tbuckley/cabot-search huggingface dataset:
Organoid‐Guided Precision Medicine: From Bench to Bedside
Authors: Boqaing Tao, Xiaolan Li, Ming Hao, Tian Tian, Yuyang Li, Xiang Li, Chun Yang, Qirong Li, Qiang Feng, Hengzong Zhou, Yicheng Zhao, Dongxu Wang, Weiwei Liu
Journal: MedComm (2025)

ABSTRACT Organoid technology, as an emerging field within biotechnology, has demonstrated transformative potential in advancing precision medicine. This review systematically outlines the translational trajectory of organoids from bench to bedside, emphasizing their construction methodologies, key regulatory factors, and multifaceted applications in personalized healthcare. By recapitulating physiological architectures and disease phenotypes through three‐dimensional culture systems, organoids leverage natural and synthetic scaffolds, stem cell sources, and spatiotemporal cytokine regulation to model tissue‐specific microenvironments. Diverse organoid types—including skin, intestinal, lung, and tumor organoids—have facilitated breakthroughs in modeling tissue development, drug efficacy and toxicity screening, disease pathogenesis studies, and patient‐tailored diagnostics. For instance, patient‐derived tumor organoids preserve tumor heterogeneity and genomic profiles, serving as predictive platforms for individualized chemotherapy responses. In precision medicine, organoid‐guided multiomics analyses identify actionable biomarkers and resistance mechanisms, while clustered regularly interspaced short palindromic repeats‐based functional screens optimize therapeutic targeting. Despite preclinical successes, challenges persist in standardization, vascularization, and ethical considerations. Future integration of artificial intelligence, microfluidics, and spatial transcriptomics will enhance organoid scalability, reproducibility, and clinical relevance. By bridging molecular insights with patient‐specific therapies, organoids are poised to revolutionize precision medicine, offering dynamic platforms for drug development, regenerative strategies, and individualized treatment paradigms.
Clinical Characteristics of Difficult‐To‐Treat Allergic Bronchopulmonary Aspergillosis and Its Prediction Score
Authors: Jun Tanaka, Tsuyoshi Oguma, Takashi Ishiguro, Hirokazu Taniguchi, Teruaki Nishiuma, Hiroki Tateno, Hisako Matsumoto, Naoki Koshimizu, Yutaka Ito, Kazuto Matsunaga, Hidekazu Matsushima, Yoshitaka Uchida, Koshi Yokomura, Hirotaka Yasuba, Junko Suzuki, Shigeaki Hattori, Naoki Okada, Katsuyoshi Tomomatsu, Koichiro Asano
Journal: Allergy (2025)

ABSTRACT Background and Objective Administration of oral corticosteroids and/or azole antifungals for 4–6 months remains the standard treatment for allergic bronchopulmonary aspergillosis (ABPA). This study investigated the clinical characteristics of patients with difficult‐to‐treat ABPA who failed to achieve clinical remission within 6 months. Methods Among the participants of a nationwide survey conducted in Japan in 2020, treatment‐naïve patients with ABPA who satisfied Asano's criteria were enrolled in this study. Clinical remission was defined as stable disease without exacerbation for ≥ 6 months under minimal treatment (oral prednisolone: ≤ 5 mg/day and no antifungal medication). A risk prediction score for difficult‐to‐treat ABPA was developed and validated in an independent cohort comprising patients with ABPA from a prospective registration study in Japan. Results In total, 316 treatment‐naïve patients with ABPA were enrolled in the study. The median time to minimal treatment status was 4.8 months in the group receiving standard treatment. The clinical remission rate at 6 months after standard treatment was 51%. Age ≤ 50 years at onset of ABPA ( p = 0.04), serum A. fumigatus ‐specific IgE titer of ≥ 20 U A /mL ( p = 0.006), positive culture for Aspergillus spp. in the sputum/bronchial lavage fluid ( p = 0.05), and presence of high attenuation mucus (HAM; p = 0.10) were associated with difficult‐to‐treat ABPA. The number of positive indicators indicated the risk of failure of standard treatment to yield clinical remission within 6 months in the derivation ( n = 87, p &lt; 0.001) and validation ( n = 64, p = 0.009) cohorts. Conclusion Multiple components, including age at onset, allergic sensitization, airway fungal burden, and HAM, were associated with difficult‐to‐treat ABPA.
