Objective To evaluate the efficacy and safety of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) for a salvage therapy of patients with myelofibrosis (MF). Methods We conducted a retrospective study of 17 MF patients with poor performance status, refractory disease, or progressive disease who underwent RIC-allo-HSCT. Overall survival (OS), progression-free survival (PFS), hematopoietic reconstitution, the cumulative incidence of relapse and improvements in myelofibrosis and splenomegaly were analyzed. Results All 17 patients received RIC regimens. The neutrophil and platelet engraftment rates were 94.1% and 88.2%, respectively, with median engraftment times of 16 days (range, 11-22 days) and 22 days (range, 10-148 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) within 100 days post-transplant was 41.2%, and that of grade III-IV aGVHD was 17.6%. The overall incidence of chronic GVHD (cGVHD) was 35.3%. The reactivation rates of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were 47.1% and 29.4%, respectively. Before transplantation, there were 10 patients (58.8%) with MF-3 and splenomegaly. At six months after transplantation, the proportion of MF-3 decreased to 26.7%, MF-0 increased to 40.0%, and the proportion of splenomegaly decreased to 53.3%. As of the follow-up date, the proportion of MF-3 had decreased to 21.4%, MF-0 had increased to 57.1%, and all eight remaining patients with splenomegaly had shown varying degrees of spleen size reduction. The estimated 1-year OS and PFS were 88.2% (95% CI, 60.6%-96.9%) and 81.9% (95% CI, 53.8%-93.8%), and the estimated 3-year OS and PFS were 70.6% (95% CI, 26.0%-91.4%) and 65.5% (95% CI, 25.7%-87.7%), respectively. Conclusion RIC-allo-HSCT is a feasible and effective alternative for salvage therapy in MF patients.

Cancer patients are at an elevated risk for SARS-CoV-2 infection and require vigilant monitoring. The efficacy and safety of Azvudine in treating COVID-19 among this vulnerable group remain under-researched. We conducted a multicenter, retrospective cohort study of nine hospitals involving cancer patients with COVID-19 hospitalized from December 2022 to January 2023. To minimize immortal time bias, patients who died or were discharged within 24 h of drug administration were excluded. A 2:1 propensity score matching (PSM) was performed to balance baseline characteristics, explicitly adjusting for tumor metastasis, tumor classification, and COVID-19 vaccination status. The primary outcome was 30-day all-cause death, and the secondary outcome was composite disease progression. Robustness was verified using Probit regression and double robust estimation with Augmented Inverse Probability Weighting (AIPW). A total of 1,829 patients were included in the final matched cohort (1,200 in the control group and 629 in the Azvudine group). Azvudine treatment was significantly associated with a reduced risk of all-cause death (adjusted hazard ratio [HR]: 0.65, 95

Hypertension is widely acknowledged as a major risk factor for disease severity and death in patients with coronavirus disease 2019 (COVID-19). Azvudine is recommended for COVID-19 patients in China. However, its clinical efficacy and safety for individuals with hypertension remain unclear. This nine-center retrospective cohort study included 32,864 hospitalized COVID-19 patients in Henan Province, China, from December 2022 to January 2023. Among these patients, those with hypertension were identified and divided into the Azvudine and control groups (standard treatment without antiviral medication) after propensity score matching (PSM) at a 1:1 ratio. The primary outcomes measured were all-cause mortality and composite disease progression. Subgroup analyses and sensitivity tests were conducted to verify the robustness of the results. Safety was assessed based on adverse events (AEs). After PSM to balance baseline characteristics, the analysis included 2434 Azvudine recipients and 2434 controls, forming a final matched cohort. Azvudine was associated with a lower risk of all-cause mortality (HR: 0.64, 95% CI 0.519-0.780; P < 0.001) and composite disease progression (HR: 0.84, 95% CI 0.719-0.985; P = 0.032) in hypertensive patients with COVID-19. In five sensitivity analyses, Azvudine showed a highly robust effect in reducing all-cause mortality, while the evidence for a reduction in the progression of composite disease progression was less consistent. No significant difference in severe AEs (≥ Grade 3) was observed between groups. These real-world findings suggest Azvudine may be a promising antiviral option for hypertensive COVID-19 patients, but further prospective trials are necessary to confirm these results.

Although azvudine has become a priority in the treatment of SARS-CoV-2, its effectiveness and safety among COVID-19 patients who already have chronic respiratory diseases (CRDs) have not been sufficiently validated. A retrospective, multicenter cohort study involving 10 hospitals in Henan Province was performed to assess inpatients with COVID-19 and CRDs (Clinical Trial Registration Number: NCT06349655). Azvudine recipients and the control group were matched at a 1:1 ratio using propensity scores. The clinical outcomes (all-cause death and composite disease progression) were analyzed using Kaplan-Meier and Cox regression analyses, with additional subgroup and sensitivity analyses performed. Eighteen clinical features were included to construct a nomogram for predicting the survival of inpatients with COVID-19 and CRDs. Out of 37,606 hospitalized COVID-19 patients, 1462 azvudine recipients and 1462 matched controls were included in the analysis. The results of Kaplan-Meier and multivariate Cox regression analyses demonstrated that in contrast to the controls, azvudine use was associated with a decreased risk of all-cause death in patients with COVID-19 and pre-existing CRDs (log-rank: p = .012; HR: 0.73; 95% CI: 0.553-0.956); but was not significantly different in terms of composite disease progression (log-rank: p = .82; HR: 1.15; 95% CI: 0.948-1.383). An analysis of subgroups and three sensitivity appraisals validate the above outcomes. The number and type of adverse events associated with azvudine treatment were acceptable. The concordance index (0.8499, 0.8497) and area under the curve (86.1%, 80.4%) of the nomogram showed satisfactory discriminative ability in the training and test sets. Azvudine could be effective in reducing all-cause death among inpatients with COVID-19 and CRDs and had few serious adverse events.

