Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignancy. Although the R-CHOP regimen has significantly improved the prognosis for most patients, a subset continues to experience poor therapeutic outcomes. Recent studies have highlighted the role of the nervous system in cancer, yet its impact on DLBCL remains unclear. In this study, 21 neuro-related (NR) genes were identified from the Gene Ontology database, and a prognostic risk scoring model for DLBCL was developed and validated across multiple cohorts. The NR-based score effectively stratified patients according to survival outcomes. The high NR score group was characterized by an immunosuppressive microenvironment, activation of pro-proliferative pathways, and increased mutation frequencies of oncogenes such as TP53 and MYC. In contrast, the low NR score group exhibited enriched inflammatory responses and immune activation signals. The key gene TRPV2, associated with favorable prognosis, was found to promote M1-like polarization in monocytes/macrophages and enhance antigen presentation in B cells. This study establishes the NR risk score as a novel prognostic tool for DLBCL and underscores neuro-immune interactions as potential therapeutic targets.

Importance:Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. Objective:To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. Design, Setting, and Participants:This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. Interventions:Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. Main Outcomes and Measures:The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. Results:Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. Conclusions and Relevance:Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. Trial Registration:ClinicalTrials.gov Identifier: NCT04231448.

BACKGROUND:During progressive kidney injury, pericytes and resident fibroblasts migrate, proliferate and differentiate into myofibroblasts, which are the major source of extracellular matrix deposition. Both interstitial fibroblasts and macrophages contribute to kidney fibrosis and coexist within the fibrotic niche. However, the potential interaction between fibroblasts and macrophages and its role in kidney fibrosis remains incompletely understood. Previous studies have indicated a role for kidney prostaglandins to limit fibroblast activity and myofibroblast transformation. METHODS:Inducible PDGFRß-Cre mice were crossed to the indicated floxed mice to selectively delete either cyclooxygenase 2 (COX-2) or the PGE2 receptors EP2 and EP4. Unilateral ureteral obstruction was utilized as a model of progressive kidney fibrosis. RESULTS:Selective deletion of cyclooxygenase-2 expression in fibroblasts (FibCOX-2-/-) increased kidney fibrosis in association with kidney macrophages with a proinflammatory and profibrotic phenotype. The highest differentially expressed gene in these macrophages was the profibrotic factor SPP1/osteopontin, and deletion of kidney macrophages with clodronate inhibited kidney expression of SPP1 and ameliorated fibrosis in FibCOX2-/- mice. CONCLUSIONS:Our findings suggest that fibroblast COX-2 protects against progressive kidney fibrosis, potentially through a regulatory interplay that modulates the surrounding macrophage phenotype during chronic kidney injury.

To investigate whether 18 F-FDG Positron Emission Tomography/Computed Tomography (PET/CT) and Flow Cytometry (FCM) can serve as alternatives to bone marrow biopsy (BMB) in diagnosing bone marrow involvement (BMI), prognostic prediction, and clinical application of mantle cell lymphoma (MCL). This retrospective analysis was conducted to assess the impact of PET/CT, FCM, and BMB results on BMI in 122 patients diagnosed with MCL who underwent PET/CT and bone marrow examinations, and 97 patients with complete survival data were included in the survival analysis. Taking BMB positive as the standard, the sensitivity of PET/CT was 57.4

Ubiquitin-specific protease 20 (USP20) belongs to the ubiquitin-specific protease (USP) family, which represents the largest subfamily of deubiquitinating enzymes. It plays a critical role in regulating cellular signaling transduction, maintaining protein stability, and influencing the development of various diseases. This study revealed that USP20 expression was significantly upregulated in transverse aortic constriction (TAC)-induced hypertrophic hearts and in angiotensin II (AngII)-stimulated neonatal rat cardiomyocytes (NRCMs). This study aims to investigate the potential protective role of USP20 deficiency in pressure overload-induced cardiac hypertrophy and to elucidate the underlying molecular mechanisms. Pathological cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) surgery. Following the procedure, relevant groups of mice were administered shUSP20 adenovirus via tail vein injection, with the TAC intervention lasting 28 days. The results showed that USP20 significantly exacerbated TAC-induced cardiomyocyte apoptosis and inflammatory responses, while simultaneously impairing cardiac function and aggravating myocardial hypertrophy. In vitro experiments further confirmed that USP20 markedly aggravated angiotensin II (AngII)-induced cardiomyocyte hypertrophy. Moreover, USP20 enhanced inflammatory responses and apoptosis levels in hypertrophic myocardium, as evidenced by increased levels of Bax, TNF-α, IL-6, and IL-1β, along with a decrease in Bcl2. Mechanistically, USP20 elevated the phosphorylation level of P65, and the protective effect of USP20 knockdown against AngII-induced cellular hypertrophy was further enhanced by co-treatment with the NF-κB inhibitor Bay11-7082. USP20 exacerbates cardiac hypertrophy by promoting P65 phosphorylation, which subsequently enhances the release of inflammatory cytokines and apoptotic proteins.

