tbuckley/cabot-search huggingface dataset:
Oxaliplatin, ATR inhibitor and anti-PD-1 antibody combination therapy controls colon carcinoma growth, induces local and systemic changes in the immune compartment, and protects against tumor rechallenge in mice
Authors: Alexandra Fauvre, Chiara Ursino, Veronique Garambois, Elodie Culerier, Louis-Antoine Milazzo, Nadia Vezzio-Vié, Laura Jeanson, Candice Marchive, Augusto Faria Andrade, Eve Combes, Salima Atis, Gérald Lossaint, François Quenet, Henri-Alexandre Michaud, Lakhdar Khellaf, Ileana Corbeau, Diego Tosi, Nadine Houede, Nathalie Bonnefoy, Olivia Sgarbura, Céline Gongora, Julien Faget
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Colorectal cancer (CRC) is the third most common cancer type and one of the leading causes of cancer-related death worldwide. The treatment of advanced metastatic CRC relies on classical chemotherapy combinations (5-fluorouracil, oxaliplatin or irinotecan). However, their use is limited by the emergence of resistance mechanisms, including to oxaliplatin. In this context, we recently showed that the combination of oxaliplatin and ataxia telangiectasia and Rad3-related protein inhibition (VE-822) is synergistic and may have a potential therapeutic effect in metastatic CRC management. Methods In this study, we investigated the role of the VE-822+oxaliplatin (Vox) combination on the immune response and its potential synergy with an anti-programmed-cell Death receptor-1 (PD-1) antibody. We used cell lines and organoids from metastatic CRC to investigate in vitro Vox efficacy and orthotopic syngeneic mouse models of metastatic CRC to assess the efficacy of Vox+anti-PD-1 antibody and identify the involved immune cells. Results The Vox+anti-PD-1 antibody combination completely cured tumor-bearing mice and protected them from a rechallenge. Vox was associated with a reduction of tumor-infiltrated neutrophils, CD206 + macrophages and regulatory T cells. Vox also induced a deep depletion of blood neutrophils. The increased bone marrow granulopoiesis failed to compensate for the Vox-mediated mature neutrophil depletion. Neutrophil depletion using a mouse recombinant anti-Ly6G antibody partially mimicked the Vox effect on the tumor microenvironment, but to a lower extent compared with the Vox+anti-PD-1 antibody combination. Vox, but not neutrophil depletion, led to the emergence of an Ly6C + PD-1 + CD8 + T-cell population in the blood and spleen of tumor-harboring mice. These cells were proliferating, and expressed IFN-γ, CD62L, CXCR3 and Eomes. Moreover, the proportion of tumor antigen-specific T cells and of CD122 + BCL6 + T cells, which shared phenotypic characteristics with stem-like CD8 + T cells, was increased in treated mice. Conclusions Our work strongly suggests that the Vox+anti-PD-1 antibody combination might significantly improve survival in patients with metastatic and treatment-refractory CRC by acting both on cancer cells and CD8 + T cells.
Orlistat facilitates immunotherapy via AKT-FOXO3a-FOXM1-mediated PD-L1 suppression
Authors: Qingyun Tang, Jie Li, Lianhua Zhang, Shuo Zeng, Qiyu Bao, Weichao Hu, Lijiao He, Guiping Huang, Liting Wang, Yunyi Liu, Xiaoyan Zhao, Shiming Yang, Changjiang Hu
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The immunotherapy targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death ligand-1 (PD-L1) has achieved significant breakthroughs, but further improvements are still needed in cancer treatment. Methods We investigated orlistat, a drug approved by the Food and Drug Administration for the treatment of obesity and found that it can enhance the efficacy of CTLA-4 blockade immunotherapy. We conducted both in vivo and in vitro experiments to explore the mechanism by which orlistat increased antitumor immunity. Results Orlistat enhances the efficacy of anti-CTLA-4 immunotherapy by suppressing tumor cell PD-L1 protein expression and boosting the transcription of interferon-stimulated genes (ISGs) and MHC-I. Mechanistically, orlistat inhibits AKT activity and subsequent phosphorylation of forkhead box O3a (FOXO3a) at its threonine (T) 32, serine (S) 253, thereby downregulating Forkhead box M1 (FOXM1) expression, which ultimately suppresses PD-L1 transcription. Specifically, inhibition of FOXM1 leads to FOXO3a accumulation through impaired AKT activity. FOXM1 activates protein kinase B (AKT) via acting as a scaffold to facilitate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT and interaction. In addition, orlistat enhances phosphorylated signal transducer and activator of transcription 1 (p-STAT1) at tyrosine (Y) 701, resulting in upregulation of ISGs and MHC-I. Conclusions Orlistat plays a crucial role in modulating the immune response and supporting the combination with CTLA-4 blockade to promote antitumor immunotherapy.
