Gastric cancer (GC) is a major global digestive malignancy with high incidence and mortality. Circular fanconi anemia complementation group B (circFANCB) expression is elevated in cancer, and its suppression suppresses tumor progression. However, research on the function of circFANCB in GC has not been reported yet. The role and mechanism of circFANCB in GC were investigated through circular RNA (circRNA) sequencing, database prediction, and experimental validation, including quantitative real-time PCR (qRT-PCR), ribonuclease R assay, nuclear-cytoplasmic fractionation, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, wound healing assay, Transwell assay, tube formation assay, western blot, dual-luciferase reporter assay, and enzyme-linked immunosorbent assay. Furthermore, its mechanism was further explored in vivo using a xenograft nude mouse model and immunohistochemistry. Online prediction tools, methylation-dependent RNA immunoprecipitation (MeRIP), and RNA immunoprecipitation (RIP) assays were employed to investigate whether methyltransferase-like protein 3 (METTL3) targeted circular FANCB (circFANCB) via m6A methylation. In GC, circFANCB expression was upregulated. Knockdown of circFANCB inhibited cell proliferation, migration, invasion, and angiogenesis while promoting cell death. CircFANCB increased CEACAM5 expression by binding to miR-454-3p. CEACAM5 suppressed ferroptosis in GC cells. Rescue experiments confirmed that circFANCB inhibited ferroptosis by upregulating CEACAM5, thereby promoting GC cell proliferation. Animal models demonstrated that circFANCB knockdown inhibited GC tumor growth. Additionally, METTL3 enhanced circFANCB expression through m6A methylation. Rescue experiments further confirmed that METTL3 promotes the malignant phenotype of GC cells by upregulating circFANCB. The m6A-modified circFANCB promotes the malignant progression of GC by regulating ferroptosis via the miR-454-3p/CEACAM5 axis, providing a theoretical basis for potential clinical therapeutic strategies.

BACKGROUND:Proteinuria and hematuria are both significant predictors of impaired kidney function in IgA nephropathy (IgAN). We evaluated the efficacy and safety of ambrisentan, a selective endothelin A receptor antagonist, as adjunctive therapy in a real-world cohort of high-risk IgAN patients. METHODS:In this retrospective, single-center study, we analyzed 169 patients with biopsy-proven IgAN who received adjunctive ambrisentan for ≥6 months. A propensity score-matched historical control group (138 pairs) was generated from patients receiving standard care prior to the ambrisentan era. Laboratory test results were gathered at baseline, and at 3 and 6 months. A generalized estimating equation model was employed to adjust for potential confounders. RESULTS:In the full ambrisentan cohort (n = 169), median urinary protein-to-creatinine ratio (UPCR) decreased significantly by 58.4% (95% confidence interval [CI], 49.8-62.3) at 6 months, with 75.7% of patients achieving a ≥30% reduction. Hematuria was also significantly reduced (P < .001), and kidney function remained stable. Compared to the matched controls, the ambrisentan group (n = 138 after propensity score-matching) demonstrated a greater median relative reduction in UPCR (-59.7% vs. -53.7%; P = .015). However, a decrease in hemoglobin levels was observed, with an increased incidence of anemia. The proteinuria-lowering effect was enhanced in patients concurrently receiving angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARBs) or finerenone. CONCLUSIONS:In this analysis incorporating a matched historical control, adjunctive ambrisentan significantly reduced proteinuria and hematuria in patients with IgAN without affecting kidney function. The proteinuria-lowering effect was more pronounced when ambrisentan was added to an ACEi/ARB or finerenone. Notably, a significant decline in hemoglobin levels was observed, indicating a need for monitoring. These results warrant further prospective trials to confirm the long-term renal benefits and safety of ambrisentan in IgAN.

Importance:Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. Objective:To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. Design, Setting, and Participants:This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Interventions:Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. Main Outcomes and Measures:The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Results:Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). Conclusions and Relevance:In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. Trial Registration:ClinicalTrials.gov Identifier: NCT04012606.