Diffuse large B-cell lymphoma (DLBCL) is biologically heterogeneous and is associated with variable clinical outcomes. We aimed to develop a tumor-associated macrophage (TAM)-related ferroptosis–glycolysis prognostic signature and to explore selected signature genes in preclinical models. This retrospective multi-cohort computational prognostic biomarker-development study integrated public single-cell and bulk transcriptomic datasets. GSE10846 was used for feature selection, model fitting, and parameter tuning, whereas GSE32918, GSE69051, and TCGA-DLBC were used as model-selection validation cohorts. Exploratory immune, genomic, and computational drug-sensitivity analyses were performed. Signature-gene expression was assessed in 27 archived DLBCL tissues, and GCLC and SLC1A5 were further examined in TAM-related preclinical models in vitro and in vivo. An 11-gene TAM-related ferroptosis–glycolysis signature (TAMFGS) was developed. The time-dependent AUCs (95

OBJECTIVE:To analyze the efficacy and safety of ifosfamide + vincristine + dexamethasone/etoposide + mitoxantrone (IVD/EM) regimen as maintenance therapy in adult patients with T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL). A total of 53 patients with T-LBL/ALL were enrolled, with a median age of 27 (range, 18-73) years and a male-to-female ratio of 2.5:1. Compared with the transplantation group, the 1‑, 3‑, and 5‑year progression‑free survival (PFS) rates in the alternating maintenance group were 77.8% vs 71.4%, 66.7% vs 64.8% and 58.3% vs 60.7%, respectively; the 1‑, 3‑, and 5‑year overall survival (OS) rates were 94.4% vs 74.3%, 66.2% vs 71.4% and 66.2% vs 71.4%, respectively. No statistically significant differences were observed in PFS and OS rates between the two groups (P = 0.908; P = 0.972). Although the recurrence rate in the maintenance group tended to be higher than that in the transplantation group (P = 0.129), non‑relapse mortality was significantly reduced in the alternating maintenance group (P = 0.046). Multivariate analysis demonstrated that male and elevated β2‑microglobulin levels were independent adverse factors for PFS in patients with T‑LBL/ALL (P < 0.05), while the presence of elevated β2-microglobulin levels at diagnosis was an independent prognostic factor for OS (P < 0.05). SAFETY:In terms of safety, adverse events in the alternating maintenance group were predominantly grade 1-2, and no treatment-related deaths were observed. CONCLUSION:The IVD/EM maintenance regimen is safe and effective in post-remission therapy for adult patients with T-LBL/ALL.

Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.

BackgroundHepatocellular carcinoma (HCC) is a highly aggressive primary liver malignancy characterized by limited therapeutic options and poor prognosis. Within the tumor microenvironment (TME), tumor-associated macrophages (TAMs) predominantly exhibit an M2-like phenotype, contributing to immune escape and tumor progression. Zymogen granule protein 16 (ZG16) has been reported to be downregulated in HCC, but its precise biological function and molecular mechanisms remain poorly understood. Therefore, we aimed to investigate the impact of ZG16 on HCC cell metastasis and TAM infiltration, as well as to elucidate its molecular mechanism.MethodsGain- and loss-of-function assays were used to verify the effect of ZG16 on HCC cell metastasis, as well as the recruitment and M2 polarization of TAMs. The underlying mechanism of ZG16 was explored by immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC/MS) analysis, co-immunoprecipitation (co-IP) assay, and GST pull-down assay.ResultsOur results demonstrated that ZG16 overexpression significantly inhibited metastasis of HCC cells while also suppressing the recruitment and M2 polarization of TAMs, suggesting its dual role in both tumor cell-intrinsic and microenvironmental regulation. Notably, sorting nexin 9 (SNX9), a facilitator of HCC, was identified as a downstream target of ZG16. Mechanistically, we uncovered that ZG16 physically interacted with SNX9 and promoted its protein degradation through the ubiquitin-proteasome pathway. Functional rescue experiments provided compelling evidence that SNX9 overexpression effectively counteracted ZG16-mediated suppression of both HCC progression and TAM M2 polarization. Further mechanism exploration confirmed that ZG16 promoted the ubiquitination and degradation of SNX9 by recruiting itchy E3 ubiquitin protein ligase (ITCH).ConclusionsOur findings certify that ZG16 suppresses tumor progression and M2 polarization of TAMs in HCC through ITCH-mediated ubiquitination and subsequent degradation of SNX9. The ZG16/ITCH/SNX9 axis may represent an important regulatory pathway and potential therapeutic target for HCC.