Systemic immunomodulation by irreversible electroporation versus stereotactic ablative body radiotherapy in locally advanced pancreatic cancer: the CROSSFIRE trial
Authors: Bart Geboers, Florentine Timmer, Danielle Vos, Hester Scheffer, Joyce Bakker, Alette Ruarus, Laurien Vroomen, Anita Stam, Sinéad Lougheed, Evelien Schouten, Robbert Puijk, Petrousjka van den Tol, Frank Lagerwaard, Jan de Vries, Anna Bruynzeel, Martijn Meijerink, Tanja de Gruijl
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Irreversible electroporation (IRE) and stereotactic ablative body radiotherapy (SABR) are cytoreductive therapies for locally advanced pancreatic cancer (LAPC). Both may signify immunogenic cell death. We aimed to compare systemic immune responses between the treatments. Methods As part of the randomized phase II CROSSFIRE trial ( NCT02791503 ), comparing the oncological efficacy of IRE to SABR in patients with LAPC, pre- and post-treatment (2 weeks and 3 months) peripheral blood samples were collected. Frequency and activation status of lymphocytic and myeloid subsets were determined using flow cytometry. T cell responses to pancreatic cancer associated with Wilms tumor-1 (WT-1) and survivin tumor antigens were determined by interferon-γ enzyme-linked immunospot assay. Results In total, 20 IRE and 20 SABR-treated participants were analyzed (20 men; median age 65 (IQR 55–70)). IRE induced immediate decreases in systemic regulatory T cell (Treg) and conventional type-1 dendritic cell rates, coinciding with CD4 + /CD8 + T cell activation by upregulation of PD-1, which was associated with improved overall survival (OS). SABR similarly induced immediate CD4 + /CD8 + T cell activation by upregulation of Ki67 and CD25 but resulted in asynchronously delayed Treg downregulation. SABR also induced a durable increase in CD4 + EM T cells, associated with improved OS. Ablation-induced WT-1 or survivin-specific T cell responses were observed in 9/16 (56%) immune competent participants (IRE n=5, SABR n=4) and were associated with longer OS. Conclusion Distinct immune stimulatory responses associated with improved OS, suggest that SABR might benefit from combined Treg depletion strategies while IRE could benefit from PD-1 checkpoint inhibition. Trial registration number The trial was registered on clinical trials.gov ( NCT02791503 ).
Differential regulation of calcium-NFAT signaling pathway by Akt isoforms: unraveling effector dynamics and exhaustion of cytotoxic T lymphocytes in tumor microenvironment
Authors: Wen-Ling Chen, Yong-Lin Chang, Su-Fang Lin, Ulrike Protzer, Masanori Isogawa, Hung-Chih Yang, Li-Rung Huang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Impairment of Akt signaling has been observed in antigen-specific cytotoxic T lymphocytes (CTLs) during chronic viral infections or tumor progression. Despite numerous studies emphasizing Akt’s role in driving CTL effector functions, there is limited exploration of using Akt molecules in T-cell engineering to enhance their antiviral or antitumor capabilities for therapeutic purposes. Some studies even conclude that inhibiting Akt activation during the in vitro expansion process can prevent T-cell exhaustion and boost the antitumor effector functions of chimeric antigen receptor-T cells in vivo. Given the unique expression patterns and functions of the three Akt isoforms in immune cells, we proposed that Akt isoforms in CTLs may regulate effector functions and T-cell exhaustion distinctly. Methods In this study, we genetically modified tumor/virus-antigen-specific T-cell receptor tg CTLs to ectopically express Akt isoforms via retroviral transduction. We subsequently conducted western blotting, flow cytometry, and RNA sequencing analysis to assess their Akt expression, expression of immune checkpoints, antitumor/antivirus functionalities, and transcriptome. Additionally, we employed a persistent Hepatitis B Virus mouse model and a syngeneic hepatocellular carcinoma mouse model for further evaluation of their antivirus/antitumor efficacies. Results We found that both Akt1 and Akt2 overexpression enhanced the cytotoxic capabilities of mouse CTLs, although with different dynamics. Specifically, Akt2 signaling in CTLs accelerated effector functions, leading to a rapid attack on tumor cells. Conversely, Akt1 signaling triggered calcium influx and subsequent nuclear factor of activated T cells (NFAT) activation, while Akt2 signaling suppressed calcium influx, preventing excessive NFAT expression and nuclear translocation. This repression of NFAT transcriptional activity by Akt2 signaling during prolonged antigen stimulation subsequently led to reduced expression of transcription factors associated with T-cell exhaustion, such as Egr2, Nr4a, Tox, and immune checkpoints. Consequently, Akt2-overexpressed CTLs displayed reduced T-cell exhaustion within the tumor microenvironment and efficiently eradicated tumors. Conclusion These findings highlight the essential role of Akt signaling in enabling tumor-specific CTLs to eliminate cancer cells in the solid TME, with Akt isoforms differentially regulating the calcium–calcineurin–NFAT signaling pathway. This discovery suggests the potential of AKT2 in T-cell engineering technology to enhance the survival and effector functions of adoptively transferred T cells for treating liver malignancies or chronic viral infections.
