Abstract Background: Adoptive cell therapy, particularly CAR-T therapy, has transformed the treatment of hematologic malignancies, but autologous products remain limited by high cost, long manufacturing, and insufficient functional T cells in heavily pretreated patients. These challenges underscore the need for off-the-shelf allogeneic approaches. Invariant natural killer T (iNKT) cells are an attractive cell platform because they recognize lipid antigens via the non-polymorphic CD1d molecule, avoiding graft-versus-host disease (GvHD). CAR-engineered iNKT cells also provide multimodal tumor killing, tumor microenvironment modulation, enhanced infiltration, and natural bone marrow homing. However, their scarcity in peripheral blood poses manufacturing challenges. To address this, we developed GT719, an allogeneic anti-CD19 CAR-iNKT therapy generated through in vitro differentiation of cord blood-derived CD34+ hematopoietic stem cells. Rational CAR design and optimized manufacturing enable scalable production capable of treating thousands of patients per batch. Extensive preclinical studies show that GT719 eliminates malignant B cells through coordinated CAR-, invariant TCR-, and NK receptor-mediated cytotoxicity and selectively depletes immunosuppressive macrophages and myeloid-derived suppressor cells. Study Design and Methods: Based on promising preclinical results, a first-in-human investigator-initiated clinical trial (NCT06948981) has been launched to evaluate the safety, toxicity, dose-limiting toxicities (DLTs), and recommended treatment dose of GT719 for patients with relapsed or refractory CD19-positive B cell malignancies, including both B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). This open-label Trial in Progress begins with two single-patient acceleration cohorts testing doses of 5× 107 and 1 × 108 cells per patient, followed by a classical 3+3 dose-escalation design testing doses of 5 × 108 and 1 × 109 cells per patient. Enrolled patients undergo a standard lymphodepletion regimen consisting of cyclophosphamide and fludarabine from Day -5 to Day -2, consistent with protocols used for autologous CAR-T therapies. GT719 is administered intravenously on Day 0, and the primary safety observation window for DLTs extends from Day 1 to Day 28. Adverse events are assessed for incidence and severity according to CTCAE version 5.0. Although the trial is ongoing, we anticipate presenting preliminary safety and efficacy data for GT719 at the meeting. Clinical trial registration number: NCT06948981 Citation Format: Dehui Zou, Wei Liu, Yan Yu, Huimin Liu, Yi Wang, Sisi Feng, Xiaona Xu, He Zhang, Ershao Zhang, Jiang Li, Jingman Wang, Jing Hao, Ning Wang, Huipin Zheng, Yin Cheng, Jun Cui, Jingwei Sun, Yarong Liu. Stem cell-derived allogeneic anti-CD19 CAR-iNKT cell therapy GT719 for relapsed/refractory B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3725.

Clear cell renal cell carcinoma (ccRCC), a kidney cancer subtype, is characterized by its aggressive nature and limited treatment options, leading to a poor prognosis. We observed elevated levels of CSF1R and PIK3CD in ccRCC tissues. A new CSF1R/PI3Kδ dual inhibitor, JMC14, greatly reduced the growth of xenografts originating from ccRCC A498 cells despite showing only moderate activity against cell proliferation in vitro. Single-cell RNA sequencing of A498 tumors demonstrated that JMC14 altered the tumor microenvironment (TME) by decreasing the presence of immunosuppressive macrophages. JMC14 modulated macrophage polarization towards the M1-like phenotype and inhibited M2 tumor-associated macrophage (TAM)-mediated tumor angiogenesis by decreasing the secretion of IL-8 and VEGF, which might be associated with blocking the STAT3 and NF-κB pathways in macrophages. JMC14 significantly impeded the growth of xenografts derived from ccRCC 786-O cells and patient samples while also decreasing M2 macrophage infiltration and attenuating angiogenesis. Taken together, simultaneously targeting CSF1R and PIK3CD displayed significant efficacy in ccRCC and inhibited tumor angiogenesis via reshaping the TME, providing a promising rationale for the therapy of ccRCC.

Receptor-interacting protein kinases (RIPKs) are a family of serine/threonine kinases that regulate innate immunity, inflammation, and several modalities of regulated cell death, and are increasingly implicated in cardiovascular disease. Increasing evidence suggests that dysregulated RIPK signaling contributes to cardiomyocyte injury, fibrosis, maladaptive remodeling, mitochondrial dysfunction, and inflammatory amplification in multiple cardiac pathologies. While the roles of RIPK1 and RIPK3 in necroptosis are well recognized, recent studies indicate broader and more complex role in heart disease, including broader non-canonical functions involving mitochondrial regulation, oxidative stress, inflammasome activation, and metabolic remodeling. RIPK2 is emerging as a significant but underrecognized modulator of sterile cardiac inflammation and pathological remodeling. Similarly, RIPK4 has recently been associated with oxidative stress responses and ferroptosis, although direct cardiac evidence remains limited. This review provides an updated overview of RIPK1-RIPK4 signaling within the framework of cardiovascular disease, emphasizing both canonical necroptotic and non-canonical signaling mechanisms. We discuss the involvement of RIPKs in myocardial ischemia/reperfusion injury, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, myocarditis, and doxorubicin-induced cardiotoxicity. We further summarize current and emerging therapeutic strategies targeting RIPKs, including small-molecule inhibitors, natural compounds, and endogenous regulators approaches. Finally, we highlight major knowledge gaps and translational challenges, including isoform-specific functions, temporal dynamics of RIPK activation, safety considerations, and the clinical translation of preclinical findings.

