Background:Patients with acute leukemia are at increased risk of microbial infections due to factors such as the disease itself, intensive chemotherapy, and transplantation. Untimely or inadequate treatment can prolong therapy, raise costs, and even threaten patient survival, impacting overall cancer treatment outcomes. Traditional microbial identification relies on blood cultures (BCs), but their low positivity rate and lengthy processing time often hinder prompt diagnosis and the identification of the infecting pathogens. This study aimed to use droplet digital polymerase chain reaction (ddPCR), known for its sensitivity in single-molecule amplification, to detect pathogen DNA and drug-resistant genes in blood. Methods:We included a total of 47 patients with hematologic malignancies who were over 18 years old and had neutropenia accompanied by fever [suspected bloodstream infection (BSI)] from August 2022 to November 2022. Patients who failed resuscitation after severe shock, with severe liver or kidney dysfunction, and in the terminal stage were excluded. We conducted ddPCR testing for bacteria/fungi/viruses with the patient's blood on the first day, third day, and fifth day of the occurrences of neutropenic fever with suspected BSI. In case of positive results indicating the presence of bacteria, we used the remaining nucleic acid samples to detect drug resistance genes. Results:BC and ddPCR yielded positive results indicating the presence of bacteria in five patients (10.64%) and 14 patients (29.79%), respectively, with ddPCR demonstrating acceptable positive rate (81.44%). Regarding the breadth of detection, ddPCR identified 10 different pathogens, while only two pathogens went undetected. In contrast, BC detected only five different pathogens. In terms of the diversity of pathogens detected in single samples, among the 14 polymerase chain reaction (PCR)-positive patients, three had the presence of two different pathogens synchronously. Furthermore, ddPCR also revealed the presence of drug resistance genes. Among the 14 PCR-positive patients, four were found to have drug resistance genes, including one case of Klebsiella pneumoniae carbapenemase (rendering patients' immunocompromised system) and three cases of methicillin resistance determinant A (mecA). Conclusions:ddPCR is a versatile and adaptable platform that can serve as a complement to traditional BCs.

Abstract Background Acute myeloid leukemia (AML) remains a highly lethal malignancy, with relapse primarily driven by resistance to chemotherapy or targeted therapies. Existing chimeric antigen receptor T cell (CAR-T) strategies are limited by toxicity and complex manufacturing, underscoring the need for transient, controllable, and safe CAR-engineering platforms that can selectively target multidrug-resistant (MDR) AML cells. Methods We developed a lipid nanoparticle (LNP)–based mRNA delivery platform for scalable generation of C-type lectin-like molecule-1 (CLL-1) CAR-NK cells. NK phenotype, cytotoxicity, cytokine secretion, and safety were evaluated ex vivo against AML cell lines and patient-derived blasts, with in vivo efficacy tested in xenograft NSG mouse models. Mechanisms of adaptive resistance were investigated through transcriptomic profiling, modulation of the NKG2A/HLA-E axis, and functional interrogation of the JAK2–STAT1 signaling pathway. Results Drug-response profiling across AML cohorts identified a multidrug-resistant subgroup marked by a distinct transcriptomic program in which CLL-1 was the only validated CAR target upregulated. mRNA–LNP transfection enabled efficient generation of primary CLL-1 CAR-NK cells with preserved phenotype and potent, antigen-specific cytotoxicity against AML cells, while sparing normal hematopoietic progenitors. In vivo, repeated CAR-NK infusions markedly suppressed leukemia progression and prolonged survival. Transcriptomic analyses of tumor cells surviving CAR-NK exposure revealed inflammatory activation with progressive HLA-E upregulation, which impaired CAR-NK function. NKG2A blockade restored cytotoxicity ex vivo and enhanced leukemia clearance and survival in vivo. Mechanistically, prolonged CAR-NK engagement or IFN-γ stimulation activated a JAK2–STAT1 axis that drove sustained HLA-E induction. JAK2 knockdown reduced HLA-E expression and sensitized AML cells to CAR-NK–mediated killing, whereas pharmacologic JAK2 inhibition also decreased HLA-E expression but concurrently impaired NK-cell activation, thereby limiting the overall therapeutic benefit. Conclusions Transient, non-integrating mRNA–LNP–transfected CLL-1 CAR-NK cells provide a safe and effective strategy for MDR AML. Repeated dosing enables robust antitumor activity, while adaptive resistance via NKG2A/HLA-E axis can be mitigated through checkpoint blockade. The JAK2–STAT1 pathway represents a potential upstream modulator, providing opportunities for rational combinatorial approaches to optimize CAR-NK therapy.