Supplementary Fig. 4 A. Progression-free survival by PD-L1 status. B. Overall survival by PD-L1 status. Dot marks indicate censored data.

Supplementary Fig. 3 A. Progression-free survival by CD8+ TIL density. B. Overall survival by CD8+ TIL density. Dot marks indicate censored data.

Supplementary Fig. 4 A. Progression-free survival by PD-L1 status. B. Overall survival by PD-L1 status. Dot marks indicate censored data.

BACKGROUND:Irreversible electroporation (IRE) has augmented the effects of certain immunotherapies in pancreatic ductal adenocarcinoma (PDA). Yeast-derived particulate beta-glucan induces trained innate immunity and successfully reduced murine pancreatic cancer burden. This is a phase II study to test the hypothesis that IRE may augment beta-glucan-induced trained immunity in patients with PDA. STUDY DESIGN:In this phase II clinical trial (NCT03080974), surgical ablative IRE was performed on clinical stage III PDA followed by oral beta-glucan administration for 12 months or until disease recurrence. Peripheral blood was taken preoperative, 14 days, and every 3 months and was evaluated by mass cytometry and compared with patients who received IRE alone. RESULTS:Thirty consecutive patients with preoperative clinical stage III PDA were treated with IRE and then initiated on oral beta-glucan postoperatively were compared with 20 patients treated with IRE alone. There were no dose-limiting toxicities with oral beta-glucan, and compliance with therapy was 96% in all patients. Seven patients (23%) developed grade 3 or 4 treatment-related adverse events at 90 days; none required a dose modification of oral beta-glucan. A median disease-free interval (DFI) was 18 months (range 6 to 48 months), with a median overall survival (OS) of 32.5 months (range 4 to 53 months). At 12 months post-IRE, immunophenotyping was demonstrated a significant effect with improvement in the IRE-beta-glucan-treated group. This also resulted in a significant decrease on naive CD4 and CD8 T cells with increased CD4 and CD8 terminal effector cells in the IRE-beta-glucan-treated group, which correlated with a significant improvement in DFI and OS (p = 0.001). CONCLUSIONS:Combined beta-glucan with IRE-ablated PDA tumor cells elicited a potent trained response and augmented antitumor functionality at 12 months post-IRE, which translated into an improved DFI and OS.

Supplementary Fig. 1 Forest plot of subgroup analysis for progression-free survival (A) and overall survival (B).

This study was conducted to examine the effects and mechanisms of hypoxia-preconditioned human dental pulp stem cells (H-hDPSCs) transplantation on microglial pyroptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). The hDPSCs were extracted using the tissue block method and identified by immunofluorescence staining. The HIBD model was constructed using the classical Rice–Vannucci method. 24 h after HIBD, normoxic preconditioning hDPSCs (N-hDPSCs) and H-hDPSCs were transplanted into the lateral ventricle. The brain damage was examined by hematoxylin & eosin and Nissl stainings 72 h after transplantation. The expression of signal transducer and activator of transcription 3 (STAT3)/NOD-like receptor family pyrin domain-containing 3 (NLRP3)/Caspase-1 axis-related proteins was analyzed by immunofluorescence staining and western blots. Tissue levels of interleukin-1 beta (IL-1β) were derived from ELISA. After modeling, the neural cells in the HIBD group were disordered and sparsely scattered, with a deficiency of nitrosamines. The data revealed that the phosphorylated STAT3, NLRP3, Cleaved-Caspase 1, N-terminal fragment of gasdermin D (GSDMD-N), and IL-1β protein expression were significantly lower in the H-hDPSCs and N-hDPSCs groups compared to the HIBD group. The protein expression in the H-hDPSCs group was considerably lower than in the N-hDPSCs group. H-hDPSCs may protect microglia from pyroptosis by regulating the STAT3/NLRP3/Caspase-1/GSDMD axis to alleviate inflammatory damage, and attenuate HIBD in newborn rats at the same time. Moreover, the therapeutic effect of H-hDPSCs transplantation was superior to that of N-hDPSCs transplantation.