Follicular lymphoma (FL) is an indolent yet highly heterogeneous B-cell lymphoproliferative disorder. The introduction of CD20 monoclonal antibodies has significantly improved patient survival; however, the optimal therapeutic strategy for grade 3A FL remains controversial. The Ki-67 proliferation index may reflect tumor aggressiveness, but its prognostic and therapeutic implications are not fully established. This study aimed to evaluate the prognostic significance of Ki-67 expression and to develop a predictive model for progression-free survival (PFS) in patients with grade 3A FL. Clinical data from 110 patients with grade 3A FL were retrospectively analyzed. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for PFS. Kaplan-Meier survival analysis with log-rank tests was used to compare PFS between subgroups stratified by Ki-67 expression and treatment regimen. A nomogram-based predictive model was constructed and validated using the concordance index (C-index), calibration plots, and decision curve analysis (DCA). High Ki-67 expression (≥ 50

KEY POINTS:Discoidin domain receptor 1 (DDR1) translocated to the mitochondria of proximal tubule cells after AKI. DDR1 contributed to AKI by promoting the production of mitochondrial reactive oxygen species and cell apoptosis. Mechanistically, DDR1 translocated to mitochondria by interacting with Hsp60 and promoted oxidative stress by regulating phosphorylation of p66Shc. BACKGROUND:Mitochondrial damage with overproduction of mitochondrial reactive oxygen species (mtROS) and apoptosis is a hallmark of AKI. Discoidin domain receptor 1 (DDR1) is a collagen receptor tyrosine kinase that contributes to AKI. Mass spectrometry analysis of DDR1-interacting proteins identified several mitochondrial proteins, suggesting that DDR1 associated with mitochondria. Thus, we analyzed whether DDR1 translocated to mitochondria and promoted mitochondrial dysfunction after AKI. METHODS:We analyzed DDR1 localization in kidneys of patients with AKI and mice after ischemia/reperfusion-induced AKI. To determine whether mitochondrial DDR1 (mtDDR1) regulated mitochondrial functions, we generated kidney cells expressing wild-type or a kinase dead DDR1. Then, we investigated the location of wild-type or mutated DDR1 on collagen stimulation, the steps involved in DDR1 mitochondrial translocation, and the contribution of mtDDR1 in regulating mtROS production and apoptosis. RESULTS:mtDDR1 was detected in injured human and mice kidneys, and collagen-activated DDR1 translocated to the mitochondria where it increased mtROS production and tubule cell apoptosis. Collagen-activated DDR1 translocated to the outer membrane of mitochondria through its association with the chaperone mtHsp60 and induced oxidative stress and apoptosis by promoting tyrosine phosphorylation of p66Shc, a regulator of the cellular redox state and apoptosis. Moreover, cells expressing a kinase dead DDR1, treated with a DDR1 inhibitor, or expressing p66Shc mutated in the DDR1-targeted phosphorylation sites had reduced mtROS and apoptosis. CONCLUSIONS:We describe a novel noncanonical pathway whereby activated DDR1 translocates to the mitochondria to promote oxidative stress and cell apoptosis.