The LncRNAs PART1 and ADAMTS9-AS2 act in an Antithetic Manner on AR Signaling and Induction of Cellular Senescence in Prostate Cancer Cells
Authors: Mohammad Taheri, Katrin Schindler, Aria Baniahmad
Journal: International Journal of Surgery (2025)

Background: Prostate cancer (PCa) is initially a hormone-dependent disease and the development and spread of PCa are tightly linked to the androgen receptor (AR) signaling activity. Therapy that targets the AR pathway is a standard approach for treating PCa including AR antagonists and supraphysiological androgen levels (SAL) used in bipolar androgen therapy. Here, we identified that the two lncRNAs PART1 and ADAMTS9-AS2 mediate in part androgen signaling in PCa cells by examining PCa specimen and response to AR antagonists or SAL as well as functionally by knockdown. Methods: This study utilized expression analysis of tumor tissues (TT) samples in comparison to their corresponding normal tissue adjacent to the tumor (NTAT) counterparts of 50 patients. RNA-seq and treatment of patient prostatectomy samples ex-vivo confirmed regulation of lncRNAs by SAL. Knockdown of both lncRNAs were used to analyze androgen signaling of AR target genes by qRT-PCR and in PCa senescence pathway by analyzing senescence markers. Correlation analyses of patient tumor samples confirmed co-expression. RNA immunoprecipitation (RIP) used in both LNCaP and C4-2 cells detect AR-lncRNA interaction. Bioinformatic analyses were employed to identify ligand-specific lncRNAs and miRNA interactions with PART1 and ADAMTS9-AS2 and confirmed by treatment of patient prostatectomy samples ex-vivo. Results: PART1 and ERVH48-1 were significantly overexpressed in TT samples, ADAMTS9-AS2 expression is lower in TT samples compared to NTAT samples. SAL treatment indicates opposite regulation in two human PCa cell lines and patient tumor samples. While ADAMTS9-AS2 is upregulated, PART1 is repressed by SAL. Further, the obtained data suggest that ADAMTS9-AS2 may act as a co-activator and PART1 as a co-repressor of AR signaling. Interestingly, the knockdown indicates that both lncRNAs ADAMTS9-AS2 and PART1 regulate AR activity and protein level as well as SAL-mediated induction of cellular senescence. Thus, the data suggest that suggest that ADAMTS9-AS2 and PART1 control AR signaling at SAL. Conclusion: In summary, we identified novel AR signaling pathways that involve lncRNAs oppositely regulated by SAL and in PCa tumorigenesis.
Assessing antibiotic effectiveness for reducing postoperative infectious complications in acute cholecystitis: a multicenter randomized controlled trial
Authors: Sung Eun Park, Tae Yoon Lee, Chang Ho Seo, Eui Soo Han, Tae Ho Hong
Journal: International Journal of Surgery (2025)

Background: Patients with acute cholecystitis (AC) often receive antibiotics to reduce the risk of infectious complications after cholecystectomy. This study investigated the clinical significance of antibiotic use in patients with mild-to-moderate AC who required emergency laparoscopic cholecystectomy. Methods: This multicenter, double-blind, randomized controlled trial was conducted at four centers between February 2023 and January 2024. Patients with AC eligible for emergency laparoscopic cholecystectomy were randomly assigned to the antibiotic or placebo group. The antibiotic group received 1 g of intravenous cefazolin daily for three days during hospitalization and oral antibiotics for 4 days after discharge, whereas the placebo group received 10 mL of intravenous normal saline during their hospital stay. The primary endpoint was the rate of infectious complications. Results: An imputed per-protocol analysis of 370 patients (185 in each group) found comparable postoperative infection rates between the antibiotic group (7.6%, 14 patients) and placebo group (7%, 13 patients), showing no statistically significant difference ( P = 0.842). Overall, the non-infectious complication rates did not differ significantly between the two groups: 21 (11.5%) cases in the antibiotic group vs. 30 (16.2%) cases in the placebo group ( P = 0.591). Considering a non-inferiority margin of 10%, the absence of antibiotic treatment did not result in worse clinical outcomes than the antibiotic treatment. Conclusions: Administering antibiotics, even in sufficient doses, did not significantly reduce the risk of infectious complications in patients with AC compared to the group that did not receive antibiotics.