Objective: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare T-cell lymphoma. Anthracycline-based combination chemotherapy is the first-line treatment with a high remission rate, but the necessity of hematopoietic stem cell transplantation (HSCT) for consolidation remains inconclusive. This study aims to summarize the clinical characteristics of ALK+ ALCL and explore prognostic factors and treatment efficacy. Methods: A retrospective analysis was conducted on 52 ALK+ ALCL patients treated at the Institute of Hematology, Chinese Academy of Medical Sciences from May 2011 to November 2024. All patients had completed at least one line of chemotherapy with or without HSCT. Clinical characteristics, treatment outcomes, and prognostic factors were analyzed. Results: The median age of onset was 25.5 years (range: 11-64), with a male-to-female ratio of 2.3:1. At initial diagnosis, 81.1% (42/52) of patients were in advanced stages (III-IV), 55.8% (29/52) presented with B symptoms, and 28.8% (15/52) had elevated LDH levels. Extranodal involvement was observed in 59.6% (31/52) of patients, with 40.4% (21/52) having ≥2 extranodal sites involved. The International Prognostic Index (IPI) score was intermediate-high/high (3-5) in 21.2% (11/52) of patients. The median number of first-line treatment cycles was 6 (range: 2-8). First-line regimens included EPOCH (44.2%, 23/52), EPOCH (25%, 13/52), BV+CHP (21.2%, 11/52), and CHOP (9.6%, 5/52). With a median follow-up of 45.7 months, the complete remission (CR) rate for first-line treatment was 75% (39/52), and the overall response rate (ORR) was 90.4% (47/52). The 5-year overall survival (OS) rate was 91%, and the 5-year progression-free survival (PFS) rate was 67%. Primary refractory disease (n=5) and early relapse within 3 months of CR (n=6) were identified as significant prognostic factors for OS (P=0.039). Among these 11 patients, one who did not undergo transplantation had an OS of only 9.3 months, while the remaining 10 patients who achieved CR/PR with subsequent treatments and underwent HSCT had 8 survivors and 2 deaths due to relapse. In the chemotherapy-only group (n=30), IPI scores of 3-5 were significant prognostic factors for both OS and PFS (P=0.016; P=0.011). Among the 11 patients with IPI scores of 3-5, 4 received chemotherapy only (1 death, 1 sustained CR, 1 sustained PR, 1 lost to follow-up after progression), while 7 underwent chemotherapy followed by HSCT (6 survivors, 1 lost to follow-up within one year post-transplantation). The sustained CR rates for intermediate-high/high-risk patients treated with chemotherapy alone versus chemotherapy plus HSCT were 25% and 71.43%, respectively (P=0.24), with 5-year OS rates of 75% and 100% (P=0.19). CR rates for first-line regimens were 72.6% for EPOCH/EPOCH, 81.2% for BV+CHP, and 100% for CHOP. The corresponding ORRs were 88.8%, 90.9%, and 100%. The 5-year OS rates were 89%, 100%, and 100% (P=0.6).It was noting that the 5-year PFS rates were 74%, 40%, and 30% ( P=0.03). Conclusion: ALK+ ALCL predominantly affects males under 30 years of age, with most patients presenting at advanced stages. Pathological features include CD30 and EMA positivity. The disease shows high chemosensitivity, with EPOCH/EPOCH regimens demonstrating superior remission maintenance compared to other regimens. Overall survival is favorable, but primary refractory disease/early relapse within 3 months, and IPI scores ≥3-5 are poor prognostic factors. These patients may benefit from sequential HSCT following chemotherapy.

