancer other than small cell lung cancer and represents the majority of cases in lung cancer. The immune response against NSCLC relies significantly on the vital role by CD4+ T cells, contributing to the regulation of immune system and the suppression of tumor growth. Various CD4+ T cell subtypes, such as T conventional cells (Tconv cells) and T regulatory cells (Treg cells), perform distinct functions within the immune system. Tconv cells boost immune responses against specific pathogens, while Treg cells play a role in suppressing immune reactions. Investigating the correlation between Tconv cells and Treg cells in NSCLC could serve a valuable biomarker for evaluating the immune status of lung cancer patients. We examine the connection between particular CD4+ T cells in the lung and specific gene expressions associated with NSCLC. Through single-cell analysis, we classified the proportions of Treg cells and Tconv cells within CD4+ T cells in both the lungs and spleen of mice. Our discovery revealed that the proportion of Tconv cells in the lungs exceeded that in the spleen. From the differential gene expression (DEG) analysis using RNA-Seq data for Treg cells and Tconv cells in NSCLC, compared to the control group of Peripheral Blood Mononuclear Cells (PMBC), we identified 1823 genes uniquely expressed in NSCLC Treg cells and 711 genes in Tconv cells. Within these genes, we verified the expression of IL2RA and CTLA4, known to be expressed in NSCLC. Additionally, we identified high expression of genes TM4SF1 and KRT6A. By comparing the genes specific to Tconv and Treg cells in the lungs with those significantly expressed in NSCLC, we were able to identify 114 co-expressed genes in Treg cells and 71 in Tconv cells. We conducted GO and KEGG pathway analyses on these genes and examined the interaction networks among the associated genes. Furthermore, we found receptor interactions between Tconv cell subtypes (Th1, Th2, Th17, and Tfh) and Treg cells through cell-cell interaction analysis. We explored the mouse phenotypes associated with these genes. These discoveries unveiled connections within lung-specific gene networks of Treg and Tconv cells associated with NSCLC, highlighting candidate genes for targeted therapy in cancer. Citation Format: Hyunmin Woo, JiHye Yang, Siyoung Yang, Seong-il Eyun. Unraveling immune dynamics of CD4+ in non-small cell lung cancer through single-cell analysis and gene expression profiling [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 2278.
Abstract 2960: Deciphering the role of miRNA146-a and its crosstalk with cellular redox state in senescence escape in breast cancer cells
Authors: Shazib Pervaiz, Angeline Q. Liew, Marie-Veronique Clement
Journal: Cancer Research (2024)

Abstract Senescence serves as a double-edged sword in cancer as studies revealed that senescence exhibits both tumor-suppressing and tumor-promoting effects. A subpopulation of cancer cells that enters senescence can evade senescence to proliferate, thereby resulting in tumor regrowth, which has been associated with chemoresistance and tumor aggressiveness. Unlike senescent cells, the senescence-escaped cells harbor low levels of reactive oxygen species (ROS), however, the mechanism(s) underlying this redox dichotomy in senescence and senescence evasion remains elusive. In this regard, recent reports have highlighted the pivotal role of miRNAs in regulating cellular senescence. To that end, miR-146a has been reported as a biomarker of senescence probably via modulating pro-inflammatory and antioxidant pathways. We set up a model of doxorubicin-induced senescence in MDA-MB-231 breast carcinoma cells to study the role and involvement of miRNA146a in senescence induction and its regulation. Senescence induction was confirmed by upregulation of p21, increase in senescence-associated beta galactosidase and C12FDG staining, as well as propidium iodide positivity. We show that, following the initial phase of apoptotic cell death, as evidenced by increased yH2AX and cleaved caspase 3, a population of senescent cells escaped growth arrest to re-enter cell cycle and proliferate. Senescence-escaped cells harbored lower ROS levels compared to senescent cells, which correlated with upregulation of antioxidant enzymes such as MnSOD and CuZnSOD as well as increased transcription of NRF2 and NQO1. Our results also provide evidence for a novel senescence associated redox state, which implicates intracellular peroxynitrite as a driver of cellular senescence. Interestingly, in our model system, p21 upregulation was not associated with intracellular ROS accumulation, which was reported in earlier findings. Interestingly, these changes coincided with a significant increase in miR-146 expression (during senescence), which was previously shown to downregulate ROS in other model systems. While modulating miR-146a did not seem to change ROS levels upon doxorubicin-induced senescence in MDA-MB231 cells, the precise crosstalk between cellular ROS, miR146-a and senescence evasion is currently being pursued. Citation Format: Shazib Pervaiz, Angeline Q. Liew, Marie-Veronique Clement. Deciphering the role of miRNA146-a and its crosstalk with cellular redox state in senescence escape in 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 2960.