tbuckley/cabot-search huggingface dataset:
Abstract 4741: Targeting sorafenib-resistant HCCs by protein X-armed T cell immunotherapy
Authors: Mai-Huong Thi Ngo, Michael Chen, Pei-Chi Lan, Kuo-Hsiang Chuang, Yen-Hua Huang
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer globally, ranking fourth according to the World Health Organization's GLOBOCAN database. Sorafenib and lenvatinib are single-drug therapies used for advanced HCC, but only around 30% of patients benefit from them, and drug resistance typically develops within a few months. Our previous study has demonstrated the specific IL-6-IGF-1R-YAP signaling in regulating the stemness expressions, tumor metastasis, and drug-resistance of the sorafenib resistant HCC (2015 Clinical Cancer Res, 2019 J Exp Clinical Cancer Research, 2021 Cancers, 2023 Cancers). In advance our previous study, this study aims to develop a novel immune therapeutic strategy for sorafenib-resistant HCC treatment. We found, when compared to peri-tumor tissues, the immunohistochemical staining showed a high co-expression of both protein X and PD-L1 in liver tumor tissues (6.25%, n=32 versus 28.125%, n = 64, respectively). To further confirm this observation, we used in vitro cell line models with sorafenib-naïve HCCs (HepG2215_N, Hep3B_N, Huh7_N, and PLC5_N) and sorafenib-resistant HCCs (HepG2215_R, Hep3B_R, Huh7_R, and PLC5_R) in this study. As PD-L1 on tumor cells can dampen T cell cytotoxicity, we generated CD3/protein X bispecific antibodies, which can bind to both CD3 and protein X, and coupled them to T cells (Arm-T cells) and normal T cells (N-T cells). We tested their cytotoxic effects on sorafenib-resistant HCCs using the sorafenib-resistant HepG2215_R cells, co-cultured with Arm-T cells and N-T cells for 24 hours. Our results showed that Arm-T cells exhibited a significantly stronger cytotoxic effect on sorafenib-resistant HepG2215_R cells, with several notable findings: (1) The binding time of Arm-T cells to HepG2215_R cells was significantly longer than that of N-T cells (248.9 ± 146.6 minutes, n=23 versus 28.3 ± 13.49 minutes, n=24); (2) The cytotoxicity of Arm-T cells was significantly higher than that of N-T cells (29.7 ± 2.3% versus 13.6 ± 3.3%); and (3) The secreted levels of INFγ and TNFα by Arm-T cells were significantly higher than those of N-T cells (138.1 ± 7.2 ng/ml and 34.6 ± 0.7 ng/ml versus 31.4 ± 2.5 ng/ml and 3.6 ± 1.1 ng/ml, respectively). These findings were also consistent when using Hep3B-R cells (data not shown). To summarize, our study shows that Arm-T cells possess strong cytotoxic abilities against sorafenib-resistant HCC. These findings have implications for developing effective immuno-therapeutic strategies for patients with sorafenib-resistant HCCs. Citation Format: Mai-Huong Thi Ngo, Michael Chen, Pei-Chi Lan, Kuo-Hsiang Chuang, Yen-Hua Huang. Targeting sorafenib-resistant HCCs by protein X-armed T cell immunotherapy [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 4741.