Three CD19-directed CAR T-cell therapies - axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) - are FDA-approved for relapsed/refractory large B-cell lymphoma (R/R LBCL) following ≥2 prior lines of therapy or early relapse within 12 months of first-line treatment. Clinical studies have shown ORRs of 52-83% (CR 40-58%) in ≥3rd-line and 46-86% (CR 28-66%) in 2nd-line settings, with median PFS of 2.9-6.8 months (≥3rd-line) and 14.7 months (2nd-line, ZUMA-7 trial), respectively. In China, axi-cel and relma-cel (a CD19 CAR-T therapy developed based on liso-cel's technology but with a modified manufacturing process) have been approved for R/R LBCL. Previous studies suggested that combining CAR T-cell therapy with high-dose therapy/autologous stem cell transplantation (HDT/ASCT) may improve response rates and survival in R/R LBCL (Cao et al., 2021; Liu et al., 2024). However, these studies utilized investigational or compassionate-use CAR-T products. In this study, we report single-center outcomes from combining commercial CAR-T products (axi-cel and relma-cel) with HDT/ASCT for R/R LBCL. Methods We retrospectively analyzed patients with R/R LBCL or transformed LBCL who received combination therapy of commercial CAR T-cell therapy (axi-cel or relma-cel) and HDT/ASCT from January 2022 to December 2024 at the Institute of Hematology & Blood Diseases Hospital. The conditioning regimen was determined by treating physicians, with CAR T-cell infusion administered on days +2, +3, or +4 following autologous stem cell reinfusion. This study was approved by the Institutional Review Board/Ethics Committee of the Blood Diseases Hospital, Chinese Academy of Medical Sciences. Results A total of 15 patients received the combination therapy and were included in this study. Pathological classification identified 14 patients (93.3%) with de novo DLBCL and 1 patient (6.7%) with transformed follicular lymphoma. The median age was 52 years (range: 31-61), with 9 male patients (60.0%). Most patients (93.3%) had advanced-stage disease, including 4 (26.7%) with central nervous system involvement. The median lines of prior therapy was 2 (range, 1-3). At the time of leukapheresis, 8 patients (53.3%) exhibited refractory disease to their last-line therapy, 4 patients (26.7%) had achieved responses (3 PR, 1 CR), and 3 patients (20.0%) presented with relapsed disease. Following leukapheresis, thirteen patients (86.7%) underwent bridging therapy during CAR T-cell manufacturing. After combination HDT/ASCT with CAR T-cell therapy (axi-cel [n=6] or relma-cel [n=9]), the ORR was 93.3% (CR: 80.0%, PR: 13.3%). With a median follow-up duration of 25.1 months (data cutoff: July 26, 2025), the estimated 2-year progression-free survival and overall survival rates were 65.2% and 78.0%, respectively. Ten patients (66.7%) experienced cytokine release syndrome (all grade 1-2), while immune effector cell-associated neurotoxicity syndrome occurred in 3 patients (20.0%; grade 2 in 1 patient, grade 4 in 2 patients). No treatment-related mortality or unexpected toxicities were observed. Conclusions The combination of axi-cel/relma-cel with HDT/ASCT demonstrates promising efficacy and acceptable safety in patients with R/R LBCL, representing a viable therapeutic option for transplantation-eligible candidates.

Background and Significance:Adoptive cell therapy, particularly CAR-T therapy, has transformed cancer treatment, showing remarkable efficacy in hematologic malignancies. FDA-approved CAR-T products targeting CD19 and BCMA offer hope not only to cancer patients but also those with autoimmune diseases and viral infections. However, autologous CAR-T approaches are limited by high cost, lengthy manufacturing, and inadequate T cells in heavily pretreated patients, spurring interest in off-the-shelf allogeneic CAR-T therapies with broader accessibility and lower cost. Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cell therapy due to their unique biology. They recognize lipid antigens via CD1d, a non-polymorphic MHC I-like molecule, enabling them to avoid inducing graft-versus-host disease (GvHD). CAR-engineered iNKT cells offer several advantages over conventional CAR-T cells: multi-modal tumor killing, modulation of the tumor microenvironment, improved infiltration, and bone marrow homing. However, their rarity in peripheral blood (0.001%–1%) presents a major obstacle for clinical use. To overcome this, we developed GT719, a novel anti-CD19 CAR-iNKT cell therapy derived from in vitro differentiation of cord blood CD34+ hematopoietic stem cells. Rational CAR design and optimized manufacturing enable large-scale production, potentially treating thousands of patients per batch. Preclinical studies demonstrate GT719 targets malignant B cells via multiple mechanisms: CAR-driven cytotoxicity, invariant TCR activity, NK receptor signaling, and selective depletion of tumor-associated macrophages and myeloid-derived suppressor cells. These findings support clinical evaluation of GT719. Study Design and Methods:This is a single-center, single-arm, open-label pilot trial conducted at the Chinese Academy of Medical Sciences Hematology Hospital in Tianjin, China (ClinicalTrials.gov: NCT06948981). The study population includes adults (≥18 years) with relapsed/refractory CD19-positive B cell malignancies, including B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). Key Inclusion Criteria: Relapsed/refractory CD19+ B-ALL (≥5% marrow blasts), Ph+ ALL resistant/intolerant to ≥2 TKIs (excluding T315I mutation), or B-NHL (aggressive/indolent) unresponsive to prior therapies. Key Exclusion Criteria: History or active CNS/testicular leukemia/lymphoma, recent HSCT, prior CD19 CAR-T/NK therapy. Treatment: This is a classical 3+3 dose-escalation design evaluating doses of 5 × 10⁸ and 1 × 10⁹ cells per patient. Lymphodepletion with cyclophosphamide and fludarabine is administered from Day –5 to Day –2. GT719 is infused on Day 0. The DLT evaluation window is from Day 1 to Day 28. AEs are graded using CTCAE v5.0. Endpoints: 1) Primary: Incidence and severity of DLTs and AEs within 28 days post-infusion; 2) Secondary: 3-month ORR, best overall response (BOR), progression-free survival (PFS), overall survival (OS), time to peak expansion, peak level AUC, and GT719 persistence; 3) Exploratory: Changes in peripheral immune cell populations and cytokine profiles over time. Statistics: Up to 24 patients will be enrolled. DLTs and ORR will be summarized with 95% confidence intervals (CI) via the Clopper-Pearson method. Duration of response (DOR), PFS, and OS will be analyzed using the Kaplan-Meier method. Summary: This first-in-human investigator-initiated trial evaluates the safety, DLTs, and recommended dose of GT719 for patients with CD19+ B cell malignancies. Preliminary safety data will be presented at the meeting.