Amphiregulin Mediates Epithelial Cell–Eosinophil Interactions and Amplifies Inflammation in Chronic Rhinosinusitis With Nasal Polyps
Authors: Limin Zhao, Shujian Zhang, Yuling Zhang, Yingyue Liu, Yushi Guo, Yan Li, Qiqi Wang, Zaichuan Wang, Zhennan Qu, Nan Zhang, Claus Bachert, Chengshuo Wang, Luo Zhang, Feng Lan
Journal: Allergy (2025)

ABSTRACT Background Eosinophils easily accumulate in the intra‐epithelial layer and subepithelial regions in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). While several factors influence the migration of eosinophils from peripheral blood to extravascular tissues, the triggers and role of eosinophils near the epithelial layer in CRSwNP remain unclear. Methods We examined interactions between eosinophils and epithelial cells using co‐culture systems. We assessed the expression of amphiregulin (AREG) in CRSwNP epithelial cells and investigated its impact on epithelial barrier function, eosinophil activation, and migration. These effects were further validated in a CRSwNP mouse model treated with an AREG‐blocking antibody. Results Co‐culturing blood eosinophils and primary epithelial cells from CRSwNP patients decreased tight junction expression and increased eosinophil activation. Epithelial cells from ECRSwNP patients expressed higher levels of AREG than those from non‐eosinophilic CRSwNP (non‐ECRSwNP) patients, particularly in basal cells. As measured in the culture medium by ELISA, both blood eosinophils and primary epithelial cells automatically secreted AREG. Our in vitro experiments demonstrated that AREG impaired epithelial barrier function and facilitated eosinophil migration and activation. Confirmatory studies in a CRSwNP mouse model indicated that blocking AREG reduced the number of nasal polyp‐like lesions, mucosal thickness, and eosinophil infiltration, while restoring the expression of tight junction proteins. Conclusion The upregulation of AREG triggers eosinophil migration and mediates the interaction between epithelial cells and eosinophils, thereby enhancing chronic inflammation in CRSwNP. Our study highlights the therapeutic potential of anti‐AREG antibodies in CRSwNP, offering a promising strategy for treating human eosinophilic sinus diseases.
Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire
Authors: Leonie Rosenberger, Leo Hansmann, Vasiliki Anastasopoulou, Steven P Wolf, Kimberley Drousch, Christina Moewes, Xinyi Feng, Guoshuai Cao, Jun Huang, Poh Yin Yew, Erlend Strønen, Taigo Kato, Naresha Saligrama, Johanna Olweus, Yusuke Nakamura, Gerald Willimsky, Thomas Blankenstein, Hans Schreiber, Matthias Leisegang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient’s cancer-specific T cells. Methods Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K b -presented neoantigen p68 S551F (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided. Results We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4 R24L . Conclusions We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.
Targeting nerve growth factor: an Achilles’ heel for tumors?
Authors: Elizabeth Repasky, Hemn Mohammadpour
Journal: Journal for ImmunoTherapy of Cancer (2025)

A tumor’s ability to attract innervation is a critical factor in tumor progression and immune escape, with the sympathetic nervous system playing a major role. Catecholamines released by sympathetic nerves activate adrenergic receptors on tumor cells, enhancing growth and resistance to therapies, while activation of adrenergic receptors on immune cells triggers immunosuppressive activity in the tumor microenvironment. Nerve growth factor (NGF) produced by tumor cells is a key driver of tumor innervation, making it a promising target for novel therapeutic strategies. In this commentary, we highlight a recent study by Yang et al , which examines NGF single-chain variable fragment (scFv)-secreting chimeric antigen receptor(CAR) T cells and the impact of NGF neutralization by CAR T cells on CAR T-cell function and the remodeling of the tumor microenvironment. This work shows that we may be able to exploit a tumor-derived survival factor as a vulnerability and a means to enhance antitumor immune activity.