BACKGROUND:Azvudine and nirmatrelvir/ritonavir are recommended as priority treatments for SARS-CoV-2 infection in China, but their effectiveness and safety in patients with pre-existing chronic liver diseases remains unknown. METHODS:We conducted a multicenter retrospective cohort study of hospitalized SARS-CoV-2 infected patients with chronic liver diseases in ten hospitals of Henan Province. Azvudine recipients were 2:1 propensity score matched with nirmatrelvir/ritonavir recipients. Efficacy and safety were evaluated by Kaplan-Meier analysis, multivariable Cox regression model, subgroup analysis, as well as sensitivity analyses. RESULTS:Among 37606 hospitalized patients infected with SARS-CoV-2, 1355 azvudine recipients and 373 nirmatrelvir/ritonavir recipients met the inclusion criteria. Patients with azvudine treatment showed comparable effectiveness to nirmatrelvir/ritonavir with regard to both all-cause death (P = 0.34) and composite disease progression (P = 0.32), even after adjusting for other covariates (all-cause death: HR: 0.80, 95%CI: 0.574-1.128; composite disease progression: HR: 1.31, 95%CI: 0.999-1.723). Notably, compared with nirmatrelvir/ritonavir, azvudine showed better effectiveness for patients with a comorbidity of primary malignant tumor in reducing all-cause death. Four sensitivity analyses further confirmed the robustness. CONCLUSIONS:The effectiveness of azvudine may potentially comparable to nirmatrelvir/ritonavir in SARS-CoV-2 infected patients with pre-existing liver diseases with respect to all-cause death and composite disease progression, without serious safety concerns. Due to the existence of potential biases, further studies still need to evaluate the efficacy of these two drugs. TRIAL REGISTRATION:The trial was retrospectively registered at ClinicalTrials.gov (CT.gov identifier: NCT06349655).

Objectives Azvudine and Paxlovid are the primary antiviral agents for the management of COVID-19. However, there is currently insufficient evidence regarding the effectiveness and safety of these drugs in treating COVID-19 patients with pre-existing hypertension. The objective of this study was to assess their effectiveness and safety among those patients in a real-world context. Design Retrospective cohort study. Setting Electronic medical record data of COVID-19 patients with pre-existing hypertension were extracted from nine hospitals in Henan Province from 5 December 2022 to 31 January 2023. Participants Following 2:1 propensity score matching (PSM), 996 individuals who received treatment with azvudine and 498 individuals who received treatment with Paxlovid were included in the analysis. Primary and secondary outcome measures The primary outcome was all-cause death and the secondary outcome was the composite disease progression. Results Following adherence to the inclusion and exclusion criteria and 2:1 PSM, 996 individuals were included in the azvudine group and 498 in the Paxlovid group. The Cox regression analysis revealed that the azvudine group had a significantly lower risk of all-cause death compared with the Paxlovid group (HR 0.64, 95% CI 0.455 to 0.911, p=0.013). However, there was no statistically significant difference in composite disease progression between the two groups (HR 0.93, 95% CI 0.711 to 1.229, p=0.629). Subgroup analysis indicated that, compared with Paxlovid, patients with moderate disease receiving azvudine treatment exhibited a significantly reduced risk of composite disease progression (HR 0.46, 95% CI 0.24 to 0.89). The safety analysis showed that the azvudine group had fewer adverse events. Conclusions Among COVID-19 patients with pre-existing hypertension, the effectiveness of azvudine is not inferior to Paxlovid in reducing all-cause death and composite disease progression, with fewer adverse events. Trial registration number NCT06349655 .