Liver involvement of lymphomas is not rare in clinical patients. Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) is well accepted as a potential precursor for liver cancer, but it is unknown whether MASH could promote extranodal infiltration of lymphoma. In this study, the subpopulation of tumor-initiating cells and Wnt signaling pathway activation were studied in T-lymphoblastic lymphoma cells. Tumor growth, Wnt/β-catenin signaling, and fenofibrate therapy were investigated in an MASH-lymphoma mouse model. We found that up-regulated Wnt/β-catenin and epithelial cell adhesion molecule signaling contributed to aggressive growth of T-lymphoblastic lymphoma in vitro and in vivo. Lack of fibroblast growth factor 21 (FGF21) worsened lipid metabolic disorder in the hepatic microenvironment which further promoted lymphoma growth in the MASH liver. Fenofibrate therapy upregulated the peroxisome proliferator-activated receptor alpha (PPAR-α)-FGF21 axis, thereby alleviated not only MASH but also liver infiltration of T-lymphoblastic lymphoma. In addition, down-regulated FGF21 but up-regulated Wnt signaling was found in T-cell lymphoma patient samples. In conclusion, aberrant lipid metabolism contributed to the aggressive growth of T-lymphoblastic lymphoma cells in MASH liver. Wnt/β-catenin signaling could be a potential lymphomagenetic mechanism for extranodal infiltration of T-lymphoblastic lymphoma. Fenofibrate has the potential to be an effective therapeutic strategy against liver infiltration of T-lymphoblastic lymphoma in MASH liver.

Background Exercise-induced muscle damage (EIMD) was characterized by microstructural disruption, sterile inflammation, oxidative stress, and delayed-onset soreness, transiently reducing force production and training capacity. Conventional analgesics alleviated pain yet carried safety concerns and did not consistently accelerate biological recovery. Knowledge Gap/Problem Statement Evidence for curcumin, a pleiotropic polyphenol, had grown but remained fragmented by heterogeneous dosing, formulations, timing, and outcome measures; the magnitude of benefit and key moderators were not clearly framed for practice. Objectives This review aimed to synthesize mechanistic, preclinical, and clinical evidence on curcumin for EIMD; to summarize effect sizes on soreness, function, and biomarkers; to identify moderators (formulation, dose, timing, training status); and to outline safety and translational implications. Methodology We conducted a structured narrative review with a systematic search of PubMed, Scopus, and Web of Science from inception to April 2025 using predefined terms for curcumin/turmeric, EIMD/DOMS, inflammation, and oxidative stress; English-language in-vitro, animal, and human studies were included; conference abstracts without full text and studies lacking direct relevance were excluded. Results Mechanistic and preclinical data showed that curcumin inhibited NF-κB, JAK/STAT, and MAPK signaling; reduced COX-2/5-LOX eicosanoids; activated Nrf2-driven antioxidant defenses; and preserved mitochondrial function, collectively limiting secondary muscle damage and facilitating regeneration. In human trials, curcumin supplementation—especially with bioavailability-enhanced preparations—consistently attenuated post-exercise increases in muscle-damage and inflammatory markers and improved recovery metrics. Across randomized studies and meta-analytic syntheses, curcumin reduced perceived soreness, lowered CK and IL-6 elevations, and modestly preserved ROM; dosing/timing strategies (pre- and early post-exercise, multi-day courses) and enhanced formulations strengthened effects. Conclusions The totality of evidence positioned curcumin as an NSAID-sparing adjunct that safely mitigated EIMD-related inflammation and oxidative stress and supported faster functional recovery. Standardizing PK-informed dosing and reporting, and testing long-term use across training cycles, were warranted to refine guidance for athletes and clinicians.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed to replace the term of non-alcoholic fatty liver disease (NAFLD). To investigate the effect of MASLD on liver fibrosis and validate the clinical utility of MASLD criteria, differences in disease severity and clinical outcomes between MASLD and NAFLD were compared in a biopsy-proven pediatric cohort. The retrospective clinical data of 427 children with biopsy-proven steatotic liver between 2010 and 2021 were consecutively collected and categorized into three distinct subgroups of MASLD-only, NAFLD-only, and MASLD–NAFLD according to the diagnostic guidelines. Patients with MASLD-only and MASLD–NAFLD had more features of metabolic disorders, with higher level of triglycerides but lower level of high-density lipoprotein cholesterol than NAFLD-only. The proportion of significant fibrosis was highest in MASLD-only patients (68.0%), followed by those with MASLD–NAFLD and NAFLD-only (43.3% and 19.4%, respectively; P < 0.001). More steatohepatitis was presented in MASLD–NAFLD group than the other two groups (66.1% vs 30.8% vs 22.6%, P < 0.001). Multivariate regression revealed that children with MASLD-only had 5.8-fold greater risk of significant fibrosis than those with NAFLD-only (P = 0.001). After a median follow-up of 83 months, 14 of 427 patients developed clinical outcomes. Kaplan–Meier curves indicated no difference in the cumulative incidence of clinical events between the groups (log-rank, P = 0.073). Children in MASLD group tended to have concomitant with severe liver fibrosis and related metabolic diseases compared to those with NAFLD-only in pediatric cohort. Thus, the redefinition of MASLD may improve the detection of children with severe disease that need early intervention.