Abstract 4900: Spatial Atlas of Human Anatomy (SAHA): A subcellular, multiscale spatial odyssey of immune and gastrointestinal tissues and tumors
Authors: Jiwoon Park, Roberto Gregorio, Erika Hissong, Sanjay Patel, Brian Robinson, Fabio Socciarelli, Evenlyn Metzger, Yan Liang, Jason Reeves, Joseph Beechem, Olivier Elemento, Alicia Alonso, Shauna Houlihan, Robert Schwartz, Christopher E. Mason
Journal: Cancer Research (2024)

Abstract The Spatial Atlas of Human Anatomy (SAHA) is a foundational effort to map 250 million cells and transcriptomes and proteomes of 30 non-diseased organs from healthy adults at two spatial scales: whole transcriptome of histological features (50 µm to 2 mm), and 1,000-plex RNA and 64-plex protein panels at spatial subcellular resolution (50 nm across 1 cm2). The project aims to establish and validate best practices in experimental design, sample processing, data analysis, and data standards for high-content spatial analysis across multiple human organs at whole transcriptome and proteome levels. The profiled samples will capture variability across genders and ancestries. All results, including raw and processed data, will be made available to the scientific community through the SAHA data portal and AtoMxTM Spatial Informatics Platform. Here we present the part of Phase I data collected specifically around immune (bone marrow and lymph node) and gastrointestinal tissues (ileum, appendix, colon, and liver), and compare these data to colon and liver cancer samples. On serial sections, we perform spatial whole transcriptome data (with GeoMx® Digital Spatial Profiler) and 1,000-plex RNA profiles and 64-plex protein profiles collected by the CosMx™ Spatial Molecular Imager (SMI) matched to the exact shape of functional histological organ features from H&amp;E and immunofluorescence stainings. Our data, which spans ~1.5 million cells collected across ~1,100 fields of view, enables the highest-ever subcellular resolution maps of cell types, lineage states, metabolic capacity, cellular neighborhoods, subcellular movements of organelles, and spatially resolved (and novel) ligand-receptor interactions across normal and cancer tissues. Through comparing these data to several cancer samples collected across multiple spatial platforms, we show how spatial organ atlasing at multiple scales can uncover unique insights into organ development, health, and cancer. We also show how the SAHA data can serve as a benchmark reference for spatial precision medicine. Citation Format: Jiwoon Park, Roberto Gregorio, Erika Hissong, Sanjay Patel, Brian Robinson, Fabio Socciarelli, Evenlyn Metzger, Yan Liang, Jason Reeves, Joseph Beechem, Olivier Elemento, Alicia Alonso, Shauna Houlihan, Robert Schwartz, Christopher E. Mason. Spatial Atlas of Human Anatomy (SAHA): A subcellular, multiscale spatial odyssey of immune and gastrointestinal tissues and tumors [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 4900.
Abstract 551: Investigation of the antipoliferative effect of the <i>Xylopia Aethiopica</i>extract in triple-negative breast cancer cells
Authors: Shailvi Soni, Shail Rakesh Modi, Terrick Andey
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has very limited treatment options. Xylopia Aethiopica (XA) is a common spice that is widely used in the regions of central and western Africa. It is known to have various pharmacological properties, one of which is anti-inflammatory activity. The anti-inflammatory effect may portend antiproliferative activity. We hypothesized that the extract of XA will exert antiproliferative activity against TNBC cells. The study aimed to establish the molecular mechanism underlying the antiproliferative activity of XA extract (XAE) against TNBC. The dried fruits of XA were crushed in a mixer and macerated using diethyl ether for 72 h. The macerate was subjected to vacuum and rotary evaporation to remove the organic solvent, and a stock solution was prepared in dimethyl sulfoxide (DMSO). Assessment of the efficacy of XAE was performed using serial dilutions (100 µg/ml, 50 µg/ml, 10 µg/ml, 5 µg/ml, and 1µg/ml) of the XAE stock solution, followed by in vitro testing against two TNBC cell lines (MDA-MB-231, and MDA-MB-468 cells). The cytotoxic effect of the XAE was then measured using the resazurin dye assay. XAE resulted in a concentration-dependent cell death in both cell lines. At the highest concentration (100 µg/ml), XAE induced cytotoxic cell death of 89% and 91% in MDAMB231 and MDAMB468 cells, respectively. This was consistent with IC50 values of 32.95 ± 1.32 µg/ml (MDAMB231) and 20.83 ± 1.05 µg/ml (MDAMB468). At the molecular level, western blot analysis of mitogenic markers associated with MAPK oncogenic signaling pathway demonstrated the inhibition of EGFR and AKT protein levels after a 48-h treatment. Acridine orange-ethidium bromide (AO/EB) staining showed a concentration-dependent induction of apoptosis in both cell lines. Flow cytometric analysis was performed to quantify the apoptotic cells. A significant increase of apoptotic cells was observed in treatment groups as compared to control after 72 h. Apoptotic induction was associated with increased p53 protein levels after 48 h treatment compared to control. The study results underscore the anticancer effects of XAE in TNBC cells mediated through induction of apoptosis. Citation Format: Shailvi Soni, Shail Rakesh Modi, Terrick Andey. Investigation of the antipoliferative effect of the Xylopia Aethiopicaextract 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 551.