e14515 Background: The Epstein–Barr Virus (EBV) infects over 95% of the global population. The WHO has definitively identified EBV as the first human tumor-associated virus, thereby underscoring the necessity for novel therapeutic options. KSD-101, a First-in-class autologous dendritic cell (DC) vaccine which is loaded with the EBV-related antigen, is specifically tailored to target EBV-associated lymphoproliferative diseases (EBV-LPDs). Methods: Patients (pts) with EBV-LPDs and have not respond to or relapsed after standard treatment will be enrolled. Pts will receive monotherapy with KSD-101 via subcutaneous injection once every 2 weeks for 3-5 doses, without requiring pre-treatment lymphodepletion. The study used a 3+3 dose-escalation design, aiming primarily to assess tolerability, safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD), with secondary objective to explore clinical efficacy and immune responses. Results: Between January 16, 2023, and May 21, 2024, 11 pts were ultimately enrolled and treated with KSD-101. In the escalation phase, 3 pts received 5.0 × 10 6 cells/dose and 2 pts received 7.5 × 10 6 cells/dose. Based on the safety, preliminary efficacy, and feasibility assessment, we decided to cancel the third dose group and apply 5.0 × 10 6 cells/dose to the expansion phase. In all pts, neither DLT nor MTD were explored. Vaccinations were well tolerated. Pts experienced KSD-101-related adverse events were injection site reactions (grade 1, 90.9%), fever (grade ≤ 2, 72.7%), lymphadenopathy (grade 1, 54.5%) and lymphocythemia (grade 1, 9.1%). The data cutoff was August 14, 2024 and the median follow-up was 54.1 weeks (range, 5.9-71.1 weeks). Two hemophagocytic lymphohistiocytosis pts discontinued from the study due to rapid early-stage disease progression and subsequently received alternative therapeutic interventions. The best ORR was 88.9% (8/9), with all pts achieving complete remission (CR). The DCR was 100% (9/9), with one pt demonstrating stable disease following vaccination. After vaccinations, we found that the peak proportion of EBV-specific T cells in CD3 + CD8 + cells (average, 4.21%) was significantly increased ( p < 0.05) compared to baseline (average, 0.61%) and the peak number of immune cells also increased, such as activated T cells ( p < 0.05, average increased to 2.61-fold), NK cells ( p < 0.01, average increased to 1.77-fold) and CD8 + T cells ( p < 0.05, average increased to 2.02-fold). We also found that the valley number of T-regs significantly reduced ( p < 0.01, average reduced to 58.14%). Conclusions: AS of now, KSD-101 has demonstrated good safety and efficacy and could activate immune system. Our study highlights its potential as a promising therapeutic agent for the treatment of EBV-LPDs. Larger prospective studies and a longer follow-up period is needed to be conducted. Clinical trial information: NCT05635591 .

Abstract Background:Therapeutic options for relapsed/refractory acute myeloid leukemia (R/R AML) remain limited, with poor long-term survival. Our observation of rapid blast decline kinetics in R/R AML patients treated with the selinexor-based regimen predicted therapeutic efficacy. We hypothesized that these kinetics could guide therapy intensification in AML. This prospective study evaluates the XAB regimen, leveraging blast-reduction patterns observed in R/R AML to optimize new diagnosed AML (ND AML) therapy. Methods:The single-arm prospective study was conducted at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients aged 18-60years diagnosed with R/R or ND AMLwere included. All received the XAB regimen: selinexor (35 mg/m² twice weekly), azacitidine (75 mg/m²/day days 1–5), and venetoclax (100mg day 1, 200mg day 2, and 400 mg daily days 3- 21). Bone marrow assessments at weeks 1 and 2 were combined to classify blast reduction kinetics: Type A (sensitive): complete remission with/without count recovery (CR/CRi) at both timepoints; Type B (moderately sensitive): partial remission (PR) at week 1 → PR (blast continuously to decline)/CR/CRi at week 2; Type C (low sensitivity): PR/CR/CRi at week 1 → NR at week 2; Type D (resistant): NR at both timepoints. The Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (TJ-IRB20230955, TJ-IRB202502063) approved these prospective studies. Results:Among 16 R/R AML patients, blast kinetics classified 50.0% (n=8) as Type A, 6.3% (n=1) as Type B, 25.0% (n=4) as Type C, and 18.8% (n=3) as Type D. Type A, five of these patients were soon bridged to allogenic hematopoietic stem cell transplantation (allo-HCST). However, Type B/C patients receiving XAB + cytarabine (Ara-C 50mg/day×3-5days, A50) showed Type B had PR and Type C all NR. All Type D patients discontinued therapy without response. At median follow-up of 8.2 months, 62.5% (10/16) survived—50% (5/10) of whom were Type A responders. The XAB regimen demonstrated significant efficacy within the initial two-week period, with no added benefit from the next two weeks of therapy. Consequently, the duration of treatment was restricted to two weeks, to inform subsequent therapeutic decisions. Applying this kinetic-guided algorithm to ND AML patients. Among 21 ND AML patients, 8 (38.1%) achieved CR/CRi at week 1. These early responders continued XAB for a second week, with all 8 (100%) maintaining CR/CRi; transplant-eligible patients will proceed to two cycles of consolidation (X + Ara-C + idarubicin/mitoxantrone) followed by allo-HCST The remaining 13 patients (61.9%) with PR/NR at week 1 received XAB + A50 during week 2. This approach resulted in a 92.3% (12/13) CR/CRi/PR response, indicating efficacy. Following this response, patients will be administered a third week of XAB + A50. If patients are eligible or willing to undergo allo-HCST, consolidation therapy will be administered with the aforementioned. One patient (7.7%) remained NR after two weeks and switched to alternative intensive chemotherapy.Conclusion: Bone marrow blast reduction kinetics (Types A-D) robustly predict therapeutic efficacy of the XAB regimen across AML disease states. In R/R AML, Type A kinetics identify patients benefiting from continued XAB (100% CR/CRi). In ND AML, this regimen achieves 100% CR/CRi in rapid responders. Early kinetic stratification enables real-time treatment adaptation—maintain in responders and prompt transition to intensive therapy in non-responders. This study validates bone marrow blast kinetics as a dynamic biomarker for personalized AML therapy optimization, thereby enabling timely adjustments to treatment regimens.

Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor long-term survival despite intensive therapeutic regimens. Metabolic rewiring has emerged as a hallmark of AML, with leukemia stem cells and chemotherapy-resistant cells exhibiting a preference for mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO)(Blood. 2023;141(10):1119-1135). We previously showed that AML metabolism is heterogeneous and influenced by genetic alterations and transcriptional regulation(Leukemia. 2022;36(9):2196-2207). Snail family transcriptional repressor 2 (SNAI2), a zinc finger transcription factor, is a known driver of epithelial–mesenchymal transition. Elevated expression of SNAI2 in AML is associated with poor prognosis and chemoresistance(Leukemia. 2020;34(2):380-390). Analysis of AML datasets revealed that SNAI2 expression positively correlates with metabolic gene signatures. To elucidate the metabolic role of SNAI2 in AML, we conducted integrative multi-omics analyses, metabolic flux measurements, and functional assays. Methods Human AML cell lines expressing either SNAI2 (SNAI2-OE) or an empty vector (EV) control were generated. Targeted metabolomics, transcriptomics, and proteomics were conducted to assess metabolic changes. Differentially expressed metabolites, transcripts, and proteins were subsequently identified; selected targets were validated via qRT-PCR and Western blotting. Seahorse Extracellular Flux assay was used to measure the glycolysis, mitochondrial respiration, and metabolic dependencies on glucose, glutamine, and fatty acids. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential (via TMRE), and mitochondrial mass (via MitoTracker) were measured by flow cytometry. Drug sensitivity assays were conducted to determine the IC₅₀ values for rotenone (an OXPHOS inhibitor) and etomoxir (a FAO inhibitor). Statistical analyses included two-tailed t-tests and mixed-effects models with Benjamini–Hochberg correction. Results SNAI2 overexpression markedly suppressed mitochondrial respiration without altering glycolytic rates in AML cells, indicating that the decline in OXPHOS was not compensated by glycolytic upregulation. Targeted metabolomics revealed the suppression of the tricarboxylic acid (TCA) cycle, with the levels of key intermediates (α-ketoglutarate, succinate, fumarate, and malate) significantly reduced in SNAI2-OE cells. SNAI2-OE cells exhibited decreased ROS levels and mitochondrial membrane potential, despite unchanged mitochondrial mass. RNA-seq and proteomic integration showed consistent downregulation of mitochondrial enzymes—SDHB (complex II), IDH3B, and MDH2—whereas lipid metabolism enzymes (ACSM3 and MID1IP1) were upregulated. These findings were validated using qRT-PCR and immunoblotting. Seahorse substrate oxidation stress test showed a marked reduction in mitochondrial respiration upon FAO inhibition by etomoxir in SNAI2-OE cells, indicating that SNAI2 drives a heightened reliance on fatty acids as respiratory substrates. Consistently, SNAI2-OE cells exhibited heightened sensitivity to both the OXPHOS inhibitor rotenone and the FAO inhibitor etomoxir. These data suggest that SNAI2-driven AML cells exhibit increased metabolic vulnerability due to their reliance on FAO and compromised OXPHOS capacity.Conclusions Our findings uncover a novel metabolic reprogramming mechanism in AML orchestrated by SNAI2. By suppressing TCA cycle activity and OXPHOS while enhancing FAO, SNAI2 enforces a hypo-oxidative, FAO-dependent mitochondrial phenotype. This shift renders SNAI2-high AML cells metabolically fragile and highly susceptible to inhibition of OXPHOS and FAO. Clinically, SNAI2 may serve as a biomarker for identifying AML patients who are likely to benefit from metabolism-targeted therapies. In summary, SNAI2 promotes leukemic progression through metabolic rewiring, thereby exposing novel therapeutic vulnerabilities exploitable for precision medicine in AML.

Patients with kidney disease (KD) are at high risk of contracting COVID-19 and developing severe disease. There is still a lack of guidance regarding the treatment of COVID-19 in patients with KD. The safety and effectiveness of Azvudine in treating COVID-19 patients with KD remain unknown. This study included 32,864 COVID-19 patients from nine centers in Henan Province, China. After applying the exclusion criteria and 2:1 propensity score matching, 438 and 219 participants in the Azvudine and Paxlovid groups, respectively, were subjected to analysis. Kaplan–Meier analysis revealed no significant differences in all-cause death or composite disease progression between the Azvudine and Paxlovid groups (all p values > 0.05). The same results were obtained in the Cox regression analysis after baseline characteristics adjustment. Three different sensitivity analyses contributed to the robustness of these findings. Subgroup analysis revealed that patients treated with Azvudine had a lower risk of composite disease progression than patients treated with Paxlovid did among patients with moderate disease (p = 0.016, HR: 0.51, 95