Supplementary Fig. 2 The association of CD8+ TIL density and PD-L1 expression with tumor objective response.

Pulmonary fibrosis (PF) is a progressive chronic lung disease with a high incidence and poor prognosis. Despite extensive research into the mechanisms that initiate and drive the progression of pulmonary fibrosis, developing effective treatments remains challenging due to the multiple etiologies, pathogenic links, and signaling pathways involved in PF. Indeed, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-B (NF-κB), and transforming growth factor-beta (TGF-β) are central players in the pathogenesis of pulmonary fibrosis, and each of these factors influences distinct yet interconnected processes that collectively contribute to disease progression: Nrf2 upregulates antioxidants to mitigate oxidative stress, NF-κB modulates inflammatory responses, and TGF-β promotes fibroblast activation and extracellular matrix (ECM) deposition, leading to fibrosis. Targeting these pathways may offer therapeutic strategies, uncover new insights and provide potential therapeutic targets for PF. Absolutely, the interactions between Nrf2, NF-κB, and TGF-β pathways are complex and can significantly influence the progression of PF, which indicated that targeting a single pathway may show poor efficacy in managing the condition. Moreover, few therapies that effectively intervene in these pathways have been approved. This review focused on the molecular mechanisms of Nrf2, NF-κB, and TGF-β involving in PF and the material basis of the naturally medicinal and edible homologous herbs, which provides a solid foundation for understanding the disease's pathogenesis, and supports the development of therapeutic drugs or treatments for addressing the complex nature of PF.

Spinal cord injury (SCI) induces complex inflammatory and oxidative stress responses that exacerbate secondary damage and impair functional recovery. This study investigated the role of butyrate-a microbiota-derived short-chain fatty acid (SCFA)-in ameliorating SCI using a combination of in silico, in vitro, and in vivo approaches. We first performed gut microbiota 16S rRNA sequencing and targeted metabolomics to assess microbial dysbiosis and serum SCFA levels in rats post-SCI. A marked reduction in butyrate-producing Firmicutes and serum butyrate concentrations was observed after injury. Molecular docking predicted a direct interaction between butyrate and HDAC1, which was confirmed by a ~40% reduction in HDAC1 expression in spinal cord tissue, as demonstrated by Western blot and immunofluorescence. In microglial cultures, butyrate significantly inhibited LPS + ATP-induced NLRP3 inflammasome activation by approximately 38%. For the in vivo component, a cervical hemi-contusion SCI model at the C5 level was established in rats. To restore butyrate levels, animals were either fed a high-fiber diet (HFD) or received intrathecal butyrate administration. Behavioral assessment revealed a 1.5-fold improvement in Forelimb Locomotor Scale scores at 1 month post-injury, and motor-evoked potential recordings showed nearly a 1.8-fold enhancement, indicating significantly improved locomotor and electrophysiological recovery in HFD-treated rats compared to controls. Furthermore, HFD treatment resulted in reduced oxidative stress (as evidenced by lower MDA and DHE staining), decreased inflammation, while butyrate administration promoted M2-type macrophage/microglia polarization. These findings reveal that butyrate mitigates oxidative stress and inflammation by targeting HDAC1 and the NLRP3 inflammasome. Importantly, HFD-driven restoration of microbial butyrate production represents a promising and translationally relevant non-invasive therapeutic strategy to enhance SCI recovery via the gut-spinal cord axis.