Ethical considerations on the role of artificial intelligence in defining the futility in emergency surgery
Authors: Valentina Bianchi, Filomena Misuriello, Edoardo Piras, Carmen Nesci, Maria Michela Chiarello, Giuseppe Brisinda
Journal: International Journal of Surgery (2025)

Bianchi, Valentina MD; Misuriello, Filomena MD; Piras, Edoardo MD; Nesci, Carmen MD; Chiarello, Maria Michela MD; Brisinda, Giuseppe MD Author Information
Identification of Biomarkers of Shrinkage Modes After Neoadjuvant Therapy in HER-2 Positive Breast Cancer
Authors: Zhao Bi, Yue Zhang, Xian-Rang Song, Wen-Hao Zheng, Peng Chen, Peng-Fei Qiu, Yan-Bing Liu, Yong-Jin Lu, Xing-Guo Song, Yong-Sheng Wang
Journal: International Journal of Surgery (2025)
Quantitative Bias Analysis for Single-Arm Trials With External Control Arms
Authors: Alind Gupta, Grace Hsu, Seamus Kent, Stephen J. Duffield, Evie Merinopoulou, Alexandre Lockhart, Paul Arora, Joshua Ray, Samantha Wilkinson, Nicolas Scheuer, Sreeram V. Ramagopalan, Rolf H. H. Groenwold, Sanjay Popat, Miguel A. Hernán
Journal: JAMA Network Open (2025)

Unmeasured confounding is a key concern for decision-makers when observational datasets are used to assemble external control arms (ECAs) for single-arm trials. To investigate the utility of quantitative bias analysis (QBA) for exploring the sensitivity to unmeasured confounding of nonrandomized analyses using ECAs. This study emulated 15 treatment comparisons using experimental arms from existing randomized trials in advanced non-small cell lung cancer (aNSCLC) conducted after 2011 and ECAs derived from observational data. Participants were eligible individuals diagnosed with aNSCLC between January 1, 2011, and March 1, 2020. After adjustment for measured baseline confounders, a prespecified QBA was conducted to address potential bias by known unmeasured and mismeasured confounders. The QBA relied on a synthesis of external evidence from a targeted literature search, randomized trial data, and clinician input. Hazard ratios from the original randomized trials were compared with those from their emulation based on ECA analyses. Analyses were completed from February 2022 to October 2023. Initiation of systemic therapies for aNSCLC. Hazard ratios for all-cause death. Sample sizes varied from 52 to 830 depending on the treatment group. The mean difference in the log hazard ratio estimates when using the original control arm vs the ECA for each trial was 0.247 in unadjusted analyses (ratio of hazard ratios, 1.36), 0.139 when adjusted for measured confounders (ratio of hazard ratios, 1.22), and 0.098 when adding external adjustment for unmeasured and mismeasured confounders (ratio of hazard ratios, 1.17). QBA was feasible and informative in ECA analyses in which residual confounding was expected to be the most important source of bias. These findings encourage further exploration of how QBA can help quantify the impact of bias in other settings and when using other data sources.