FMO2<sup>+</sup>cancer-associated fibroblasts sensitize anti-PD-1 therapy in patients with hepatocellular carcinoma
Authors: Wenxin Xu, Jialei Weng, Yufei Zhao, Peiyi Xie, Minghao Xu, Shaoqing Liu, Qiang Yu, Mincheng Yu, Bugang Liang, Junbo Chen, Hui-Chuan Sun, Hui Li, Qinghai Ye, Yinghao Shen
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear. Methods A specific CAF subset was identified by integrating comprehensive single-cell RNA sequencing, spatial transcriptomics and transcriptome profiling of patients with HCC with different responses to antiprogrammed cell death protein 1 (anti-PD-1) therapy. Mouse orthotopic HCC models and a coculture system were constructed, and cytometry by time-of-flight analysis was performed to investigate the functions and mechanisms of specific CAFs in the immune context of HCC. Results We identified a distinct flavin-containing monooxygenase 2 (FMO2) + CAF subset associated with a favorable response to anti-PD-1 therapy and better clinical outcomes. FMO2 + CAFs increase anti-PD-1 treatment efficacy by promoting tertiary lymphoid structure formation and increasing the infiltration of CD8 + T cells and M1-like macrophages through the C-C motif chemokine ligand 19 (CCL19)-C-C motif chemokine receptor 7 axis. Mechanistically, FMO2 promotes nuclear factor kappa B/p65-mediated CCL19 expression by competitively binding to glycogen synthase 1 (GYS1) with praja ring finger ubiquitin ligase 1 (PJA1), thereby suppressing the PJA1-mediated proteasomal degradation of GYS1. CCL19 treatment potentiated the therapeutic efficacy of anti-PD-1 therapy in mouse orthotopic HCC models. A favorable immunotherapy response was observed in patients with HCC with high serum levels of CCL19. Conclusions We identified a novel FMO2 + CAF subset that serves as a critical regulator of microenvironmental immune properties and a predictive biomarker of the immunotherapy response in patients with HCC. CCL19 in combination with anti-PD-1 therapy may constitute a novel therapeutic strategy for HCC.
B4GALT5 inhibits CD8<sup>+</sup>T-cell response by downregulating MHC-I level through ERAD pathway in PDAC
Authors: Xin Xing, Shi-Qi Yin, Xia-Qing Li, Hui Li, Hong-Tai Ma, Aziguli Tulamaiti, Shu-Yu Xiao, Yu-Tong Liu, Hao Zhang, Zhigang Zhang, Yan-Miao Huo, Xiao-Mei Yang, Yan Yang, Xue-Li Zhang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic target. Methods We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8 + T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) levels. Results Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8 + T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8 + T cells. Conclusions B4GALT5 impairs CD8 + T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.
Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy
Authors: Lisa K Poppe, Nicholas Roller, Miriam Marlene Medina-Enriquez, Wiem Lassoued, Daniel Burnett, Katherine E Lothstein, Asma S Khelifa, Masaya Miyamoto, James L Gulley, Caroline Jochems, Jeffrey Schlom, Sofia R Gameiro
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Human papillomavirus (HPV)-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced-stage disease. Despite improved outcomes with programmed cell death protein-1 (PD-1) targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in preclinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either αPD-1 or the class I histone deacetylase inhibitor Entinostat. Methods Mice bearing HPV16 + , αPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either αPD-1 or Entinostat to determine antitumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and single-cell RNA sequencing with T-cell receptor (TCR) enrichment. Results Combination of HPV vaccine and NHS-IL12 with either Entinostat or αPD-1 yielded significant antitumor activity and prolonged survival in αPD-1 refractory models of HPV16 + cancer, with superior activity employing Entinostat versus αPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8 + T-cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8 + T-cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were paralleled by strong differentiation of tumor-associated macrophages (TAMs) towards pro-inflammatory, antitumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8 + T cells and TAMs conducive to tumor control. A biomarker signature reflecting the preclinical findings was found to be associated with improved survival in patients with HPV-associated malignancies. Conclusion Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.
RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity
Authors: Hui Guo, Jie Hu, Zining Wang, Feifei Xu, Yongxiang Liu, Lei Cui, Huanling Zhang, Chunyuan Xie, Ruhui Yao, Huan Jin, Zixuan Guo, Tiantian Wang, Lin Li, Yanxun Lin, Xiaojuan Wang, Heping Li, Xiaojun Xia
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Natural killer (NK) cells are recognized for their ability to kill tumor cells for tumor control, but tumor cells often develop resistance to evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which tumor cells evade from NK cell-mediated killing may offer novel therapeutic strategies for potentiating NK-based cancer immunotherapy. Methods An in vitro tumor-NK cell co-culture system was employed to identify the most significantly altered genes in tumor cells following NK cell interaction. The cell death rate of tumor cells by NK cell exposure was quantified using flow cytometry. EL4 and HCT116 tumor models in C57BL/6, BALB/c-nu, and NOD/SCID mice were used for evaluating tumor growth differences induced by Rac2 knockdown or knockout. The cellular and molecular impact of Rac2 knockdown or knockout on the sensitivity of tumor cells to NK cell-mediated cytotoxicity was assessed using quantitative PCR, immunofluorescence, and mutation analysis. Results By screening expression levels of the Ras homology (Rho) GTPase family genes in tumor cells after co-culture with NK cells, we identified RAC2 as a key regulator of tumor cell resistance to NK cell-mediated cytotoxicity among the Rho GTPase family members. Furthermore, knockout of RAC2 in human colorectal cancer cells leads to increased tumor susceptibility to NK cell-mediated cytotoxicity in a xenograft tumor model. Mechanistically, the absence of RAC2 enhances tumor cell sensitivity to NK cell-mediated killing by facilitating cell–cell contact. Conclusions These findings indicate that the inhibition of RAC2 in tumor cells substantially enhances their susceptibility to NK cell-mediated cytotoxicity, thereby providing a potential therapeutic target for optimizing NK cell therapy.
