tbuckley/cabot-search huggingface dataset:
Sensory Horizons and the Functions of Conscious Vision
Authors: Stephen M Fleming, Matthias Michel
Journal: Behavioral and Brain Sciences (2025)

Abstract It is not obvious why we are conscious. Why can't all of our mental activities take place unconsciously? What is consciousness for? We aim to make progress on this question, focusing on conscious vision. We review evidence on the timescale of visual consciousness, showing that it is surprisingly slow: postdictive effects reveal windows of unconscious integration lasting up to 400 milliseconds. We argue that if consciousness is slow, it cannot be for online action-guidance. Instead, we propose that conscious vision evolved to support offline cognition, in tandem with the larger visual sensory horizons afforded by the water-to-land transition. Smaller visual horizons typical in aquatic environments require fast, reflexive actions of the sort that are guided unconsciously in humans. Conversely, larger terrestrial visual horizons allow benefits to accrue from “model-based” planning of the sort that is associated with consciousness in humans. We further propose that the acquisition of these capacities for internal simulation and planning provided pressures for the evolution of reality monitoring—the capacity to distinguish between internally and externally triggered signals, and to solve “Hamlet's problem” in perception—the problem of when to stop integrating evidence, and fix a particular model of reality. In line with higher-order theories of consciousness, we associate the emergence of consciousness with the emergence of this reality monitoring function. We discuss novel empirical predictions that arise from this account, and explore its implications for the distribution of conscious (vs. unconscious) vision in aquatic and terrestrial animals.
Abstract 2338: Plasma proteomics associated with ovarian cancer risk in the Nurses' Health Studies
Authors: Nan Lin, Allison F. Vitonis, Simon T. Dillion, Ngo Long, Shelley S. Tworoger, Towia A. Libermann, Kathryn L. Terry, Naoko Sasamoto
Journal: Cancer Research (2025)

Abstract Background: While inflammation and gonadotropin levels are hypothesized to contribute to ovarian cancer initiation, specific proteomic pathways and other potential mechanisms are unclear. Thus, we aimed to identify novel blood-based non-invasive proteomic risk biomarkers for invasive epithelial ovarian cancer. Method: We measured 7, 310 pre-diagnostic plasma proteins using SomaScan v4.1 in 169 incident ovarian cancer cases [140 high-grade serous (HGS) cases] and 169 matched controls nested within the Nurses’ Health Studies. We excluded proteins with coefficient of variation ≥ 25% and influenced by delayed processing, resulting in 3, 131 proteins included in this analysis. We transformed protein levels to probit scores to achieve normality and used conditional logistic regression modeling to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) per one standard deviation increase in protein levels. We used Gene Set Enrichment Analysis to identify biological pathways and STRING to conduct protein-protein interaction network and functional enrichment analysis. We also conducted analyses restricted to HGS histotype. Results: All ovarian cancer cases included in the current analysis had blood samples collected years prior to diagnosis (median=14 years). Average age at blood collection was 56.3 years in both ovarian cancer cases and controls. When examining individual proteins associated with ovarian cancer risk, 94 proteins were significantly associated with ovarian cancer risk with nominal p-value&amp;lt;0.05. Biological pathway analysis revealed complement cascade (NES=2.0; FDR p=0.049) and innate immune system (NES=1.5; FDR p=0.049) pathways being upregulated in ovarian cancer cases compared to controls. STRING analysis showed protein-protein interactions were enriched in pathways such as tissue remodeling (e.g., COL6A1, COL18A1, IGFBP2), lipid metabolism (e.g., NCOA2, ME1), and B cell function (e.g., IGLL5, MZB1) in ovarian cancer cases compared to controls. Similar results were observed for HGS ovarian cancer. Discussion: We conducted a comprehensive examination of the plasma proteins associated with ovarian cancer risk in a prospective cohort study and observed upregulation of pathways related to innate immune system and complement cascade being associated with ovarian cancer risk. Citation Format: Nan Lin, Allison F. Vitonis, Simon T. Dillion, Ngo Long, Shelley S. Tworoger, Towia A. Libermann, Kathryn L. Terry, Naoko Sasamoto. Plasma proteomics associated with ovarian cancer risk in the Nurses' Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2338.
Abstract 901: KLF4-induced melanocyte-schwann plasticity promotes immune escape in melanoma via LAG3 checkpoint
Authors: An Zhao, Xuefei Liu, Zhixiang Zuo
Journal: Cancer Research (2025)

