tbuckley/cabot-search huggingface dataset:
Incidence of Metastasis in the Central Nervous System in Advanced Breast Cancer Treated With CDK 4/6 Inhibitors: A Multicenter, Retrospective Study
Authors: Yan‐Ling Wen, Xi‐Wen Bi, Xue‐Wen Zhang, Si‐Fen Wang, Chang Jiang, Li Wang, Yong‐Yi Zhong, Yuan‐Yuan Huang, Jian‐Li Zhao, Qian‐Jun Chen, Cong Xue, Zhong‐Yu Yuan
Journal: MedComm (2025)

Abstract Central nervous system (CNS) metastasis remains a major cause of mortality in advanced breast cancer (ABC). While cyclin‐dependent kinase 4/6 inhibitors (CDKIs) combined with endocrine therapy (ET) delay resistance in hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative ABC, their impact on CNS metastasis development has not been fully elucidated. This retrospective study analyzed 435 ABC patients without baseline CNS metastases who received first‐line ET with or without CDKIs across three Chinese hospitals (August 2018–July 2022). Primary end points included CNS as the first metastatic site, CNS metastasis‐free survival (CNSM‐FS), and CNS metastasis incidence over time. Secondary end points were progression‐free survival (PFS) and overall survival (OS). The results indicated that the addition of CDKIs to ET significantly reduced the incidence of CNS as the first site of metastasis (3.7% vs. 9.5% with ET alone; p = 0.0015) and extended CNSM‐FS (71.6 months vs. 63.6 months, respectively; hazard ratio [HR], 0.53; 95% CI, 0.31–0.92). Overall, CNS metastasis incidence was lower with ET + CDKIs (7.9% vs. 15.5%, p = 0.014), and improvements were observed in both PFS and OS. These findings suggest that ET + CDKIs as first‐line therapy in ABC may reduce CNS metastasis risk and extend CNSM‐FS, offering a potential strategy for preventing CNS metastases.
Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62‐Modulated Mitophagy in Hepatocellular Carcinoma
Authors: Yingying Shao, Di Lu, Wenke Jin, Sibao Chen, Lifeng Han, Tao Wang, Leilei Fu, Haiyang Yu
Journal: MedComm (2025)

ABSTRACT Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small‐molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi‐omics approaches, indicating that inhibition of LIF would be a promising therapeutic strategy. Inhibiting LIF could suppress proliferation and metastasis by activating p38MAPK/p62‐modulated mitophagy. Interestingly, we found that the natural small‐molecule Cyclovirobuxine‐D (CVB‐D), was a new inhibitor of cytoplasmic LIF in HCC. We further validated LIF as a potential target of CVB‐D through biotin‐modified CVB‐D‐Probe utilizing mass spectrometry. Mechanistically, we showed that CVB‐D could bind to LIF at Val145, thereby inducing mitophagy, accompanied by cell cycle arrest and inhibition of invasion and migration. Moreover, we demonstrated that CVB‐D had a therapeutic potential by targeting LIF‐modulated mitophagy in patient‐derived xenograft (PDX) models, which would elucidate LIF as a druggable target and regulatory mechanisms and exploit CVB‐D as the novel small‐molecule inhibitor of LIF for future HCC drug discovery.
Phase II Trial of Hypofractionated Radiotherapy and Immunochemotherapy in Primary Refractory Diffuse Large B‐Cell Lymphoma: Preliminary Results and Insights from Digital Spatial Profiling
Authors: Yong Yang, Jing Yu, Xiao‐Mei Hu, Si‐Lin Chen, Rui‐Zhi Zhao, Cheng Huang, Jiang‐Rui Guo, Tian‐Lan Tang, Cheng Chen, Yu‐Ping Lin, Ying Wang, Tian‐Xiu Liu, Hao Zheng, Si‐Qin Liao, Jin‐Hua Chen, Hai‐Ying Fu, Ting‐Bo Liu
Journal: MedComm (2025)