Optimal post-remission therapy is crucial for long-term survival in patients with acute myeloid leukemia (AML). Multidisciplinary team (MDT) conferences address this challenge by providing comprehensive, patient-centered consultations that support individualized treatment decision-making. We evaluated the effectiveness of MDT conferences in guiding post-remission treatment decisions in adults with de novo AML. We enrolled 653 adult patients with de novo AML who were treated at our center between January 2017 and December 2022. Of the 591 eligible patients (90.5%), 501 (84.8%) attended a scheduled MDT evaluation. Allogeneic hematopoietic cell transplantation (allo-HCT) was recommended for 315 patients (62.9%), of whom 251 (79.7%) subsequently underwent transplantation. Survival analyses showed that MDT attendees had superior 3-year overall survival (68.9% vs. 53.5%, p < 0.0001) and a lower 3-year cumulative incidence of relapse (30.7% vs. 44.9%; p < 0.0001) compared with patients who did not attend MDT conferences. Patients most likely to benefit from allo-HCT following MDT recommendations included those with intermediate- or adverse-risk disease according to the European LeukemiaNet 2017 classification, and those with favorable-risk disease who showed a suboptimal response to induction therapy. The main barriers to allo-HCT were persistent or relapsed disease and patient preference. Overall, MDT conferences effectively identified patients who were most likely to benefit from allo-HCT and were associated with higher transplantation rates within a modern healthcare system.

To identify the optimal harvest time and effective utilization of Polygonatum odoratum, we explored the molecular mechanisms of secondary metabolite accumulation across four growth years (Y1-Y4) using integrated metabolomics and transcriptomics. KEGG enrichment analysis of differentially expressed genes (DEGs) and differentially accumulated metabolites revealed significant enrichment of flavonoid biosynthetic pathways. A widely targeted metabolomics approach identified 134 differentially accumulated flavonoids and 76 phenolic acid metabolites, of which 130 metabolites showed markedly higher accumulation in Y3 and Y4. Accordingly, 2516 DEGs exhibited a consistent expression trend with metabolites and were highly expressed in Y3 and Y4. WGCNA of 130 flavonoids, phenolic acids, and 2516 DEGs identified a module (2264 DEGs) that was positively correlated with Y4 and showed a peak expression at this stage. GO and KEGG analyses revealed that these genes were enriched in phenylpropanoid, flavonoid, and secondary metabolite biosynthetic pathways, indicating their key roles in elevated flavonoid and phenolic acid accumulation in Y4. Correlation analysis of genes in phenylpropanoid and flavonoid biosynthesis pathways with 130 highly accumulated flavonoids/phenolic acids in Y3/Y4 identified 22 genes that were significantly positively correlated with 30 metabolites, which were regulated by 16 transcription factors (e.g., MYB-related-3, NAC-7, bHLH-5, AP2-ERF-9). Notably, F5H was associated with the regulation of 24 metabolites, highlighting a complex TF-gene-metabolite regulatory network. These findings provide a valuable molecular framework for P. odoratum cultivation and utilization, particularly supporting that Y4 shows a higher enrichment trend of flavonoids and phenolic acids.