Effect of long‐term voclosporin treatment on renal histology in patients with active lupus nephritis with repeat renal biopsies
Authors: Brad H. Rovin, Clarissa Cassol, Samir V. Parikh, Amit Saxena, Neil Solomons, Vanessa Birardi, Ernie Yap, Clint W. Abner, David R.W. Jayne, Robert B. Huizinga
Journal: Arthritis & Rheumatology (2025)

Objective This study characterized the impact of voclosporin on kidney histology in patients with lupus nephritis (LN) who had protocolized repeat kidney biopsies in the AURORA clinical trials. Methods Patients were randomized to voclosporin or placebo treatment for up to three years; all patients received mycophenolate mofetil and low‐dose glucocorticoids. Patients had baseline kidney biopsies within 6 months prior to study start and repeat biopsies after approximately 18 months of study treatment. The revised NIH indices for LN activity (AI) and chronicity (CI) were calculated, in addition to semi‐quantitative assessment of vascular and tubular lesions. Results Sixteen patients in the voclosporin group and 10 patients in the control group had both baseline and repeat kidney biopsies. Patient clinical characteristics were similar at baseline. In the voclosporin group, most (n=13) patients had pure class IV lesions (pure class V, n=1; mixed, n=2). In the control group, three patients had pure class IV (pure class III, n=3; pure class V, n=1; mixed, n=3). Most of the voclosporin‐treated patients had no change in CI (n=8) or a change ≤2 (n=6); control‐treated patients also had no change in CI (n=3) or a change ≤2 (n=6). No trends in vascular lesions or tubular compartment changes were observed. Conclusion Outcomes from this small subgroup show exposure to study treatment was not associated with nephrotoxicity based on histopathologic evaluation after 18 months. These data are reassuring and further contribute to the safety profile of voclosporin for the treatment of adults with active LN.
Incidence, case-fatality rates and risk factors of bloodstream infections caused by Escherichia coli, Klebsiella species and Pseudomonas aeruginosa, England, April 2017 to March 2022
Authors: Olisaeloka Nsonwu, Simon Thelwall, Sarah Gerver, Rebecca L Guy, Dimple Chudasama, Russell Hope
Journal: Eurosurveillance (2025)

Background Escherichia coli , Klebsiella spp. and Pseudomonas aeruginosa are included in the mandatory surveillance of bloodstream infections (BSI) in England. Aim We aimed to investigate the epidemiology of these BSIs in England April 2017–March 2022. Methods We extracted data on E. coli , Klebsiella spp. and P. aeruginosa BSI, categorised BSIs as healthcare-associated (HA) or community-associated (CA) and linked to antimicrobial susceptibility and mortality data. We used multivariable logistic regression models to assess predictors of mortality. Results The incidence rate of E. coli BSI was 71.8 per 100,000 population (95% confidence interval (CI): 71.5–72.1), Klebsiella spp. 19.1 (95% CI: 18.9–19.3) and P. aeruginosa 7.6 (95% CI: 7.5–7.7). Most (65,467/104,957) BSI episodes were CA. Case-fatality rate was 14.8% (95% CI: 14.6–14.9) in E. coli , 20.0% (95% CI: 19.6–20.3) in Klebsiella spp. and 25.8% (95% CI: 25.2–26.4) in P. aeruginosa BSI. Urinary tract infection (UTI) was the most reported primary infection for E. coli (56,961/100,834), Klebsiella spp. (9,098/22,827) and P. aeruginosa (3,204/8,484) BSI. Insertion or manipulation of urinary catheters was reported for 26.4% (16,136/61,043) of E. coli , 41.6% (4,470 /10,734) of Klebsiella spp. and 49.0% (2,127/4,341) of P. aeruginosa BSI. The adjusted odds ratio (OR) of death among hospital-onset HA-BSI compared to CA-BSI was 2.0 (95% CI: 1.9–2.2) for E. coli , 2.1 (95% CI: 2.0–2.3) for Klebsiella spp. and 1.7 (95% CI: 1.5–2.0) for P. aeruginosa . Conclusions Appropriate management of UTIs and urinary catheterisation is essential for reduction of these BSIs.