ABSTRACT This open‐label, single‐arm phase II study assessed the safety and efficacy of sequential hypofractionated radiotherapy (RT) followed by zimberelimab and R‐GemOx (rituximab, gemcitabine, oxaliplatin) in patients with primary refractory diffuse large B‐cell lymphoma (DLBCL). Fourteen patients were enrolled between June 2022 and December 2023, with 13 included in the analysis. RT doses of 36 and 24 Gy were delivered to the gross and target volumes in 12 fractions, followed by zimberelimab and R‐GemOx. The overall response rate within the irradiated field was 92.3%, and a complete response (CR) was achieved by 61.5% of patients; however, 38.5% experienced disease progression. Treatment‐related toxicities were manageable, primarily comprising mild leukocytopenia. Digital spatial profiling revealed 53 differentially expressed genes in CD20‐rich lymphoma regions and 93 in CD3‐rich T cell regions in non‐CR patients. Reactome analysis identified key immune system pathways. T cell infiltration correlated with treatment efficacy, and multiplex immunohistochemistry validated immune pathways as potential therapeutic targets. This study demonstrated the promising role of RT combined with immunochemotherapy in refractory DLBCL and suggests immune pathways as critical targets to improve treatment outcomes.
Precise measurement of molecular phenotypes with barcode-based CRISPRi systems
Authors: Joseph H Lobel, Nicholas T Ingolia
Journal: Genome biology (2025)

Abstract Genome-wide CRISPR-Cas9 screens have untangled regulatory networks driving diverse biological processes. Their success relies on interrogating specific molecular phenotypes and distinguishing key regulators from background effects. Here, we realize these goals by optimizing CRISPR interference with barcoded expression reporter sequencing (CiBER-seq) to dramatically improve the sensitivity and scope of genome-wide screens. We systematically address technical factors that distort phenotypic measurements by normalizing expression reporters against closely matched promoters. We use our improved CiBER-seq to accurately capture known components of well-studied RNA and protein quality control systems. These results demonstrate the precision and versatility of CiBER-seq for dissecting cellular pathways.
Bacteroides uniformis-generated hexadecanedioic acid ameliorates metabolic-associated fatty liver disease
Authors: Da-Ya Zhang, Da Li, Shi-Ju Chen, Li-Jun Zhang, Xu-Li Zhu, Fa-Di Chen, Chen Chen, Qi Wang, Yiping Du, Jian-Xin Xiong, Shi-Mei Huang, Xiao-Dong Zhang, Yan-Ting Lv, Fan Zeng, Run-Xiang Chen, Xianfeng Huang, Fengjiao Mao, Shuo Zhou, Qicen Yao, Yuliang Huang, Runyu Chen, Ying Mo, Yunqian Xie, Yue-Hong Jiang, Zhai Chen, Cui-Yi Mo, Jia-Jia Chen, Fei-Hu Bai
Journal: Gut Microbes (2025)

Gut microbiota exerts a pivotal influence on the development of Metabolic Associated Fatty Liver Disease (MAFLD), although the specific contributions of individual bacterial strains and their metabolites remain poorly defined. We conducted stool shotgun metagenomic sequencing and plasma untargeted metabolomics in a large prospective cohort comprising 120 MAFLD patients and 120 matched healthy controls. The mechanisms and microbial-derived metabolites involved in MAFLD were further investigated through multi-omics analyses in vitro and in vivo. Distinct differences were identified in both the microbial community structure and metabolomic profiles between MAFLD patients and healthy controls. Bacteroides uniformis (B. uniformis) was the most significantly depleted species in MAFLD and negatively correlated with hepatic steatosis and BMI. MAFLD was characterized by marked disruptions in fatty acid and amino acid metabolism. Combined analysis of metabolomic and metagenomic data achieved high diagnostic accuracy for MAFLD and hepatic steatosis severity (AUC = 0.93). Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B. uniformis administration alleviate disease progression by inhibiting intestinal fat absorption, FFA from eWAT influx into liver via the gut-liver axis, and IRE1α-XBP1s-mediated flipogenesis and ferroptosis, as confirmed by hepatic transcriptomic and proteomic analyses. Hexadecanedioic acid (HDA), potentially identified as a key metabolite produced by B. uniformis, ameliorated MAFLD symptoms. Mechanistically, B. uniformis-derived HDA also inhibited fat absorption and transported, and entered the liver via the portal vein to suppress IRE1α-XBP1s-mediated flipogenesis and ferroptosis. B. uniformis and its potential putative metabolite HDA may contribute to MAFLD progression modulation, through regulation of the IRE1α-XBP1s axis. This study provides new insights into the gut-liver axis in MAFLD and offers promising therapeutic targets based on specific microbes and their metabolites.
Fecal microbiota transplantation from a healthy pouch donor for chronic pouchitis: a proof-of-concept study
Authors: Sabrina Just Kousgaard, Sebastian Mølvang Dall, Mads Albertsen, Hans Linde Nielsen, Ole Thorlacius-Ussing
Journal: Gut Microbes (2025)