Azvudine and nirmatrelvir-ritonavir are prioritized treatments for SARS-CoV-2 infection in China, but their effectiveness and safety in hospitalized patients with COVID-19 and pre-existing diabetes remains unknown. In this retrospective cohort study, we collected 32864 hospitalized COVID-19 patients from nine hospitals, among which 636 azvudine recipients and 318 nirmatrelvir-ritonavir recipients were enrolled for final analysis after exclusion and propensity score matching. Kaplan-Meier and multivariate Cox regression analysis results showed that azvudine had a lower risk of all-cause death compared with nirmatrelvir-ritonavir for the treatment of patients with COVID-19 and pre-existing diabetes (log-rank: P = 0.044; HR: 0.63; 95% CI: 0.431-0.934). No significant difference was found in composite disease progression between the two groups. Five sensitivity analyses verified the robustness of the results. Overall, azvudine may be comparable to nirmatrelvir-ritonavir in terms of both all-cause death and composite disease progression among hospitalized patients with COVID-19 and pre-existing diabetes, with acceptable adverse events.

Abstract Introduction Acute graft-versus-host disease (aGVHD) remains a major cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dysfunctional regulatory T cells (Tregs) are implicated in aGVHD pathogenesis, but molecular mechanisms remain unclear. Emerging evidence suggests post-transcriptional regulation may play a pivotal role in Treg mediated immunosuppression. Here, we employed an approach combining single-cell transcriptomics (scRNA-seq) of patient CD3+ T cells with a validated aGVHD murine model to identify zinc finger protein 36-like 2 (ZFP36L2), an RNA-binding protein regulating mRNA stability, as a novel molecular checkpoint in aGVHD progression. Methods Peripheral blood CD3+ T cells were isolated by magnetic bead sorting from 6 patients received allo-HSCT (3 aGVHD vs. 3 controls). The CD3+ T cells underwent scRNA-seq (Singleron GEXSCOPE®). Differentially expressed genes (DEGs) in Tregs were cross-validated with Gene Expression Omnibus (GEO) datasets (GSE17922: genes downregulated in aGVHD, GSE36832: genes rescued post-therapy) to identify hub genes. For validation, murine aGVHD model was established using female BALB/c (H-2d) as recipients, which received 6.5 Gy total body irradiation (TBI) and infused with bone marrow (1×10⁷) and splenocytes (5×10⁶) of male C57BL/6 (H-2b) as donors. Murine aGVHD model were divided into healthy control group, TBI-only group, non-aGVHD group and aGVHD group, 5 mice in each group and 3 independent replicates. ZFP36L2 expression in target organs (liver, spleen, colon, small intestine) were assessed by qPCR, immunohistochemistry (IHC), and Western blot. Results Peripheral blood CD3+ T cells were clustered into 9 subsets (including CD8+ Effector T Cells, CD8+ Effector Memory T Cells, CD8+ Exhausted T Cells, Gamma Delta T Cells, Natural Killer Cells, Naive T Cells, Proliferating T Cells and Tregs). ScRNA-seq identified higher expression of proliferation-related genes (MKI67, GAPDH, PCLAF) in Treg cells and resulted in Tregs significantly expanded in aGVHD patients (P=0.025). Cross-analysis with GEO datasets (GSE17922/GSE36832) identified ZFP36L2 as a downregulated gene in aGVHD patients’ Tregs. ZFP36L2 was significantly downregulated in aGVHD patients’ PBMCs (17 aGVHD vs. 17 non-aGVHD, P=0.03) from clinically validation. In murine models, ZFP36L2 mRNA and protein were downregulated in aGVHD target organs (liver, colon, small intestine; P<0.05) compared with other 3 groups. The reduction of p-AKT/AKT ratio is consistent with the downregulation of ZFP36L2. To evaluate the impact of phosphorylation on ZFP36L2, the aGVHD group received therapeutic intervention: rapamycin (1 mg/kg/day) or vehicle with the same dose of PBS by intraperitoneal injection from d0~d15. IHC and qPCR revealed that rapamycin upregulated ZFP36L2 expression（P<0.05）and mitigated target organ damages. While heterogeneity of ZFP36L2 level increasement exists among different organs, which was more prominent in cutaneous, splenic, and small intestinal tissues compared to hepatic and colonic tissues. Concurrently, rapamycin increased splenic Treg proportions (2.59±0.23% vs. 1.22±0.07%, P=0.03) and Foxp3+ expression in tissue-derived single-cell suspensions from liver, spleen, and small intestinal from flow cytometry analysis. Conclusions We identify ZFP36L2 as a critical downregulated target in aGVHD Tregs via scRNA-seq, aGVHD murine models and clinical validation. Restoring ZFP36L2 experssion by rapamycin could recalibrate Treg-mediated immunosuppression in aGVHD. However, the precise molecular mechanisms underlying ZFP36L2-mediated immunoregulation require further investigation.