Although direct cardiac delivery of bone marrow-derived mesenchymal stromal cells (MSCs), c-kit–positive (c-kitPOS) cardiac progenitor cells (CPCs), and cardiac mesenchymal cells (CMCs) is beneficial in preclinical models of chronic ischemic cardiomyopathy (ICM), the optimal route of cell administration and the comparative efficacy of these cell types remain unclear. Addressing these issues is important to inform translational studies of heart failure (HF). To directly compare the effects of 3 repeated intravenous infusions of syngeneic MSCs, CPCs, and CMCs in a well-established rat model of chronic ICM. Rats with a 30-day-old myocardial infarction (MI) received 3 repeated intravenous infusions, 35 days apart, of vehicle (Dulbecco’s phosphate-buffered saline [DPBS]), MSCs, CMCs, or CPCs, at a dose of 12 × 106 cells. The left ventricular (LV) function was assessed by serial echocardiography and by hemodynamic studies at the end of the protocol. Results showed that all three types of cells improved LV function assessed by echocardiography, but only MSCs and CPCs improved hemodynamic indices of LV function. In the noninfarcted LV region, all three cell types reduced fibrosis, but only MSCs and CPCs reduced cardiomyocyte cross-sectional area and CD45 positive cell infiltration. Three repeated intravenous infusions of allogeneic MSCs, CPCs, or CMCs improved echocardiographic measures of LV function and reduced myocardial fibrosis in rats with chronic MI. However, only MSCs and CPCs improved hemodynamic indices of LV function and reduced hypertrophy and inflammation in the viable, noninfarcted myocardium. These data confirm the effectiveness of intravenous cell delivery in alleviating ICM and suggest therapeutic superiority of MSCs and CPCs over CMCs.

Background: Thermal ablation is reported to increase immunogenicity in tumor cells via expressing tumor antigens. IP-001, a synthesized molecule, is created by attaching galactose molecules to the free amino groups of partially deacetylated glucosamine polymers. As a member of a new class of polycationic immunoadjuvants that activate multiple immune response pathways, IP-001 can both sequester ablation-released tumor antigens in situ and independently recruit and stimulate antigen presenting cells (APCs) to induce a potent tumor-specific Th1 type T cell response. Methods: An orthotopic HCC rat model is established by implantation of 5 x 10(6) N1-S1 cells into the left lobe of liver. When tumor size reached 1.0-1.5 cm(3), the animals were divided randomly into 4 groups, (1) MWA+IP-001; (2) MWA+saline; (3) sham MWA+IP-001 and (4) sham MWA+saline (n = 5 each group). Results: IP001 + MWA treatment significantly suppressed tumor growth in comparison to the other 3 groups. Significantly increased infiltration of inflammatory/immune cells were found in the tumor adjacent tissues of MWA+IP-001 mice, compared to the other 3 groups. Flow cytometry results indicated that there were significant increases of cytotoxic T cells, macrophages, dendritic cells and NK cell in the combination of MWA and IP001 treated mice, compared to other 3 groups (p < 0.01). Significantly decreased number of Treg cells were found in all the treatment arms compared to untreated control (p < 0.01). Conclusion: Combination of MWA and IP001 enhances tumor suppression in an orthotopic HCC rat model. The tumor suppression is associated to the enhanced immune responses in terms of recruiting the important cell subpopulations such as CD8 + T-cells and NK cells into tumor microenvironment and abolishing immune suppressor such as Treg cells.