Chronic pouchitis is a common complication after ileal pouch-anal anastomosis (IPAA) with limited treatment options. In this case series, we aimed to investigate clinical and microbiome changes, as well as adverse events, associated with using fecal microbiota transplantation (FMT) from a donor with a normal functioning IPAA to induce remission in patients with chronic pouchitis. Methods The study was a case-series including a 4-week intervention period and 12-month follow-up. Patients with chronic pouchitis who met the inclusion criteria were recruited from the Department of Gastrointestinal Surgery at Aalborg University Hospital, Denmark. Participants received FMT derived from a donor with a normal functioning IPAA. Treatment was administered by enema daily for two weeks, then every other day for two more weeks. Disease severity and quality of life (QoL) were accessed at baseline and 30-day follow-up. Clinical remission was defined as Pouchitis Disease Activity Index (PDAI) <7. Fecal samples from participants, healthy donors, and the IPAA donor were analyzed using shotgun metagenomic sequencing. Results Three patients with chronic pouchitis were included and completed the treatment protocol and follow-up visits. At the 30-day follow-up, all participants achieved clinical remission with reduced endoscopic inflammation. The median total PDAI score decreased from 8 (range 10-8) at baseline to 6 (range 6-5) at 30 days. Two participants reported improved QoL, while one reported no change. Few mild, self-limited adverse events were reported by all participants during treatment, with no serious events. Principal component analysis of fecal samples distinguished two clusters: healthy donors and the IPAA donor, with participant samples forming a separate cluster Conclusion We observed that all participants achieved clinical remission with reduced endoscopic inflammation following a 4-week FMT intervention. Adverse events were mild and self-limited. Metagenomic analysis revealed distinct microbiome clusters between IPAA donor and recipients, both of which differed from those of healthy donors.
Genetically engineered extracellular vesicles expressing decoy protein TACI provide a therapeutic effect in systemic lupus erythematosus mouse model
Authors: Menghua Cai, Feng Tian, Jingyi Han, Liang Wang, Shikai Hu, Peng Dong, Wenhua Qiao, Han Zhang, Yue Wang, Hui Chen, Wei He, Jianmin Zhang
Journal: Journal of Controlled Release (2025)

The suppression of B-cell activation and autoantibody production through immunotherapy has garnered substantial interest in advancing systemic lupus erythematosus (SLE) treatments. Although SLE patients do benefit from current therapies, no efficient therapeutic approaches are available to a substantial number of patients. In this study, we developed extracellular vesicles to express a fusion protein of the transmembrane activator and cyclophilin ligand interaction molecule (TACI). We performed a comprehensive functional evaluation, including in vitro binding assays and therapeutic efficacy assessments in a murine SLE model. Our findings demonstrate that the engineered extracellular vesicles stably express the TACI receptor, effectively bind the cytokine BLyS and inhibit the BCMA-NF-κB signaling pathway in vitro. In vivo, TACI-engineered small extracellular vesicles significantly attenuated SLE severity and reduced inflammatory kidney damage in SLE mice by blocking BLyS/APRIL signaling. Collectively, these findings highlight the therapeutic potential of TACI-engineered small extracellular vesicles as a novel approach to suppress autoimmunity, prolong survival, and ameliorate lupus nephritis in MRL/lpr mice.
Transarterial Chemoembolization plus Sorafenib versus Sorafenib Alone in Advanced Hepatocellular Carcinoma (SELECT): a Multicenter, Phase 3, Randomized, Controlled Trial
Authors: Yan Zhao, Wei Bai, Rong Ding, Nan You, Lin Zheng, Lei Li, Jianbing Wu, Peng Zhang, Wukui Huang, Hui Zhang, Yongjin Zhang, Diwen Zhu, Haiping Li, Dongdong Xia, Jie Yuan, Xiaomei Li, Zhengyu Wang, Bohan Luo, Wengang Guo, Zhanxin Yin, Wei Mu, Ming Huang, Jing Li, Weixin Ren, Daiming Fan, Yong Lv, Guohong Han
Journal: Liver Cancer (2025)