Dynamic ctDNA informs whole-course postoperative precise management of NSCLC (LUNGCA study)
Authors: Liang Xia, Qiang Pu, Ran Kang, Jiandong Mei, Lu Li, Ying Yang, Senyi Deng, Gang Feng, Yulan Deng, Fanyi Gan, Yidan Lin, Lin Ma, Feng Lin, Yong Yuan, Yang Hu, Chenglin Guo, Hu Liao, Chengwu Liu, Yunke Zhu, Wenping Wang, Zheng Liu, Yuyang Xu, Kaidi Li, Chuan Li, Weizhi Chen, Qingyun Li, Bo Du, Xiaolong Zhang, Yingli Kou, Yun Wang, Zhu Wu, Guowei Che, Yaohui Chen, Shensi Shen, Longqi Chen, Dan Xie, Lunxu Liu
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Background Circulating tumor DNA (ctDNA) is valuable for detecting minimal residual disease (MRD). However, studies involving long-term blood sampling are required to comprehensively interpret the clinical use of ctDNA analyses. Methods We conducted a prospective multicenter cohort study (LUNGCA) for dynamic ctDNA monitoring in lung cancer patients receiving curative-intent surgery. ctDNA analysis was conducted on preoperative plasma samples, at postoperative three days and one month, and then every three–six months for up to three years. Results 233 non-small cell lung cancer (NSCLC) patients and 2336 longitudinal plasma samples were included; the median follow-up was 51.4 months. Post-comprehensive treatment (after radical surgery + necessary adjuvant therapy) MRD status was better at predicting relapse than postoperative MRD status (positive predictive value: 100% vs 90.0%; negative predictive value: 90.3% vs 90.1%). Patients with positive pre-adjuvant ctDNA and targetable mutations in tumor tissues had improved recurrence-free survival (RFS) with corresponding adjuvant TKI treatment [hazard ratio (HR) = 0.01, P = .005], but adjuvant chemotherapy failed to improve RFS (HR = 0.6, P = .491). Of patients receiving adjuvant therapies, patients with a negative- or positive-negative ctDNA change pattern had favourable and similar RFS (P = .419), whereas patients with a positive- or negative-positive pattern had worse RFS (P &amp;lt; .001). TKI therapy was more effective than chemotherapy in clearing ctDNA. Post-relapse ctDNA negativity was associated with favorable OS (HR = 0.4; P = .029). Conclusions Comprehensive interpretation of dynamic ctDNA monitoring data can inform precise whole-course postsurgical management of NSCLC patients.
Mild or moderate hemophilia is not always a mild or moderate bleeding disorder: Back to the clinical phenotype
Authors: Francesco Rodeghiero, Lisanna Ghiotto, Luca Pontalto, Alessandro Casini, Giancarlo Castaman, Rezan Abdul‐Kadir, Erik Berntorp, Imre Bodó, Manon Degenaar‐Dujardin, Karin Fijnvandraat, Paolo Gresele, Nigel S. Key, Riitta Lassila, Frank W. G. Leebeek, David Lillicrap, Mike Makris, Stephan Meijer, Diego Mezzano, Patrizia Noris, Ingrid Pabinger, Margaret V. Ragni, David Silva, Alok Srivastava, Alberto Tosetto, Jerzy Windyga, Barbara Zieger
Journal: HemaSphere (2025)

Abstract In a previous paper, a comprehensive clinicopathologic approach to mild and moderate bleeding disorders (MBD) was proposed by an international working group (IWG) as a part of a project promoted by the European Hematology Association (EHA) on the development of guidelines on the various MBDs. A single pre‐diagnosis grade 4 bleeding event according to the ISTH‐BAT scale or a comparable event after diagnosis was considered sufficient to classify a patient as affected by a severe bleeding disorder (SBD). In this article, the original IWG integrated by experts and patients' representatives proposed by the European Haemophilia Consortium (EHC) and European Association of Haemophilia and Allied Disorders (EAHAD) applied these criteria to mild and moderate hemophilia A and B to establish the proportion of cases that would be reclassified as SBD taking into account bleeding phenotype, thus improving over the current classification based exclusively on basal factor VIII or IX level. To this aim, publications of unselected cases with bleeding history available from birth to the time of publication were considered to estimate the incidence of a first severe bleeding event. More than 20% of cases with mild or moderate hemophilia met the criteria for SBD by experiencing joint or non‐joint severe bleeding events. Furthermore, a significant proportion of patients developed an inhibitor against factor VIII or IX. These results, based on a rigorous methodologic approach, substantiate the criticism of the current classification of hemophilia and argue for the adoption of a new classification that takes into account bleeding phenotype in addition to basal clotting activity.
Diffusion‐Patterned Multi‐Component Supramolecular Gels Loaded with Gold Nanoparticles Direct Mesenchymal Stem Cell Growth and Differentiation
Authors: Chayanan Tangsombun, Amy Simpson, Paul G. Genever, David K. Smith
Journal: Advanced Healthcare Materials (2025)

This article describes a new fabrication method using simple paper stamps to pattern gold nanoparticles (AuNPs) in a hybrid hydrogel, creating multi-domain gels in which different domains have different cell compatibilities. Soaking a paper stamp in AuCl3 solution, and placing it on top of the gel, allows diffusion of Au(III) from the paper into the gel to create a patterned domain within the gel in which AuNPs are formed, with spatial resolution on the millimeter length-scale. The gels combine a low-molecular-weight gelator that chemically enables the in situ AuNP patterning and offers mesenchymal stem cell (MSC) compatibility with a rheologically stiff polymer gelator. Only the AuNP-loaded domains support MSC proliferation on the multi-domain system, inducing cell spreading and promoting osteogenesis with a reproducible pattern. This simple approach therefore programs a soft supramolecular material, enabling it to achieve spatially-resolved biological outcomes, and may have applications in tissue engineering.