Abstract Precision therapy is crucial to the successful treatment of rare tumors with limited treatment options. Here, we report a rare case of primary anterior mediastinal melanoma with liver metastasis. The patient had previously failed anti-PD1 treatment, leading us to profile the molecular features of the tumor to identify alternative therapeutic targets. Through comprehensive multi-omics analyses, we discovered a high degree of tumor cell plasticity in this rare case, with a subset of tumor cells displaying a Schwann cell phenotype evolved from melanocyte tumor cells. Cell-cell communication analysis revealed that the Schwann-like tumor cells may evade immune surveillance through the LAG3-LGALS3 immune checkpoint. The patient was then recommended for enrollment in a trial using combination therapy with anti-PD1 and anti-LAG3, and the disease remained stable for up to 24 months. Further investigation into the underlying mechanism showed that transcription factor KLF4-mediated transcription reprogramming drives B16 melanoma cell trans-differentiation into a Schwann cell phenotype. This trans-differentiation sensitizes the tumor cells to anti-LAG3 therapy. By analyzing melanoma tissue microarrays and external single-cell sequencing data, we found that this melanocyte-Schwann plasticity (MSP) existed in around 20% of melanoma cases. Moreover, a public immunotherapy cohort and our data indicate that MSP is associated with poor response to anti-PD1 treatment, suggesting that MSP may serve as a predictive biomarker for immunotherapy efficacy. Overall, our study not only provides a paradigm for precision immunotherapy in the context of rare tumors, but also reveals a potentially effective immunotherapeutic strategy for advanced melanoma with melanocyte-Schwann plasticity. Citation Format: An Zhao, Xuefei Liu, Zhixiang Zuo. KLF4-induced melanocyte-schwann plasticity promotes immune escape in melanoma via LAG3 checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 901.
Abstract 2124: A potent therapeutic antibody BGM-2121 targeting parathyroid hormone-related peptide (PTHrP) for pancreatic cancer
Authors: Chiawen Ho, Chi-Feng Tseng, Chong-Jen Huang
Journal: Cancer Research (2025)

Abstract Although approximately 35% of approved drugs target G-protein-coupled receptors (GPCRs), cancer-specific GPCR-targeted therapies remain limited. Notably, several GPCRs and their ligands, including parathyroid hormone-related protein (PTHrP), are overexpressed in various solid tumors, including pancreatic cancer. In about 30% of pancreatic cancer cases, the PTHLH gene is co-amplified with the KRAS oncogene on chromosome 12, a phenomenon also observed in lung and colorectal cancers. Furthermore, the PTHLH gene can drive cancer progression through self-amplification. To address this, BioGate has developed BGM-2121, a potent humanized IgG1 monoclonal antibody targeting the N-terminal region (a.a. 1-34) of PTHrP, aiming to treat pancreatic cancer by targeting the PTHrP/PTH1R pathway. Preclinical studies have confirmed the specificity and antitumor activity of BGM-2121. In vitro assays demonstrated the antibody's high affinity and specificity for PTHrP, while in vivo animal studies using human pancreatic cancer cell models in mice showed significant antitumor activity. Notably, BGM-2121 effectively reduced tumor growth, halted disease progression in mouse models, and significantly extended survival. Additionally, in lung squamous cell carcinoma models, BGM-2121 successfully prevented and even reversed hypercalcemia and weight loss—key contributors to humoral hypercalcemia of malignancy (HHM) and cancer cachexia in human patients. Comprehensive safety and pharmacokinetic (PK) studies, including toxicokinetics (TK) and GLP-compliant repeated-dose toxicity studies, have thoroughly evaluated the safety profile of BGM-2121. In conclusion, this potent PTHrP-targeting antibody shows considerable promise as a therapeutic agent for cancers with PTHrP overexpression (e.g., pancreatic and lung cancers), humoral hypercalcemia of malignancy, and PTHrP-mediated cancer cachexia. We are currently preparing to submit an Investigational New Drug (IND) application to the TFDA and plan to initiate clinical trials to evaluate its potential as a novel biologic treatment for hard-to-treat metastatic cancers in Taiwan. Citation Format: Chiawen Ho, Chi-Feng Tseng, Chong-Jen Huang. A potent therapeutic antibody BGM-2121 targeting parathyroid hormone-related peptide (PTHrP) for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2124.
Abstract 933: Effect of mRNA vaccine-induced neutralizing antibodies on human T-cell leukemia virus type-1
Authors: Diandra Frias, Nehla Banu, Xiaogang Cheng, Ancy Joseph, Zhuoming Liu, Sean Whelan, Lee Ratner, Lee Ratner
Journal: Cancer Research (2025)