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy. Despite recent therapeutic advances, patients continue to experience poor outcomes and high rates of relapse, highlighting the need for novel targeted therapies,particularly for patients with primary resistance and relapse. Selinexor, a selective inhibitor of nuclear export (SINE), targets exportin-1 (XPO1) and impedes nuclear-cytoplasmic trafficking, leading to nuclear accumulation of tumor suppressors, cell cycle regulators, and DNA damage response proteins(Cancer discovery 2014 May; 4(5): 527-537). Preclinical studies have demonstrated that selinexor induces cell cycle arrest and apoptosis in AML cell lines(Blood 2012 Aug 30; 120(9): 1765-1773). Selinexor—either as monotherapy or in combination with chemotherapy—has shown efficacy and acceptable tolerability in patients with relapsed or refractory AML(Haematologica 2018 Oct; 103(10): 1642-1653). However, the variability in patient responses highlights the urgent need for predictive biomarkers of selinexor sensitivity. LNK, encoded by SH2B3, is a member of the SH2B adaptor family, comprising conserved dimerization, pleckstrin homology, and SH2 domains(Archivum immunologiae et therapiae experimentalis 2012 Dec; 60(6): 415-429). It modulates signaling downstream of various cytokines and growth factor receptors(Journal of immunology (Baltimore, Md : 1950) 2000 May 15; 164(10): 5199-5206). LNK is highly expressed in hematopoietic stem cells, and negatively regulates thrombopoietin and erythropoietin signaling via JAK2 binding(Circulation research 2009 Apr 24; 104(8): 969-977). Here, we investigate whether SH2B3 expression levels predict selinexor sensitivity in AML, with the aim of improving patient stratification and therapeutic outcomes. Methods First, the sensitivity of eight human AML cell lines (MV4-11, OCI-AML3, MOLM-13, K562, THP-1, U937, HL-60, and SKM-1) to selinexor was assessed. Cell viability following selinexor treatment was measured using CCK-8 assays, and apoptosis was quantified by annexin V/propidium iodide staining with flow cytometry. Baseline transcriptomic data of AML cell lines were retrieved from the Cell Model Passports database. Differential gene expression analysis between selinexor-sensitive and -resistant AML cells was performed in R using the limma package (thresholds: adjusted P < 0.05, |log₂ fold-change| > 1). SH2B3 knockdown and overexpression were achieved via lentiviral transduction using pLKO.1 and pCDH vectors, respectively; transduction efficiency was verified by qRT-PCR and Western blot. Results AML cell lines segregated into high-sensitivity (MV4-11, OCI-AML3, MOLM-13, K562) and low-sensitivity (THP-1, U937, HL-60, SKM-1) groups based on half-maximal inhibitory concentration (IC₅₀) values and apoptosis response to selinexor. Comparison of transcriptome sequencing data identified SH2B3 as the most significantly differentially expressed gene between these groups. Functional modulation of SH2B3 altered selinexor response: SH2B3 knockdown in high-sensitivity AML cells attenuated drug efficacy, whereas SH2B3 overexpression in resistant AML cells enhanced proliferation inhibition and apoptotic induction of selinexor. These findings indicate that SH2B3 expression levels directly influence selinexor sensitivity in AML cells. Conclusion Our data demonstrate that SH2B3 expression correlates with selinexor responsiveness in AML cell lines. Modulation of SH2B3 influence selinexor-induced cell growth and apoptosis, suggesting its potential utility as a predictive biomarker. Given that the LNK protein interacts with JAK2 and inhibits JAK-STAT signaling(Jiang J,et al 2012; Baran-Marszak F,et al 2010; Bersenev A, et al 2010; Gery S, et al2009), we hypothesize that SH2B3's impact on selinexor sensitivity may be mediated through this pathway. Ongoing studies are investigating the mechanistic interplay between SH2B3, JAK-STAT signaling, and XPO1 inhibition, to further refine biomarker-guided therapeutic strategies in AML.

Introduction During the Omicron infection wave, diabetic patients are susceptible to COVID-19, which is linked to a poor prognosis. However, research on the real-world effectiveness and safety of Azvudine, a common medication for COVID-19, is insufficient in those with pre-existing diabetes.Methods In this retrospective study, we included 32,864 hospitalized COVID-19 patients from 9 hospitals in Henan Province. Diabetic patients were screened and divided into the Azvudine group and the control group, via 1:1 propensity score matching. The primary outcome was all-cause mortality, and the secondary outcome was composite disease progression. Laboratory abnormal results were used for safety evaluation.Results A total of 1,417 patients receiving Azvudine and 1,417 patients receiving standard treatment were ultimately included. Kaplan-Meier curves suggested that all-cause mortality (P = 0.0026) was significantly lower in the Azvudine group than in the control group, but composite disease progression did not significantly differ (P = 0.1). Cox regression models revealed Azvudine treatment could reduce 26% risk of all-cause mortality (95% CI: 0.583-0.942, P = 0.015) versus controls, and not reduce the risk of composite disease progression (HR: 0.91, 95% CI: 0.750-1.109, P = 0.355). The results of subgroup analysis and three sensitivity analyses were consistent with the previous findings. Safety analysis revealed that the incidence rates of most adverse events were similar between the two groups.Conclusion In this study, Azvudine demonstrated good efficacy in COVID-19 patients with diabetes, with a lower all-cause mortality rate. Additionally, the safety was favorable. This study may provide a new strategy for the antiviral management of COVID-19 patients with diabetes.