Abstract 6573: Targeting DLK1, a Notch ligand, with an antibody-drug conjugate in adrenocortical carcinoma
Authors: Nai-Yun Sun, Suresh Kumar, Amber Weiner, Yoo Sun Kim, Arnulfo Mendoza, Rosa Nguyen, Reona Okada, Yves Pommier, Dan Martinez, Jennifer Pogoriler, Sharon Diskin, John Maris, Jaydira Del Rivero, Nitin Roper
Journal: Cancer Research (2024)

Abstract Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with poor prognosis. First-line therapy (adrenolytic agent mitotane in combination with chemotherapy) for recurrent and metastatic ACC has limited efficacy and there are no approved second-line therapies. Antibody-drug conjugates (ADCs) are an emerging immunotherapeutic class in which a cytotoxic payload is directed to tumor cells via antibodies to cell surface proteins. As Notch ligands, such as DLL3, are ADC targets in neuroendocrine cancers, we screened for expression of Notch ligands in ACC. Among Notch ligands (DLL1, DLL3, DLK1, JAG1, JAG2), DLK1 (delta-like non-canonical Notch ligand 1) was the most highly expressed. Moreover, ACC had the near highest expression of DLK1 across all TCGA tumors likely because this ligand is of adrenal origin (with limited expression in other normal tissues apart from the pituitary gland and ovaries). By immunohistochemistry, we verified DLK1 to be expressed, at variable levels, in 97% of ACC tumors (n=30/31). We then tested a DLK1-directed antibody-drug conjugate (ADCT-701; DLK1-PBD), consisting of a humanized anti-DLK1 monoclonal antibody coupled to DNA damaging pyrrolobenzodiazepine (PBD) dimers (SG3199; drug-to-antibody ratio~1.8) via a cleavable linker in ACC pre-clinical models. ADCT-701 exhibited potent, nanomolar cytotoxicity in DLK1-expressing ACC cell lines and ACC patient-derived short-term organoid cultures. ADCT-701 cytotoxicity was dependent on DLK1 expression as DLK1 knockout and DLK1 overexpression abrogated and facilitated cytotoxicity, respectively. Mechanistically, ADCT-701 induced cytotoxicity through DLK1 dependent receptor-mediated internalization and DNA damage (γH2AX) as well as apoptosis (annexin V/PI positive cells, cleaved PARP, and cleaved caspase-3). In vivo studies showed that ADCT-701 was highly effective against DLK1-positive ACC xenografts and PDX models with durable anti-tumor activity. Our pre-clinical data demonstrate DLK1 as an important therapeutic target in ACC and support an upcoming phase I clinical trial of ADCT-701 in patients with neuroendocrine tumors including ACC (NCT06041516). Citation Format: Nai-Yun Sun, Suresh Kumar, Amber Weiner, Yoo Sun Kim, Arnulfo Mendoza, Rosa Nguyen, Reona Okada, Yves Pommier, Dan Martinez, Jennifer Pogoriler, Sharon Diskin, John Maris, Jaydira Del Rivero, Nitin Roper. Targeting DLK1, a Notch ligand, with an antibody-drug conjugate in adrenocortical 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 6573.