Abstract Introduction/Background: Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus linked to severe conditions such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The absence of a preventative therapy for HTLV-1 represents a significant gap in public health. Our lab has developed a codon-optimized HTLV-1 envelope (Env) mRNA vaccine encapsulated in lipid nanoparticles (LNP), which demonstrated partial protection in a rabbit model. However, further research is required to optimize its efficacy. Methods: The study involved evaluating the neutralizing antibody response induced by the HTLV-1 mRNA vaccine against HTLV-1a and HTLV-1c in various assays. Western blot analysis assessed the expression of the gp46 envelope glycoprotein and HIV capsid protein p24 in HEK 293T cells transfected with HTLV-1a or HTLV-1c Env plasmids. Fusion assays measured cell-cell fusion using mCherry fluorescent protein in 293T cells, with the effects of IgG serum from infected rabbits assessed. Virus titration involved VSV-HTLV Env and VSV-eGFP to evaluate viral infection inhibition. Neutralizing antibody assays tested IgG from HTLV-infected and non-infected rabbits to determine the extent of viral inhibition. Results: Expression of gp46 and HIV-1 p24 was confirmed in 293T cells co-transfected with HTLV-1a or HTLV-1c Env plasmids. Fusion assays indicated that IgG from infected rabbits effectively inhibited fusion in HTLV-1a and HTLV-1c Env-expressing cells. Virus titration presented significant inhibition of viral infection by IgG from HTLV-infected rabbits, with an IC50 of 0.05 µg. Conclusion: The study demonstrates that the HTLV-1 envelope mRNA vaccine induces neutralizing antibodies that can inhibit HTLV-1 infection and fusion processes. These findings support the potential of the mRNA vaccine as a preventive measure against HTLV-1-associated diseases and provide a basis for further research to optimize vaccine efficacy. Citation Format: Diandra Frias, Nehla Banu, Xiaogang Cheng, Ancy Joseph, Zhuoming Liu, Sean Whelan, Lee Ratner, Lee Ratner. Effect of mRNA vaccine-induced neutralizing antibodies on human T-cell leukemia virus type-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 933.
Abstract 1001: Leveraging Electronic Health Records to examine the real-world rates of cancer genetics referrals in a Singapore healthcare cluster
Authors: Jonathan Jian Hao Soon, Jianglei Wu, Nur Diana Binte Ishak, See Wei Qiang, Hing Pong Matthew Che, Michael Dorosan, Jeanette Yuen, Andrea Wan Ling Tan, Marcus Eng Hock Ong, Sean Shao Wei Lam, Hwee Lin Wee, Jianbang Chiang, Joanne Ngeow
Journal: Cancer Research (2025)