Abstract Background: Patients with relapsed/refractory acute myeloid leukemia (R/R AML) face dismal outcomes, highlighting the critical need for effective salvage therapies. The DCIA±X regimen—combining decitabine, cladribine, idarubicin, cytarabine, and optional targeted agents (X)—leverages synergistic mechanisms to overcome chemoresistance. In a previous retrospective study, a total of 10 patients with R/R AML were treated with the DCIA ±X regimen, and nine patients with R/R AML reached complete remission with/without count recovery (CR/CRi) after one course of treatment, with a CR of 90%. Bridging hematopoietic stem cell transplantation was successful in four of these patients. Consequently, a prospective study was conducted employing the DCIA±X regimen to evaluate the effectiveness and safety of the intervention in R/R AML. Methods: This single-arm prospective study was conducted at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients aged 18-60 years diagnosed with R/R AML were included. All patients received DCIA±X regimen: decitabine (20mg/m2/day days 1–5), cladribine (5mg/m2/day days 4–8), idarubicin (10mg/m2/day days 4–6), cytarabine (100-200mg/m2/day days 4–10), X (according to targeted agents). The Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (TJ-IRB202303151) approved this prospective study. Data analysis was performed using SPSS (version 27). Results: This prospective cohort study enrolled 22 R/R AML patients (including 14 males and 8 females). The median age was 45 years (IQR 35-50). Disease status included relapse (40.9%) and primary refractory (59.1%). Baseline characteristics included Initial blood routine [median WBC 3.15×10⁹/L (IQR 1.44-127.72), Hb 72 g/L (IQR 62.30-90.00), PLT 60×10⁹/L (IQR 27.30-94.30)] and bone marrow blast burden (median 50% [IQR 28-75]). Initial chromosomal abnormalities were detected in 17 out of 22 cases, while gene mutations were identified in 16 out of 22 cases. CR/CRi was 81.8% (n=18), with a partial response (PR) rate of 13.6% (n=3), yielding an overall response rate (ORR) of 95.4% (n=21). Non-response (NR) occurred in 1 patient (4.5%). Subsequently, 63.6% (n=14) underwent allogeneic transplantation. The 1-year relapse-free survival (RFS) and overall survival (OS) were 68.5% and 84.78%, respectively. Hematologic toxicity was manageable, with the median time to neutrophil recovery of 17 days (IQR 14-20) and platelet recovery of 19 days (IQR 9-21).Conclusion: This novel reinduction regimen demonstrated robust activity and acceptable toxicity in treating R/R AML patients, achieving high CR/CRi and ORR rates, facilitating successful bridge to transplant in most responders, and promising 1-year RFS and OS.

Decitabine has demonstrated efficacy in the treatment of acute myeloid leukemia (AML), though therapeutic responses vary widely due to the disease's inherent heterogeneity. To address this clinical challenge, we aimed to identify reliable biomarkers for predicting decitabine responsiveness in patients with AML. In our previous studies, integrated epigenetic and transcriptomic profiling identified BTG1 as a methylation-associated tumor suppressor gene correlated with decitabine sensitivity. We found that decitabine upregulates BTG1 expression through demethylation, and this upregulation enhances the sensitivity of AML cells to decitabine. BTG1 may exert its effect through the Wnt/β-catenin signaling pathway. Notably, BTG1 expression levels were significantly associated with treatment outcomes, including complete remission (CR) rates and measurable residual disease (MRD) negativity in patients receiving decitabine-containing regimens (either "7 + 3" or alternative combinations). Importantly, peripheral blood BTG1 mRNA expression levels reliably predicted therapeutic response to decitabine, establishing BTG1 as a robust biomarker of decitabine efficacy in AML management. Clinical trial registration: ChiCTR2000037928.