This meta-analysis compared chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs) for relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL), focusing on efficacy and safety. We analyzed 59 phase I/II trials involving 2,914 patients. CAR-T achieved higher ORR (72% [95% CI 67-77%] vs. 50% [38-62%]) and CR (54% [49-59%] vs. 33% [23-46%]) than BsAbs. However, it was associated with higher rates of grade ≥3 CRS (8% [6-11%] vs. 4% [3-7%]), ICANS (12% [9-16%] vs. 6% [2-18%]), and neurotoxicity (8% [6-10%] vs. 6% [2-13%]). Among CAR-T constructs, dual-targeting products (CD19/20 and CD19/22) showed higher efficacy with more varied toxicity profiles; among BsAbs, CD3×CD20 had a more favorable safety profile relative to CD3×CD19. These results suggest CAR-T may be preferable when deep remission is the priority, whereas BsAbs could be a better fit for frail patients or those seeking outpatient care with lower toxicity risks. Treatment selection should be tailored to patient characteristics, including age, tumor burden, and comorbidities. Together, these results provide a comprehensive, evidence-based framework to guide individualized treatment and sequencing in clinical practice.

Pyroptosis, an inflammation-driven programmed cell death, plays a pivotal role in the carcinogenicity of various tumors. Given the proven antitumor effects of statins, this study investigated whether statins suppress natural killer /T cell lymphoma (NKTCL) via pyroptosis and the underlying mechanism. NKYS and YT cells were treated with different concentrations of statins. The carcinogenicity of cells was validated through cell viability and invasion assays. The level of cell cycle, apoptosis, and the number of pyroptosis cells were evaluated via flow cytometry. Western-blot and immunofluorescence assays were conducted to verify the expressions of pyroptosis and immunity related proteins. The morphological characteristics of cell pyroptosis were observed via transmission electron microscopy. A subcutaneous transplant tumor model was used to verify the inhibitory effect of fluvastatin (FLU) on NKTCL cells in vivo. FLU inhibited the carcinogenicity of NKTCL cells in a concentration-dependent manner, and activated pyroptosis and its related immunity levels, which were represented by swelling of cell morphology, formation of inflammasome, and elevated expressions of gasdermin D, cleaved caspase-1 and interleukin-1β/18. Administration of pyroptosis inhibitors and exogenous mevalonate (MVA) or geranyl pyrophosphate (GGPP) partially weakened the inhibitory effect of FLU on NKTCL cells both in vitro and in vivo. Lastly, FLU and gemcitabine demonstrated satisfactory synergistic effects in tumor suppression and pyroptosis activation. Our data suggest that FLU represses NKTCL growth by promoting pyroptosis via the MVA-GGPP pathway.

BACKGROUND:Toll-like receptor 7/8 agonists (TLR7/8a), such as resiquimod (R848), are highly potent in activating dendritic cells and thus hold promise for T cell-mediated tumor immunotherapies. However, the short half-life of these small molecules in the lesion and the associated systemic immunotoxicity post-leakage of the drug into the circulation make their clinical application challenging. MATERIALS:To overcome these shortcomings, we tested prolonged TLR7/8a therapy by intratumoral infusion of R848 for 25 h using a micropump to achieve durable therapeutic effects while minimizing the proinflammatory cytokine levels in the plasma post leakage of the drug into the circulation. RESULTS:The results showed that prolonged immunotherapy with R848 (as low as 1 μg) significantly suppressed tumor growth (inhibition rates up to 98%, p < 0.01) in treated mice compared to control mice receiving regular intratumoral injection of R848. Higher levels of CD86+or CD11c+ D.C.s, CD4+/CD8+/OX40+ T cells, and cytokines (TNF-α/IFN-γ) were observed in the tumors and spleens of the mice in the treated group compared to the sham group (p < 0.05), indicating efficient activation of local and abscopal immunity by prolonged therapy with R848. Furthermore, the R848 functional concentration assay demonstrated that the micropump prolonged the treatment time of R848 drugs in tumors and reduced the requirement for higher doses, enhancing safety. CONCLUSION:Taken together, this study provides new insights into TLR7/8a immunotherapy for improved clinical performance, with potential benefits for patients with superficial tumors amenable to prolonged intratumoral infusion via micropump.