Abstract Identifying patients with hereditary cancer syndromes through genetics referral enhances early detection and reduces healthcare costs. Despite potential benefits, genetics referral rates globally, including Singapore, remain low. This study investigates the real-world rates of genetics referrals in eligible cancer patients at Singapore’s largest healthcare cluster using Electronic Health Records. Referral criteria for genetics referrals were based on international guidelines. The institution’s data repository was queried for eligible patients with relevant diagnosis codes from 2017 to 2021. We assessed genetics clinic attendance among eligible patients to evaluate referral rates. Variations in referral rates over time were analyzed using linear regression and two-tailed t-test. Of the 10080 patients eligible for a genetics referral, 17.1% (1719) were referred to a cancer genetics clinic. Breast, ovarian, colorectal, and endometrial cancers accounted for 42.9%, 33.5%, 11.3%, and 8.6% of referrals, respectively. Other tumor types accounted for 3.7% of referrals. Referral rates for suspected Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancers were higher (19.7%) than referrals for suspected Lynch syndrome (12.2%). Among HBOC referrals, women (20.7%) were more likely to be referred than males (7.8%). From 2017 to 2021, the referral rates among eligible patients steadily increased from 11.6% (483/4174) in 2017 to 23.6% (403/1705) in 2021, an increase of 12%, p=0.005. From 2017 to 2021, we found an increase in referral rates for HBOC (12.8% to 28.6 %, p= 0.005) but not for Lynch syndrome-related indications (8% to 12.6%, p=NS). The increase in referral rates for suspected HBOC in women was more significant than in men (p=0.03) This study found lower referral rates for Lynch syndrome than HBOC, and identified a gender discrepancy, with men with HBOC being less likely to be referred. Efforts to increase referral rates should include raising clinician awareness and electronically identifying suspected cases, especially for male breast cancer and Lynch Syndrome. Citation Format: Jonathan Jian Hao Soon, Jianglei Wu, Nur Diana Binte Ishak, See Wei Qiang, Hing Pong Matthew Che, Michael Dorosan, Jeanette Yuen, Andrea Wan Ling Tan, Marcus Eng Hock Ong, Sean Shao Wei Lam, Hwee Lin Wee, Jianbang Chiang, Joanne Ngeow. Leveraging Electronic Health Records to examine the real-world rates of cancer genetics referrals in a Singapore healthcare cluster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1001.
Abstract 872: High quality on-demand gene edited human primary T cells
Authors: John Latimer, Daniel Orozco, Paolo Piazza, Alex Brown
Journal: Cancer Research (2025)

Abstract EditCo unveils a breakthrough in T cell engineering aimed at benefiting cancer research: a rapid platform delivering premium-quality edited human CD4+ and CD8+ T cells with unprecedented efficiency. The platform achieves knock-out efficiency greater than 80% in less than 2 weeks, with edited cell pools maintaining viability above 70% before cryopreservation. These cells can be thawed and expanded at least 30-fold over 14 days independent of TCR stimulation, with no loss in editing efficiency. The platform's versatility has been demonstrated across multiple unique gene targets critical to cancer research and diverse donor populations, ensuring broad applicability. Notably, edited CD4+ T cells retain robust functionality after cryo-recovery, producing IL2, IFNγ, and TNFα upon stimulation. Similarly, edited CD8+ T cells maintain their endogenous antigen-specific cytotoxic activity, successfully express lentiviral CAR-T constructs, and demonstrate bi-specific engager-mediated cell killing. This comprehensive validation establishes EditCo's platform as a versatile, high-performance solution for T cell editing, maintaining cellular integrity and functionality while delivering consistent results across multiple genetic targets and donor populations. Citation Format: John Latimer, Daniel Orozco, Paolo Piazza, Alex Brown. High quality on-demand gene edited human primary T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 872.
Abstract 1258: Deciphering evolutionary dynamics and transcriptomic adaptions under therapy in small cell lung cancer
Authors: Laura Constanze Kaiser, Marcel Schmiel, Christian Müller, Maria Cartolano, Martin Peifer, Roman K. Thomas, Julie George
Journal: Cancer Research (2025)