BackgroundThe N-formyl peptide receptor family (FPRs) is implicated in the progression of diverse cancer types, yet studies specifically exploring their roles in breast cancer remain scarce.MethodsA comprehensive analysis integrating bulk RNA-seq transcriptomics, methylomics, single-cell transcriptomics, and spatial single-cell transcriptomics data was conducted to elucidate the distinctive characteristics of FPRs in breast cancer. This study particularly focused on delineating the e xpression profiles of FPR3 across distinct breast cancer subtypes, while systematically investigating its prognostic implications and association with macrophage polarization patterns in breast cancer patients. Furthermore, molecular docking analysis was performed to screen potential therapeutic compounds targeting FPR3, providing insights into its druggability.ResultsNotably, FPR3 was found to be highly expressed in macrophages within breast cancer tissues, with a notably elevated level in HER2-positive and triple-negative breast cancer (TNBC) subtypes, both of which are associated with poor prognosis. FPR3 expression inversely correlates with promoter methylation levels. Further analysis of pan-cancer immune infiltration patterns uncovered a striking association between FPR3 and macrophage infiltration, as well as their polarization status. Knockdown of FPR3 expression in macrophages markedly enhanced the expression of IL6, TNF-alpha, and TGF-beta, while significantly reducing IL10 levels, indicative of a shift towards an M1-like macrophage phenotype. Through computational molecular docking analyses, Otamixaban and Rivaroxaban emerged as promising candidate inhibitors of FPR3.ConclusionsThese findings underscore the profound infiltration of FPR3 + macrophages in breast cancer patients with adverse prognoses, highlighting FPR3 as a potential therapeutic target for intervening breast cancer aggressiveness.

With the growing elderly population and increasing incidence of various aging-related diseases, the scientific community is faced with an urgent challenge to identify natural anti-aging agents. Traditional Chinese medicine (TCM) polysaccharides have been proven to have good anti-aging activities. This article reviews the literature on the anti-aging pathways of traditional Chinese medicine polysaccharides applied to Caenorhabditis elegans models in the past decade. In our study, we found that 45 TCM polysaccharides from 28 genera and 26 families could delay the aging process of C. elegans. Traditional Chinese medicine polysaccharides delay the aging of C. elegans mainly by anti-oxidative stress, eliminating free radicals, repairing DNA damage, and insulin/insulin-like growth factor signaling pathway (IIS signaling pathway). In addition, an increasing number of traditional Chinese medicine polysaccharides have been found to prolong the lifespan of C. elegans by reducing inflammation, regulating intestinal flora, and affecting immune cell function. In this paper, C. elegans was used as an animal model to clarify the anti-aging pathway of traditional Chinese medicine polysaccharides, so as to provide theoretical guidance for future research and clinical experiments on the anti-aging effect of traditional Chinese medicine polysaccharides.