Abstract 1095: Prox1 transcription factor and its downstream signaling - A new therapeutic target for rhabdomyosarcoma
Authors: Nebeyu Y. Gizaw, Tom Böhling, Mika Sampo, Kari Alitalo, Riikka M. Kivela
Journal: Cancer Research (2024)

Abstract Rhabdomyosarcoma (RMS) stands as the predominant soft tissue sarcoma in children, characterized by a high-grade neoplasm composed of cells resembling skeletal myoblasts. Despite being prevalent, patients with metastatic or recurrent rhabdomyosarcoma still experience poor outcomes, underscoring the necessity for novel treatments. We have recently shown that PROX1 is a critical factor in RMS tumor growth and myogenic characteristics (Gizaw NY, et al. PNAS 2022). As PROX1 has previously been associated with tumor metabolism in colorectal cancer, we investigated further its role in RMS metabolism. Our findings demonstrate that PROX1 plays a crucial role in regulating RMS cell metabolism. Specifically, silencing of PROX1 resulted in decreased lipid and oxidative metabolism, which was accompanied by an increase in glycolysis and triglyceride accumulation. RNA sequencing and Gene Set Enrichment Analysis revealed downregulation of all genes involved in the cholesterol synthesis pathway in PROX1-silenced RMS cells. Our studies further reveal that inhibiting cholesterol synthesis, akin to PROX1 silencing, can effectively inhibit RMS cell growth. Our results provide novel insights into the role of PROX1 in RMS metabolism and highlight the potential of PROX1-regulated metabolic pathways as promising targets for the development of novel RMS therapies. Citation Format: Nebeyu Y. Gizaw, Tom Böhling, Mika Sampo, Kari Alitalo, Riikka M. Kivela. Prox1 transcription factor and its downstream signaling - A new therapeutic target for rhabdomyosarcoma [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 1095.
Cost-effectiveness of active tuberculosis screening among high-risk populations in low tuberculosis incidence countries: a systematic review, 2008 to 2023
Authors: Nino Gogichadze, Arnau Sagrera, José Ángel Vicente, Joan-Pau Millet, Francesc López-Seguí, Cristina Vilaplana
Journal: Eurosurveillance (2024)

BackgroundIn countries with a low TB incidence (≤ 10 cases/100,000 population), active pulmonary tuberculosis (PTB) mostly affects vulnerable populations with limited access to healthcare. Thus, passive case-finding systems may not be successful in detecting and treating cases and preventing further transmission. Active and cost-effective search strategies can overcome this problem.AimWe aimed to review the evidence on the cost-effectiveness (C-E) of active PTB screening programmes among high-risk populations in low TB incidence countries.MethodsWe performed a systematic literature search covering 2008-2023 on PubMed, Embase, Center for Reviews and Dissemination, including Database of Abstracts of Reviews of Effects (DARE), National Health Services Economic Evaluation Database (NHS EED), Global Index Medicus and Cochrane Central Register of Controlled Trials (CENTRAL).ResultsWe retrieved 6,318 articles and included nine in this review. All included studies had an active case-finding approach and used chest X-ray, tuberculin skin test, interferon-gamma release assay and a symptoms questionnaire for screening. The results indicate that screening immigrants from countries with a TB incidence > 40 cases per 100,000 population and other vulnerable populations as individuals from isolated communities, people experiencing homelessness, those accessing drug treatment services and contacts, is cost-effective in low-incidence countries.ConclusionIn low-incidence countries, targeting high-risk groups is C-E. However, due to the data heterogenicity, we were unable to compare C-E. Harmonisation of the methods for C-E analysis is needed and would facilitate comparisons. To outline comprehensive screening and its subsequent C-E analysis, researchers should consider multiple factors influencing screening methods and outcomes.