Abstract Introduction: Small cell lung cancer (SCLC) represents a major medical challenge due to its aggressive progression and a dismal 5-year overall survival rate of only 7%. While SCLC initially responds well to chemotherapy, the rapid relapse and emergence of therapy-resistant tumors remain critical barriers to effective treatment. We hypothesized that therapy response is associated with genome evolution, which, in turn, influences transcriptional plasticity. This study aims to decipher the clonal evolution and transcriptomic adaptations in response to chemotherapy in SCLC. Methods: We established over 100 patient-derived xenotransplant models from clinical SCLC specimens, capturing diverse genetic features and clinical characteristics. A representative subset of 33 models was selected to replicate clinical scenarios in mice, modeling the effects of platinum-based chemotherapy and evaluating tumor responses under controlled conditions. Whole-exome sequencing and single-cell transcriptome profiling were performed to investigate genomic evolutionary trajectories and transcriptional plasticity in therapy-naïve and relapsed tumors. Results: Xenotransplant models accurately reflect patient responses to chemotherapy. To our surprise, several models from relapsed patients retained sensitivity to treatment. Chemotherapy-resistant models maintain their tumor clones, whereas sensitive models show dynamic shifts from a common ancestral clone with emerging subclones shaped by mutations associated with platinum damage, APOBEC activity, and defective DNA damage repair. The genomic landscape, defined by subclonal mutations and copy number alterations, strongly impacts transcriptomic patterns. Specifically sensitive models post-chemotherapy reveal a strong shift of transcriptional programs reflecting adaptive plasticity as a consequence of genome evolution. Conclusion: Here we provide an in-depth functional in vivo characterization of clonal adaptions in SCLC under therapy. Chemotherapy drives the selection of subclones with favorable genomic features, which in turn impact the broader transcriptomic landscape. Our data provides critical insights into the molecular mechanisms of therapy resistance. Citation Format: Laura Constanze Kaiser, Marcel Schmiel, Christian Müller, Maria Cartolano, Martin Peifer, Roman K. Thomas, Julie George. Deciphering evolutionary dynamics and transcriptomic adaptions under therapy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1258.
Abstract 946: Novel oncolytic virus targeting GPC3 and CTNNB1 demonstrates complete response in hepatocellular carcinoma (HCC) xenograft with a single, systemic administration
Authors: Chad M. Moles, Rupsa Basu, Brenda Ho, Manal Farhat, Jason Kent, Peter Weijmarshausen, Bruce F. Smith, Michael A. Whitt
Journal: Cancer Research (2025)

Abstract Introduction: Oncolytic viral therapies (OVTs) have shown promise in cancer treatment, though efficacy and selectivity challenges remain. HGI627 is an engineered vesicular stomatitis virus (VSV) featuring a synthetic glycoprotein retargeted to glypican-3 (GPC3) and a beta-catenin (CTNNB1)-dependent aptazyme as a genetic ON switch. This dual targeting strategy enhances specificity to liver cancer cells. Methods: HGI627 was constructed and rescued using a synthetic virology platform [Moles et al., Viruses 2024], and viral titers were measured by TCID50 assay on Hep3B cells. Cytotoxicity and selectivity were evaluated using real-time imaging (IncuCyte system) on liver cancer (e.g. Hep3B), off-target (e.g. SW-480), and normal (e.g. THLE-2) cells. To further evaluate this virus in vivo, an efficacy study performed in Hep3B xenograft-bearing NSG mice. To evaluate potential acute toxicity and maximum tolerated dose (MTD), a study in NSG mice (n=5/group) was then conducted using single and multiple 1x109 TCID50 doses. Results: HGI627 demonstrated robust lytic activity in vitro at low MOIs (0.01) in GPC3+/CTNNB1+ cells with minimal to no cytotoxicity in off-target and normal cells at MOI=10. In vivo, a single intraperitoneal (i.p.) injection of 1×10 TCID50 HGI627 (n=9) achieved a 100% complete response and significantly extended survival to day 49 (end of study) compared to median survival of 15 days in vehicle group (p&amp;lt;0.005). In the safety study, even multiple (n=3) high-dose (1×10 TCID50) administrations of HGI627 were well tolerated, and no signs of clinical toxicity were observed up to 14 days; Importantly, this highest dosing group received an equivalent of &amp;gt;100× the proposed first-in-human starting dose without adverse effects. Conclusion: These results highlight HGI627's potency, selectivity, and safety, overcoming previous OVT challenges. HGI627 exemplifies a promising approach for liver cancer treatment using a dual-targeting mechanism for enhanced precision. Current studies include an orthotopic HepG2-luciferase model to further validate efficacy. Citation Format: Chad M. Moles, Rupsa Basu, Brenda Ho, Manal Farhat, Jason Kent, Peter Weijmarshausen, Bruce F. Smith, Michael A. Whitt. Novel oncolytic virus targeting GPC3 and CTNNB1 demonstrates complete response in hepatocellular carcinoma (HCC) xenograft with a single, systemic administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 946.