Polatuzumab vedotin (Pola), an anti-CD79b monoclonal antibody-drug conjugate, has been approved for first-line treatment of diffuse large B-cell lymphoma (DLBCL) based on results from the POLARIX phase III trial. This study demonstrated that Pola-R-CHP significantly improved progression-free survival (PFS) compared to R-CHOP in patients with LBCL and IPI scores of 2-5 (Tilly et al., 2022). Meanwhile, R-DA-EPOCH has shown superior PFS to R-CHOP in DLBCL patients with IPI 3-5 (Bartlett et al., 2019) and is the preferred regimen for primary mediastinal large B-cell lymphoma (PMBCL) or high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements. However, the safety and efficacy of incorporating Pola into modified R-EDCH (with vincristine omission and dexamethasone substitution) remains unknown. To investigate this novel combination, we conducted a prospective phase 2 study evaluating R-EDCH plus Pola in high-risk aggressive non-Hodgkin's lymphoma or PMBCL. Methods This study enrolled patients aged 18-65 years with newly diagnosed aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma not otherwise specified (HGBL-NOS), and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH). Non-PMBCL DLBCL patients were required to have high-risk disease, defined as an International Prognostic Index (IPI) score ≥3 or age-adjusted IPI (aaIPI) score ≥2. All participants received six 21-day cycles of Pola-R-EDCH, consisting of polatuzumab vedotin (1.8 mg/kg IV, day 1), rituximab (375 mg/m² IV, day 0), etoposide (50 mg/m²/day continuous IV infusion, days 1-4), liposomal doxorubicin (30-40 mg/m² IV, day 1), cyclophosphamide (750 mg/m² IV, day 5), and dexamethasone (30 mg IV, days 1-5). The study protocol was approved by the Institutional Review Board/Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences. Results From July 2023 to April 2025, 16 patients were included in the study, with a median age of 41.5 years (range: 18-63 years). Among them, 4 patients (25%) were diagnosed with PMBCL, while the remaining 12 patients (75%) had DLBCL. Key clinical characteristics showed that 81.3% of patients had non-GCB subtype, 75% had elevated LDH levels, 37.5% presented with extranodal involvement, and 25% were classified as double-expressor lymphoma. Cytogenetic and molecular analysis revealed TP53 depletion/mutation in 5 patients (31.3%), CDKN2A depletion in 5 patients (31.3%), and concurrent TP53 and CDKN2A abnormalities in 3 patients (18.8%). No MYC rearrangements were detected in any patient. As of July 26, 2025, all 16 patients had undergone at least one efficacy evaluation. The best overall response rate was 100%, with a complete response rate of 81.3%. After a median follow-up of 10.1 months, disease progression occurred in 4 patients. Three of these progressing patients (75%) harbored TP53 depletion/mutation, and 2 (50%) had both TP53 depletion/mutation and CDKN2A depletion. The estimated 1-year progression-free survival (PFS) rate was 62.5%, while the 1-year overall survival (OS) rate was 87.5%.Treatment-related adverse events included grade ≥3 neutropenia in 15 patients (93.8%) and grade ≥3 thrombocytopenia in 5 patients (31.3%). Febrile neutropenia was reported in 43.8% of cases. Peripheral neuropathy occurred in 50% of patients, all of which were grade 1 or 2. Conclusions The Pola-R-EDCH regimen demonstrated high response rates in patients with PMBCL or high-risk LBCL. The addition of polatuzumab vedotin did not result in unexpected toxicities. Patients with TP53 abnormalities, with or without CDKN2A depletion, showed an increased risk of disease progression.

PURPOSE:Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. Bruton's tyrosine kinase inhibitors have shown promising outcomes, yet achieving deep remission (very good partial remission or complete remission) remains challenging. and time-limited therapy with proteasome inhibition has not been reported. We conducted a phase II clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib, and dexamethasone (ZID) in patients with newly diagnosed WM. PATIENTS AND METHODS:A total of 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-day cycles, followed by consolidation therapy for a total of 24 cycles. The primary endpoint was the deep remission rate. RESULTS:Overall, 24 of the 27 enrolled patients completed induction treatment. One patient (4.2%) achieved complete remission. Ten patients (41.6%) achieved very good partial remission. The overall, major, and deep remission rates were 100%, 95.8%, and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of the 22 patients had a CXCR4 mutation, with no disparity in deep remission between the patients with and without a CXCR4 mutation (40% vs. 50%; P = 0.594). The median abnormal lymphocyte (7.6% vs. 1.6%; P = 0.0019) and plasma cells (0.28%-0.02%; P = 0.0306) in bone marrow were significantly reduced after treatment. The median follow-up was 30.9 months (range, 15-42). The estimated median progression-free survival and overall survival were 40 months (95% confidence interval, 35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4 mutations. The most common adverse event was hematologic toxicity. CONCLUSIONS:The ZID regimen might offer deep remission and provide a time-limited Bruton's tyrosine kinase inhibitor therapy in patients with WM.