Background Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a first-in-class mutant p53 reactivator, has shown broad anticancer activity across various tumor types. Palbociclib (PD0332991), a CDK4/6 inhibitor, targets CyclinD1-CDK4/6 complexes to counteract aberrant cell cycle regulation. This project will further explore the anti-tumor efficacy and the potential mechanism of APR-246 combined with PD0332991 in MCL. Methods In vitro, through assessments of cell proliferation, apoptosis, ROS levels, comet assays, and measurements of DNA damage and apoptosis-related proteins, along with CDX models in vivo, collectively investigated the synergistic anti-tumor efficacy of APR-246 combined with PD0332991 in MCL. Subsequently, through RNA-seq, along with GO functional annotation, KEGG pathway and GSEA enrichment analyses, we were further elucidated the underlying mechanisms and this was confirmed by UHRF1 rescue or knockdown experiments. Results In vitro, we found that APR-246 combined with PD0332991 showed synergistic inhibiting cell proliferation, enhancing apoptosis, increasing ROS, and promoted DNA damage in mut/del p53 MCL cells. In vivo, we observed synergistic inhibiting tumor growth without significant toxicity in CDX models. For the mechanism, we further inferred that the APR-246 combined with PD0332991 may coordinate downregulation the expression of UHRF1 and BRCA1 to inhibits the homologous recombination (HR) repair pathway. Conclusion These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL.

Purpose: Brentuximab vedotin (BV) has been increasingly used in the treatment of CD30-positive lymphomas since its approval in China in 2020. We aimed to evaluate the effectiveness and safety of BV-based regimens in a real-world setting with a larger cohort and longer follow-up period from a 2022 study. Patients and Methods: This multi-center, retrospective study included patients diagnosed with lymphoma treated with BV-based regimens between August 2020 and April 2025 at three real-world centers in central China. Results: A total of 252 CD30-positive lymphoma patients were collected: 44.8% were cHL, 27.4% were sALCL and 27.8% were other types of lymphoma, who accomplished a median of 4 cycles of BV-based therapy. Effectiveness analysis was performed on 234 patients, revealing an overall response rate (ORR) of 67.1% and a complete response (CR) rate of 39.7%. After a median follow-up of 17.6 months (range: 0.1-55.6 months), the 1-year, 2-year and 3-year progression-free survival (PFS) rates were 72.7%, 69.4% and 69.4%, respectively, while the 1-year, 2-year and 3-year overall survival (OS) rates were 87.0%, 83.7% and 83.7%, respectively. Firstline BV-based treatment yielded significantly better CR rates, although no significant survival advantage was observed after adjustment for confounding factors. The overall incidence of adverse events (AEs) of any grade was 85.7%, with the most frequently reported AEs being anemia, leukopenia, and infections. A total of 44 patients underwent stem cell transplantation (SCT), with 31 patients receiving BV-based bridge therapy and 10 patients receiving BV as consolidation therapy following SCT. Conclusion: Our findings further solidify the role of BV as an efficacious and generally well-tolerated treatment in CD30-positive lymphomas. Its clinical activity was observed across first-line, bridging, and post-SCT settings. However, given the heterogeneous lymphoma subtypes and treatment settings included in this real-world cohort, further prospective studies are warranted.

BACKGROUND:Primary central nervous system lymphoma (PCNSL) is an aggressive, immune-privileged, large B-cell lymphoma with limited frontline treatment options. METHODS:This study was an open-label, single-arm, phase 1/2 trial evaluating orelabrutinib combined with an anti-programmed cell death protein-1 (PD-1) antibody and a non-methotrexate chemotherapeutic agent (fotemustine) in patients with newly diagnosed PCNSL (ClinicalTrials.gov identifier NCT04831658). Orelabrutinib was tested at three dose levels (100, 150, and 200 mg), and the recommended phase 2 dose was determined as 150 mg. In phase 2, patients received orelabrutinib 150 mg orally once daily, a PD-1 inhibitor 200 mg intravenously on day 1, and fotemustine 100 mg/m2 intravenously on day 2 every 21 days for six cycles. The primary endpoint was the objective response rate. RESULTS:From February 2021 to October 2023, 31 patients (median age, 62 years; age range, 37-70 years) were treated, and 27 were evaluable for efficacy. The objective response rate was 85.2% (complete response, 66.7%; partial response, 18.5%). The median progression-free survival was 9.4 months (95% confidence interval, 5.4-13.4 months), and the median overall survival was 22.8 months (95% confidence interval, 1.1-44.5 months). The 1-year and 2-year overall survival rates were 68.0% and 48.0%, respectively. The most common grade 3/4 adverse events were thrombocytopenia (45.2%), pulmonary infection (38.7%), and leukopenia (25.8%). CONCLUSIONS:Orelabrutinib combined with PD-1 blockade and fotemustine demonstrated high antitumor activity with manageable toxicity, supporting its potential as a frontline regimen for PCNSL.