Background Some newly diagnosed (ND) acute myeloid leukemia (AML) or higher-risk myelodysplastic syndrome (MDS) patients (pts) are ineligible for or unwilling to receive intensive chemotherapy. These pts usually receive low-intensity regimens. preliminary data from clinical trials have indicated that non-intensive chemotherapy containing selinexor can achieve a relatively high response rate in unfit AML. Therefore, we explored selinexor-based chemotherapy-free or low-dose chemotherapy regimens in the above-mentioned ND AML or MDS. Aims To investigate the efficacy and safety of selinexor based non-intensive chemotherapy for the ND AML or MDS, and evaluate the timing for early adjustment of the regimens. Methods Pts who refused or were ineligible for intensive chemotherapy were enrolled and received the following regimens: selinexor was initially dosed at 35 mg/m2 twice a week (60mg BIW). Azacitidine 75 mg/m2/d for 5 to 7 days, venetoclax was administered at 100 mg, 200 mg, and 400 mg on d1-3, respectively, followed by 400 mg daily days 3 to 14 (XAB regimen). Bone marrow puncture was performed every week during the treatment. According to whether CR/CRi was achieved in the first and second weeks, subsequent treatments were adjusted according to the response. Pts who achieved CR/CRi early subsequently received allo-HSCT if they were fit for or willing to undergo transplantation. Other pts were treated with low-dose cytarabine (Ara-C) 50mg/d on the basis of XAB regimen for 5 days, followed consolidation and maintenance therapy. The specific treatment process can be found in flow chart figure. Results As of July 2025, 29 pts were enrolled, median age of 58, comprising 17 males. 18 pts with AML, 11 pts with MDS. Risk stratification was as follows: AML: 5 adverse, 6 intermediate, 1 favor, 6 unknown (owing to the absence of available mutation or chromosomal information); MDS: 1 very high, 5 high, 3 intermediate, 2 unknown. After one week of XAB treatment, 17 pts (58.6%) achieved CR/CRi, 4 (13.7%) PR, and 8 (27.5%) NR. After the second week of treatment, 20 pts (68.9%) CR, 7 (24.1%) PR, 2 (6.8%) NR (3 of NR and 3 of PR acquired CR/CRi respectively, and 4 of NR acquired PR). Five pts subsequently received allo-HSCT. The median follow-up time was 60 days, and 22 pts (75.9%) were survived. In the most recent 14 pts enrolled, we adjusted the frequency of selinexor in the XAB regimen from BIW to three times a week (60mg TIW). We found that this could enable the bone marrow blasts≤5% more rapidly (64.3% of pts in the first week and 71.4% in the second week), while in the BIW group were 53.3% and 66.7% respectively. After 2 weeks of treatment, among pts evaluable for safety, the incidence of grade 4 neutropenia was 80.0% (12/15) in BIW group, with a median recovery time of 13 (range, 0 to 20) days. In TIW group, the incidence was 92.8% (13/15), and the median recovery time was 8 (range, 1 to 41) days. The incidence of grade 4 thrombocytopenia was 40% (6/15) in BIW group, with a median recovery time of 1 (range, 0 to 16) days. In TIW group, the incidence was 57.1% (8/15), and the median recovery time was 1 (range, 0 to 25) days. Conclusion A high rate of early remission could be achieved in ND AML/MDS pts treated with non-intensive regimen containing Selinexor, and administration of selinexor TIW achieves a higher rate of early remission compared with BIW. Selinexor-containing regimens provide a new treatment option for these pts.

Abstract Azvudine is recommended as a priority treatment for patients with Coronavirus Disease 2019 (COVID‐19) during Omicron wave in China, but its efficacy and safety in elderly patients is unknown. In this multicenter, retrospective study, we identified 19763 elderly patients (aged over 60 years) with COVID‐19 from nine hospitals in Henan Province, China. The primary outcome is all‐cause death and the secondary outcome is composite disease progression. After propensity score matching, 4109 Azvudine recipients and 4109 matched controls is included, with average age of 75.15 years. Kaplan–Meier analysis reveales a notably survival and progression‐free benefit in Azvudine treatment. The Cox analysis shows that compared with controls, Azvudine recipients have a 33% lower risk of all‐cause death (95% confidence Interval (CI): 0.580–0.772, p < 0.001), but have no significant difference in composite disease progression (hazard ratio: 0.93, 95% CI: 0.833‐1.046, p = 0.234). Subgroup analysis suggested Azvudine have a stronger protective effect in patients concomitant with antibiotics. Three sensitive analyses confirm the robustness of the findings. The safety of Azvudine in elderly patients is acceptable. These findings indicate that Azvudine therapy can reduce the rate of all‐cause death in hospitalized elderly patients with COVID‐19, and without obvious adverse events.

Abstract Despite azvudine being prioritized for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, its effectiveness and safety remain inadequately substantiated in hospitalized SARS‐CoV‐2 infected patients with liver diseases. A retrospective nine‐center cohort study along with an independent validation cohort is conducted to examine the efficacy of azvudine (Clinical Trial Registration Number: NCT06349655). The primary outcome is all‐cause mortality and the secondary outcome is composite disease progression. Efficacy is assessed via Kaplan–Meier analysis and Cox regression, with subgroup and sensitivity analyses for further validation. Among 32 864 hospitalized SARS‐CoV‐2 infected patients, 1022 eligible azvudine recipients, and 1022 controls are included through propensity score match. Kaplan–Meier analysis reveals that azvudine treatment is associated with a lower risk of all‐cause mortality and composite disease progression (both p<0.0001). Cox regression analysis suggests azvudine recipients could have a 39% lower risk of all‐cause mortality than controls (95% confidence interval [CI]: 0.468–0.795, p<0.001), but with no notable significance in composite disease progression (hazard ratio: 0.85, 95% CI: 0.686‐1.061, p = 0.154). Subgroup analysis suggests that azvudine has a greater benefit for both all‐cause mortality and composite disease progression in patients with kidney diseases or without autoimmune diseases. Three sensitivity analyses and validation cohorts confirm the robustness of the findings. Safety analysis observes few adverse events in azvudine recipients. Within 15 days after azvudine administration, no significant difference in liver function indexes and kidney function indexes is observed between the two groups except for a few time points. These findings demonstrate that azvudine shows potential clinical efficacy in improving all‐cause mortality in hospitalized SARS‐CoV‐2 infected patients with liver diseases, with acceptable adverse effects.