ETHNOPHARMACOLOGICAL RELEVANCE:Cardiac aging is closely associated with the occurrence and progression of various cardiovascular diseases (CVD). Buyang Huanwu Decoction (BYHWD), a classical traditional Chinese medicine formula, is widely used clinically for cerebrovascular and cardiovascular diseases. However, its role in delaying cardiac aging and the underlying molecular mechanisms remain unclear. AIM OF THE STUDY:This study aimed to investigate the role of BYHWD in cardiac aging and explore its potential molecular mechanisms. MATERIALS AND METHODS:D-galactose (D-gal) was used to establish in vivo and in vitro aging models, with BYHWD administered as an intervention. Histopathological examination and biochemical assays assessed cardiac tissue damage, and Western blot detected aging-related markers. Untargeted metabolomics and network pharmacology identified potential targets and pathways. Finally, molecular biology methods such as RT-qPCR, Immunohistochemistry, and Western blot were used to validate the expression levels of genes and proteins in key pathways. RESULTS:BYHWD effectively alleviated cardiac pathological injury, significantly inhibited the mRNA levels of pro-inflammatory factors Il-1β, Il-6, and Tnf-α in cardiac tissues, and downregulated the expression of senescence-related proteins p16, p21, and p53. Untargeted metabolomics analysis revealed that BYHWD might restore metabolic disorders in the hearts of aging rats by regulating energy and amino acid metabolism pathways. Network pharmacology analysis demonstrated that BYHWD might delay cardiac aging by modulating immune and inflammatory responses, with the CaM/CaMKII/MAPK pathway being significantly enriched in its mechanism of action. RT-qPCR, Immunohistochemistry, and Western blot further confirmed that BYHWD exerted its anti-aging effects on the heart by inhibiting the CaM/CaMKII/MAPK pathway. CONCLUSION:BYHWD was found to effectively delay D-gal-induced aging in both rat hearts and cardiomyocytes. Mechanistically, BYHWD modulated energy and amino acid metabolic pathways while inhibiting the CaM/CaMKII/MAPK axis to exert anti-inflammatory effects. Overall, this study provides novel insights into the mechanisms through which BYHWD delays cardiac aging.

Supplemental Figure 5. Survival outcomes in patients with or without deep remission.

Chemoresistance is a considerable challenge for gastric cancer (GC), and the combination of cisplatin (DDP) and anti-EGFR therapy failed to show remarkable benefit. So other targets in EGFR-overexpressed and DDP-resistant GC need to be explored. Both cytological experiments and database bioinformatics analysis were applied in this study. It was confirmed that the prognosis of GC patients with EGFR oe was poor. EGFR regulated intracellular redox metabolism, enhanced GSH content and led to DDP resistance. A subset of miRNAs including miR-135b, miR-106a, miR-29a, miR-23a and miR-15a was upregulated in EGFR-overexpressed and DDP-resistant GC cells. Furthermore, EGFR inhibited CYBRD1 via enhancing the miRNA subset and scavenged the redundant ROS to cause DDP resistance. Therefore, to inhibit the miRNA subset at the same time of anti-EGFR therapy might reverse DDP resistance, serving as a potential novel drug for the future treatment of EGFR-overexpressed and DDP-resistant GC.

Ethnopharmacological relevance Brain aging can promote neuronal damage, contributing to aging-related diseases like memory dysfunction. Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine formula known for tonifying qi and activating blood circulation, shows neuroprotective properties. Despite this, the specific mechanism by which BYHWD improves age-associated memory impairment (AAMI) has not been explored in existing literature. Aim of the study This study aimed to investigate the mechanism of BYHWD in the improvement of AAMI based on the “co-occurrence network regulation of intestinal microecology-host metabolism- immune function”. Materials and methods Firstly, D-galactose was performed to induce a rat model of AAMI. Learning and memory deficits was assessed by the Morris water maze test. H&E and Nissl staining were used to observe the pathological changes in neurons in the hippocampus of rats. Meanwhile, the levels of pro-inflammatory cytokines and the activation of antioxidant enzymes in rat serum were measured using ELISA. Finally, an integrated pharmacological approach was applied to explore the potential mechanism of BYHWD in improving AAMI. Results Our results indicated that BYHWD significantly mitigated the pathological structure of the hippocampus, reversed the levels of IL-6, TNF-α, GSH, and CAT in the serum, and improved learning and memory in aging rats. Transcriptomics combined with network pharmacology showed that energy metabolism and the inflammatory response were the key biological pathways for BYHWD to ameliorate AAMI. Integrative analysis of the microbiome and metabolomics revealed that BYHWD has the potential to restore the balance of abundance between probiotics and harmful bacteria, and ameliorate the reprogramming of energy metabolism caused by aging in the brain. The co-occurrence network analysis demonstrated that a strong correlation between the treatment of AAMI and the stability of intestinal microecology, host metabolism, and immune network. Conclusion The findings of this study collectively support the notion that BYHWD has a superior therapeutic effect in an AAMI rat model. The mechanism involves regulating the “intestinal microecology-metabolism-immune function co-occurrence network” system to restore the composition of gut microbiota and metabolites. This further improves the metabolic phenotype of brain tissue and maintains the homeostasis of central nervous system's immunity, leading to an improvement in AAMI. Consequently, this study offers a unique perspective on the prevention and treatment of AAMI. And, BYHWD is also considered to be a promising preclinical treatment for improving AAMI.