Abstract 2063: Using the edge wells in 96-well plates without increasing variability in cytotoxicity assays through thermal controls
Authors: Alicia D. Henn, Shannon Darou, Randy Yerden
Journal: Cancer Research (2024)

Abstract There are very few things as fundamental to cancer research as the 96-well-plate, yet edge effect has continued to cause problems since its introduction. The most common remedy for edge effect is to avoid using edge wells altogether, which eliminates 37% of the plate from the assay. If all of those wells could be used, an estimated USD $119M could be saved in research costs annually across the globe. We have shown previously that maintaining constant thermal control of plating conditions reduces variability in stem cell toxicity assays. Here, we ask the question: can we use the edge wells in cancer screening assays if we control thermal changes that happen in the traditional lab as cells are plated at room temperature and incubated at 37 degrees C? We had the null hypothesis that including the edge wells would add variability to an A549 cytotoxicity assay, even if the cell handling and incubation temperatures were matched and held constant. We plated A549 cells at either room temperature (like a BSC) or at 37 degrees C using the Xvivo System, which maintains constant temperature, oxygen, CO2, and relative humidity levels around cell handling operations. The cells were treated with serial dilutions of peracetic acid/hydrogen peroxide solution. After incubation for 3 days, the plates were stained with Crystal Violet and assessed for cell density (n=3 separate experiments). The null hypothesis was disproven. We found that if the plates were maintained at 37 degrees C during cell handling as well as incubation, that cell distribution was random and even across all wells, even edge wells. We found that there was no statistical difference between edge well and center well results in cytotoxicity assays. Edge wells were usable without increasing variability in the assays. This is consistent with earlier findings showing that when temperature changes between cell plating and incubation were averted, stem cell distribution across the plate was random and the edge effect was eliminated. Citation Format: Alicia D. Henn, Shannon Darou, Randy Yerden. Using the edge wells in 96-well plates without increasing variability in cytotoxicity assays through thermal controls [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 2063.
Abstract 697: Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell therapy
Authors: Nahum Puebla, Gitika Srivastava, Sara Nizzero, Natalie Wall Fowlkes, Hampartsoum Barsoumian, Yun Hu, Carola Leuschner, Thomas Riad, Marko Loparic, Marija Plodinec, James Welsh
Journal: Cancer Research (2024)

Abstract Background: Solid tumors remain a significant challenge in cancer therapy due to their resistance to conventional treatments. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for treating solid tumors, but its effectiveness is often limited by the poor infiltration of CAR-T cells into the tumor microenvironment. Thus, enhancing a robust infiltration of chimeric antigen receptor T cells into solid tumors is essential for an effective antitumor response and therapeutic success. Methods: In this study, we investigated the combined effects of multiple doses of low-dose radiotherapy (LD-RT) and CAR T-cell therapy on tumor growth and survival using two models of NSG mice implanted with gastric carcinoma (GSU) or pancreatic adenocarcinoma (CAPAN-2) cells. The engineered CAR-T cells were designed to target guanyl cyclase-C (GCC) or mesothelin, respectively. Furthermore, our study employed atomic force microscopy (AFM) in a small cohort to investigate the impact of LD-RT and CAR-T cell therapy on tumor stiffness and plasticity. Results: The synergistic effect of combining low-dose radiotherapy (LD-RT) with T-cell therapy resulted in enhanced tumor control and prolonged survival in mice with tumors, surpassing the outcomes observed with either monotherapy alone. This combined treatment holds promise for improving responses in patients with solid tumors by leveraging LD-RT to enhance the intratumoral infiltration of effector T cells. Our findings suggest that the nanomechanical signature may be a potential biomarker for LD-RT combined CAR T cell therapy in solid tumors. Conclusions: Our findings substantially contribute to treating solid tumors using cell therapies, highlighting the potential for improved infiltration of adoptively transferred T cells following radiotherapy (RT), which can transform existing therapeutic strategies for solid tumors while minimizing toxicity. Citation Format: Nahum Puebla, Gitika Srivastava, Sara Nizzero, Natalie Wall Fowlkes, Hampartsoum Barsoumian, Yun Hu, Carola Leuschner, Thomas Riad, Marko Loparic, Marija Plodinec, James Welsh. Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell 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 697.