Introduction: Patients with advanced hepatocellular carcinoma (HCC) face an extremely poor prognosis. Sorafenib, a multikinase inhibitor, remains an essential treatment for advanced HCC in certain clinical settings where immunotherapy is either contraindicated or unavailable. However, the survival benefit of transarterial chemoembolization (TACE) plus sorafenib remains under investigation. Methods: The SELECT trial was a multicenter, randomized, controlled study conducted across twelve centers in China. From September 7, 2013, to December 4, 2019, 199 patients with advanced-stage HCC were randomly assigned in a 1:1 ratio to receive either TACE plus sorafenib or sorafenib monotherapy. Results: The median age of the study population was 55 years (IQR 46-63), with hepatic virus infection being the predominant cause of HCC. In the intention-to-treat (ITT) population, the overall survival (OS) analysis did not show a statistically significant difference between the combination and sorafenib monotherapy groups (14.9 months [95%CI 10.5-19.3] vs. 11.9 months [95%CI 9.0-14.8], HR 0.862, P=0.312). However, the combination therapy group demonstrated significantly improved time to progression (TTP) (10.0 months [95%CI 6.4-13.6] vs. 5.9 months [95%CI 3.1-8.7]; P=0.016) and post-hoc progression-free survival (PFS) (8.5 months [95%CI 6.7-10.3] vs. 5.6 months [95%CI 4.1-7.1]; P=0.034). In predefined per-protocol analysis, the combination therapy group showed a significantly longer median OS compared to the monotherapy group (14.6 months [11.3-17.9] vs. 7.4 months [95%CI 4.3-10.5], HR 0.539, P=0.001). Conclusion: Although the combination of TACE and sorafenib did not demonstrate a significant improvement in OS in the ITT analysis, it met the secondary endpoints, including TTP and post-hoc PFS. These findings provide valuable insights for the design of future trials and highlight the importance of integrating locoregional interventions with systemic therapies in the management of advanced-stage HCC.
In vivo FAP-CAR macrophages enhance chemotherapy and immunotherapy against pancreatic cancer by removing the fibrosis barrier
Authors: Wenguang Wang, Kaiyuan Hu, Junjie Xue, Jingyi Chen, Xiuli Du, Tian Zhao, Yiwei Chen, Xinying Tang, Lu Xu, Xinbao Hao, Xianjing Li, Yong Yang
Journal: Journal of Controlled Release (2025)
Osteomodulin modulates the inflammatory responses via the interleukin-1 receptor 1/nuclear factor-κB signaling pathway in dental pulpitis
Authors: Yueyi Yang, Xuchen Hu, Meiling Jing, Xiaohan Zhu, Xiaoyu Liu, Wenduo Tan, Zhanyi Chen, Chenguang Niu, Zhengwei Huang
Journal: International Journal of Oral Science (2025)

Abstract Pulpitis is a common infective oral disease in clinical situations. The regulatory mechanisms of immune defense in pulpitis are still being investigated. Osteomodulin (OMD) is a small leucine-rich proteoglycan family member distributed in bones and teeth. It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells (hDPSCs). In this study, the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated. The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining. Intriguingly, the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens. The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide (LPS)-induced inflammation. A conditional Omd knockout mouse model with pulpal inflammation was established. LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice, whereas OMD administration exhibited a protective effect against pulpitis. Mechanistically, the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB (NF-κB) signaling pathway. Interleukin-1 receptor 1 (IL1R1), a vital membrane receptor activating the NF-κB pathway, was significantly downregulated in OMD-overexpressing hDPSCs. Additionally, the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking. In vivo, excessive pulpal inflammation in Omd -deficient mice was rescued using an IL1R antagonist. Overall, OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway. OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis
Authors: Linfei Huang, Meng Wei, Huilong Li, Mingxin Yu, Luming Wan, Ruzhou Zhao, Qi Gao, Lijuan Sun, Xufeng Hou, Yunhai Mo, Qing Huang, Lan Zhen, Xiaopan Yang, Jingfei Li, Nan Wang, Chundong Zhang, Haoran Jin, Li Zhou, Yixin Xu, Haotian Lin, Xuhui Zhang, Boan Li, Yue Han, Jing Yuan, Rui Zhang, Feixiang Wu, Hui Zhong, Congwen Wei
Journal: Molecular Cancer (2025)

Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.
Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease
Authors: Lina Zhang, Cortney Cagle, Du Hanh Nguyen, Graziela Scheuer Gomes, Barbora Gromova, Eva Csizmadia, Arian Karimitar, Ghee Rye Lee, Guanqing Chen, Efi Kokkotou, Laurie Grossberg, Sizun Jiang, Adam S Cheifetz, Satya K Kota, Maria Serena Longhi
Journal: Cellular and Molecular Immunology (2025)
NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma
Authors: Bin Gong, Yahui Liu, Weiwei Yan, Chao Cheng, Huiling Yang, Jiyu Huang, Qing Liu, Yuyan Liu, Jiankang Guo, Xiaojie Deng, Beixian Zhou, Dayong Zheng, Xiong Liu, Zhen Liu, Weiyi Fang
Journal: Molecular Cancer (2025)

Nucleosome assembly protein 1-like 1 (NAP1L1) has been implicated in promoting tumor cell proliferation. However, its role in regulating autophagy in tumors, including nasopharyngeal carcinoma (NPC), remains unclear. In this study, we observed that autophagy-inducing agents reduced NAP1L1 protein levels without affecting its mRNA expression. Reduced NAP1L1 enhanced autophagosome formation and maturation, thereby promoting cisplatin (DDP) chemosensitivity in both in vitro and in vivo NPC models. Mechanistically, reduced NAP1L1 impaired the recruitment of ubiquitin-specific protease 14 (USP14), limiting the deubiquitination of heparin-binding growth factor (HDGF) and decreasing HDGF protein levels. In turn, reduced HDGF suppressed USP14-mediated p62 deubiquitination, leading to further declines in p62 protein levels. Notably, the F-box and WD repeat domain-containing protein 7 (FBXW7), an inhibitory E3 ubiquitin ligase, directly interacted with and ubiquitinated NAP1L1, promoting its degradation. This degradation triggered NPC autophagy and enhanced DDP chemosensitivity by disrupting NAP1L1-induced HDGF/p62 signaling. Clinically, NAP1L1 protein expression was inversely correlated with FBXW7 levels in NPC tissue samples. Patients exhibiting high NAP1L1 and low FBXW7 levels had the poorest DDP chemosensitivity and survival outcomes. Our findings demonstrate that FBXW7-mediated NAP1L1 degradation suppresses HDGF-p62 signaling, thereby inducing autophagy and enhancing DDP chemosensitivity. These results underscore the potential of NAP1L1 and FBXW7 as therapeutic targets for NPC treatment.
Approved trends and product characteristics of digital therapeutics in four countries
Authors: Jun Liang, Qichuan Fang, Xiaoyi Jiao, Peng Xiang, Junhao Ma, Zijiao Zhang, Yongcheng Liu, Yunfan He, Yingjun Li, Zhixu He, Jianbo Lei
Journal: npj Digital Medicine (2025)

Digital therapeutics (DTx) provide innovative treatment options. In this study, we identified and compared approved DTx in China, the US, Germany, and Belgium. In total, 507 DTx applications were identified (US, 192; China, 235; Germany, 55; Belgium, 25). China has approved the most, whereas the US initiated approval as early as 2017. In China, most DTx applications focus on disease treatment (88.09%), particularly for neurological (45.96%) and ophthalmic (21.28%) diseases. The US and Belgium emphasize disease management (US: 52.60%, Belgium: 72.00%), whereas Germany focuses on the treatment of mental and behavioral disorders (47.27%). Regarding therapeutic approaches, China's DTx predominantly utilizes computerized cognitive correction (26.38%), whereas the US and Belgium primarily rely on health status monitoring (US, 44.27%; Belgium, 80.00%). Germany's DTx primarily employs cognitive behavioral therapy (69.09%). An online database was established to ensure ease of access. Future studies should focus on generating further evidence to support the broader adoption of DTx.
Nonhypermutator Cancers Access Driver Mutations Through Reversals in Germline Mutational Bias
Authors: Marwa Z Tuffaha, David Castellano, Claudia Serrano Colomé, Ryan N Gutenkunst, Lindi M Wahl
Journal: Molecular Biology and Evolution (2025)

Abstract Cancer is an evolutionary disease driven by mutations in asexually reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Nonhypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and nonhypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and nonhypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.