We explored the role of Polygonatum Rhizoma polysaccharide (PRP) in delaying aging and improving Alzheimer's disease (AD) and revealed its potential molecular mechanism. Through chemical characterizations to clarify the physicochemical properties of PRP, it was found that PRP mainly consists of mannose, glucose, galactose, and arabinose, with molecular weights ranging from 7.4 × 104 to 9.1 × 104 Da; using Caenorhabditis elegans (C. elegans) models, its anti-AD activity was verified by combining approaches using pharmacodynamics, molecular biology, metabolomics, and transcriptomics sequencing. The results of this study showed that PRP significantly extended the lifespan of C. elegans, reduced the accumulations of lipofuscin and increased the ability of C. elegans to resist oxidative stress, and reduced the aggregation of Aβ protein in the AD model C. elegans, and improved neuromuscular dysfunction. Transcriptomic analysis revealed that PRP modulated the expression of genes involved in key processes, including anti-stress and senescence (daf-12, skn-1, gst-4, ctl-1, sod-3, age-1, gcs-1), autophagy (unc-51, bec-1, lgg-1), and mitochondrial function (clk-1, mev-1, isp-1). Metabolomic analysis revealed that PRP improved metabolic disorders in C. elegans by regulating phenylalanine/purine metabolism pathway. These results indicated that PRP exerted its effects through multiple pathways to delay C. elegans aging and improve AD symptoms, providing a strong theoretical basis for the development of AD treatment drugs based on traditional Chinese medicine.

Objective: Peripheral T-cell lymphoma (PTCL) is a rare but challenging malignancy, in which the TFH (T follicular helper)-derived PTCL subtype has a poor prognosis and limited treatment options. In this study, chidamide in combination with azacitidine, mitoxantrone liposomes and prednisone (CAMP regimen) was used for the treatment of treatment-naïve TFH-derived peripheral T-cell lymphoma, aiming to evaluate the efficacy and safety of this treatment regimen and provide a new treatment option for clinical practice. Methods:This study is a multicenter, prospective phase II clinical trial (clinical trial ID: IIT2023003), the main purpose of which is to investigate the safety and preliminary efficacy (ORR rate) of chidamide in combination with azacitidine, mitoxantrone liposome and prednisone (CAMP regimen) in the treatment of treatment-naïve TFH-derived PTCL. Eligible treatment-naïve TFH-derived PTCL patients were included in the program who received CAMP regimen combination therapy, the specific regimen was: chidamide 30mg/day orally, biw; azacitidine 75mg/m2 subcutaneously, d1-d7; mitoxantrone liposome 16mg/m2 d1; prednisone 60mg/m2, d1-5; 28 days is a cycle of treatment. Patients who achieve CR/PR after four-six cycles could choose to undergo autologous hematopoietic stem cell transplantation, followed by chidamide maintenance therapy for 2 years. Results: A total of 20 treatment-naïve patients with TFH-derived PTCL were enrolled, of whom 45% were male, with a median age of 56 (39-70) years, 95% of whom had Ann Arbor stage III-IV, 45% of the patients had B symptoms, 75% of the patients had extranodal involvement, and 55% of the patients were EBER-positive. 40% of patients were IPI score 3, and 50% of patients were PIT score≥2. The median number of treatment courses was 5 (4-8), and 4 patients (20%) underwent autologous hematopoietic stem cell transplantation, with a complete response (CR) rate of 95%，a partial response (PR) rate of 5% and an overall best objective response rate (ORR) of 100%. At a median follow-up of 10 (3-17) months, the estimated 1-year PFS and OS rate of all patients was 61% and 78% respectively. During CAMP regimen therapy, 13 patients (65%) developed myelosuppression, with a 25% incidence of grade 3-4 myelosuppression, which could be recovered after supportive therapy. Eight patients (40%) developed pulmonary or urinary tract infections and were cured with active anti-infective therapy. Conclusion: Chidamide combined with azacitidine, mitoxantrone liposome and prednisone (CAMP regimen) in the treatment of treatment-naïve TFH-derived PTCL has a high complete response rate and a controllable safety profile, which is expected to become a new treatment option for treatment-naïve TFH-derived PTCL, but the cohort needs to be further expanded to verify its safety and efficacy.