OBJECTIVE:In our previous study, we found that local release of curcumin from nanomicelles prevents peritendinous adhesion during Achilles tendon healing. The aim of this study is to further investigate the signaling integrated by curcumin to direct the tenogenetic program of tendon stem cells contributing to tendon healing. METHODS:A surgical model of tendon rupture and repair (TRR) was established in rats. Peritendinous adhesion and inflammation, biomechanical function, and expression of β-catenin and epithelial cellular adhesion molecule (EpCAM) were determined. A dataset was analyzed to investigate differentially expressed genes and enriched genes related to the signaling pathways. Tendon stem cells were treated with curcumin to investigate the cellular and molecular events as well as the signaling pathway. RESULTS:In rat TRR model, curcumin treatment resulted in not only significantly decreased peritendinous inflammatory but also improved tendon functional recovery along with significantly increased expressions of EpCAM and β-catenin. Analysis of the dataset indicated that the enriched genes were positively related to differentiation pathways but negatively related to proliferation pathways. In rat tendon stem cells, curcumin treatment inhibited proliferation but promoted differentiation. Curcumin's antioxidative activity was associated with tenogenesis. The upregulated expression of tendon lineage-specific markers was dependent on phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway which could be a potential mechanism of tenogenesis of curcumin treatment. CONCLUSION:Curcumin could improve tendon functional recovery via promoting tenogenesis in addition to its antioxidant and anti-inflammatory activities. Curcumin induced differentiation of tendon stem/progenitor cell into tenocytes via PI3K/Akt signaling pathway. This finding provided evidence for the application of curcumin to prevent adhesion during tendon repair.

Background Excess body weight has been found to associate with an increased risk of lymphomas and some metabolic pathways are currently recognized in lymphomagenesis. Bioactive lipid metabolites such as sphingosine-1-phosphate (S1P) have been proposed to play an important role linking obesity and lymphomas. However, the underlying mechanism(s) of S1P signaling in obesity-lymphomagenesis have not been well addressed. Methods The gene expression of sphingosine kinase (SPHK), lymphoma prognosis, and S1P production were analyzed using Gene Expression Omnibus (GEO) and human lymphoma tissue array. Obesity-lymphoma mouse models and lymphoma cell lines were used to investigate the S1P/SPHK-YAP axis contributing to obesity-lymphomagenesis. By using the mouse models and a monocyte cell line, S1P-mediated polarization of macrophages in the tumor microenvironment were investigated. Results In human study, up-regulated S1P/SPHK1 was found in human lymphomas, while obesity negatively impacted progression-free survival and overall survival in lymphoma patients. In animal study, obesity-lymphoma mice showed an aggressive tumor growth pattern. Both in vivo and in vitro data suggested the existence of S1P-YAP axis in lymphoma cells, while the S1P-ALOX15 signaling mediated macrophage polarization towards TAMs exacerbated the lymphomagenesis. In addition, treatment with resveratrol in obesity-lymphoma mice showed profound effects of anti-lymphomagenesis, via down-regulating S1P-YAP axis and modulating polarization of macrophages. Conclusion S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis. Graphical Abstract

AbstractPurpose: To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC). Patients and Methods: In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240 mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3), or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2. Results: A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate (ORR) than Schedule D14 for non-ablation lesions (37.5% vs. 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher ORR than with toripalimab alone (33.8% vs. 16.9%; P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 vs. 3.8 months; P < 0.001) and median overall survival (18.4 vs. 13.2 months; P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, eight (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis. Conclusions: In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone, with an acceptable safety profile.