Background: Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cell (CAR-T) therapy are highly regarded immunotherapeutic approaches, serving as critical treatments for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Both modalities eradicate tumor cells by leveraging sophisticated immune mechanisms. Although typically administered sequentially in clinical practice, emerging in vitro and in vivo evidence suggests potential synergy between them. This retrospective study investigated the efficacy and safety of BsAbs-containing bridging therapy administered prior to CD19-specific CAR-T therapy alone or in combination with high-dose therapy and autologous stem cell transplantation (HDT/ASCT). Methods: We assessed patient demographics, clinical characteristics, and prior lines of treatment. Responses were evaluated using PET-CT. Key endpoints included complete response rate (CRR), objective response rate (ORR) before and after cellular therapy, progression-free survival (PFS), and overall survival (OS). Safety profiles of BsAbs and CAR-T therapy were also evaluated. Results: Eleven patients (median age 54 years, range 37-65; male/female ratio 5:6) were enrolled. Most patients (81.8%, 9/11) had advanced-stage disease (Ann Arbor stage III-IV); 36.4% (4/11) presented with B symptoms. Pathologically, 72.7% (8/11) were DLBCL NOS, while the remainder were DLBCL transformed from indolent B-cell lymphoma (follicular lymphoma or marginal zone lymphoma). TP53 abnormalities (deletion or mutation) were detected in 55.6% (5/9) of tested patients. Molecular subtypes were distributed as follows: MCD (22.2%, 2/9), BN2 (22.2%, 2/9), EZB (22.2%, 2/9), A53 (11.1%, 1/9), and other (33.3%, 3/9). The median number of prior treatment lines before bridging therapy was 2 (range 1-4). Bridging therapy consisted of glofitamab monotherapy (3 patients) or glofitamab combined with chemotherapy (GVM [gemcitabine, vinorelbine, mitoxantrone hydrochloride liposome] in 4 patients; GemOx [gemcitabine, oxaliplatin] in 4 patients). All patients were planned for combination CD19 CAR-T therapy with HDT/ASCT. However, 3 patients received CD19 CAR-T therapy alone due to autologous hematopoietic stem cell mobilization failure. Response to BsAbs-containing bridging therapy before cellular therapy was: complete remission (CR) in 27.3% (3/11), partial remission (PR) in 54.5% (6/11), stable disease (SD) in 9.1% (1/11), and progressive disease (PD) in 9.1% (1/11). The best response after CAR-T therapy by PET-CT was CR in 81.8% (9/11) and PR in 18.2% (2/11), yielding an ORR of 100%. With a median follow-up of 12 months (range 4-16 months), no patient experienced disease progression or death. Adverse events included cytokine release syndrome (CRS): 63.6% (7/11) after BsAbs (all grade 1, predominantly after the first two doses) and 90.9% (10/11) after CD19 CAR-T therapy (with or without HDT/ASCT; all grade 1). No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred during treatment. Conclusions: These preliminary data suggest that BsAbs-containing bridging therapy prior to CD19-specific CAR-T therapy, either alone or combined with HDT/ASCT, is effective and safe in DLBCL. More detailed data will be presented at the conference.

BACKGROUND AND AIM:The acute pulmonary infectious disease caused by influenza viruses is known as influenza virus pneumonia (IVP). In recent years, Gegen Qinlian Decoction (GQD) has been widely used to treat pulmonary inflammation; however, the underlying mechanism of action of GQD in IVP remains unclear. This study aimed to elucidate the molecular mechanism through which GQD improved IVP. MATERIALS AND METHODS:The efficacy of GQD was evaluated using classical pharmacodynamic indicators in a murine model of H1N1-induced IVP. Network pharmacology predicted the material basis of GQD in improving IVP, while metabonomics and 16 s rDNA sequencing assessed its regulation on small molecule metabolites and intestinal flora. Additionally, molecular biology techniques were used to investigate the molecular mechanism underlying the improvement of IVP by GQD. RESULTS:The study results demonstrated that GQD exhibited a significant ameliorative effect on the inflammatory response in lung tissue of IVP mice. The potential pharmacological substances of GQD for improving IVP were identified by network pharmacology combined with ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) analysis, including puerarin, baicalin, berberine, and glycyrrhizin. Further analysis of biological processes and mechanisms of action predicted that GQD could improve IVP by inhibiting activation of inflammasomes, regulating the body's immune system, and intestinal microecology. Metabolomics and microbiomics findings revealed that GQD could bi-directionally regulate lipid and amino acid metabolites by increasing the abundance of beneficial bacteria like Akkermansia and Acetobacter, thereby maintaining host metabolic balance and immune homeostasis. RT-qPCR and immunohistochemistry results indicated that GQD improved IVP by inhibiting the complement C3/NLRP3 inflammasome pathway. CONCLUSION:The findings of this study confirmed that GQD effectively inhibited IVP by modulating the "gut microbiota-metabolomics-immune/inflammation" axis in the host, thereby establishing a solid immunological foundation for the clinical application of GQD.

The activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL) displays a worse outcome than the germinal center B-cell-like subtype (GCB-DLBCL). Currently, targeting the tumor microenvironment (TME) is the most promising approach to cure DLBCL with profound molecular heterogeneity; however, the factors affecting the tumor-promoting TME of ABC-DLBCL remain elusive. Here, cytokine interleukin-16 (IL-16) is expressed in tumor cells of ABC-DLBCL and secreted by the cleavage of active caspase-3. The serum IL-16 levels are not only a sensitive marker of treatment response, but also positively correlated with unfavorable prognosis in DLBCL patients. While IL-16 shows few direct promotional effects on tumor cell growth in vitro, its bioactive form significantly promotes tumor progression in vivo. Mechanically, IL-16 increases the infiltration of macrophages by the chemotaxis of CD4+ monocytes in the TME, enhancing angiogenesis and the expression of cytokine IL-6 and IL-10, as well as decreasing T-cell infiltration to accelerate tumor progression. This study demonstrates that IL-16 exerts a novel role in co-ordinating the bidirectional interactions between tumor progression and the TME. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, reverses the tumor-promoting effects of IL-16, providing new insights into treatment strategy in ABC-DLBCL.