Chronic obstructive pulmonary disease (COPD) increases the risk of lung cancer (LC), but the underlying mechanisms remain unclear. Interleukin-8 (IL-8), a proinflammatory cytokine, has been implicated in tumor progression and epithelial–mesenchymal transition (EMT). This study explored how IL-8 contributes to COPD-associated LC progression. A COPD-like microenvironment was established using cigarette smoke extract (CSE)-exposed HBEC3-KT bronchial epithelial cells co-cultured with A549 or 95D LC cells. IL-8 expression was assessed by qRT-PCR, ELISA, and Western blotting. Gain- and loss-of-function experiments were conducted to examine IL-8’s effects on migration, invasion, and EMT markers. STAT3 signaling involvement was evaluated using the inhibitor Stattic. Conditioned medium from CSE-treated HBEC3-KT cells was applied for functional verification. Immunohistochemical analysis of LC tissues from patients with and without COPD validated clinical relevance. IL-8 expression was markedly elevated in CSE-treated and co-culture systems, peaking in co-cultured cells. IL-8 overexpression enhanced, whereas silencing attenuated, the migratory, invasive, and EMT phenotypes of A549 and 95D cells. Mechanistically, IL-8 activated STAT3 phosphorylation, and inhibition of STAT3 abolished IL-8–induced EMT. Conditioned medium from CSE-treated epithelial cells promoted EMT and invasiveness, effects reversed by IL-8 depletion. Clinically, COPD-related LC tissues exhibited increased IL-8 and N-cadherin, alongside reduced E-cadherin expression. IL-8 acts as a critical mediator connecting COPD-associated inflammation to EMT and tumor aggressiveness via STAT3 activation. Therapeutically targeting IL-8 signaling may offer new strategies for managing COPD-related LC.

Although increasing nitrogen (N) deposition seriously threatens soil microbial communities and plant-microbe interactions, little research has been conducted on endangered plants. In this study, the impacts of simulated N deposition on root morphology, soil properties, as well as the arbuscular mycorrhizal (AM) fungal and bacterial communities in the rhizosphere of the endangered species Calycanthus chinensis were investigated. Based on the results, N deposition altered root morphology (e.g., root diameter, length, volume, and surface area) of C. chinensis seedlings and soil extracellular enzyme activities (e.g., urease and catalase). Additionally, N deposition increased soil microbial biomass N but not soil microbial biomass carbon, particularly at high N levels. Although N deposition had no significant effect on AM fungal diversity and community composition, it significantly reduced bacterial diversity. Notably, AM fungal co-occurrence networks became more complex with increasing N deposition, suggesting enhanced network stability, whereas bacterial networks exhibited the opposite pattern. The variation of soil properties, particularly soil pH, nitrate and available potassium, contributed to the co-occurrence network structures. These findings provide insights into the differential responses of soil microbial communities to N deposition and their potential implications for the growth and survival of endangered plants in disturbed ecosystems.

Ruxolitinib is first-line therapy for intermediate/high-risk myelofibrosis (MF), but ∼50% of patients discontinue within 1 year due to loss of efficacy or intolerance. Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for ruxolitinib-pretreated MF, with no head-to-head trials comparing their efficacy and safety. This study used matching-adjusted indirect comparison (MAIC) to compare these four agents, aiming to provide evidence-based insights for treatment decision-making in ruxolitinib-resistant or intolerant MF. Individual patient data (IPD) of gecacitinib (100 mg BID; ZGJAK006/ZGJAK017, n = 78) and published data of comparators (fedratinib: JAKARTA-2/FREEDOM2; pacritinib: PAC203; momelotinib: SIMPLIFY-2/MOMENTUM) were analyzed. Eight baseline characteristics were matched. Efficacy outcomes (week-24 SVR35, TSS50, transfusion independence [TI]) were reported as odds ratios (ORs); safety as risk differences (RDs). Gecacitinib showed superior SVR35 versus fedratinib (JAKARTA-2: OR = 3.96, 95% CI = 1.37-11.39, P = 0.0108), pacritinib (PAC203: OR = 6.10, 95% CI = 1.54-24.23, P = 0.0101), and momelotinib (SIMPLIFY-2: OR = 8.65, 95% CI = 1.86-40.31, P = 0.0060), and superior TSS50 versus pacritinib (OR = 7.62 95% CI = 1.84-31.51, P = 0.0050) and momelotinib (MOMENTUM: OR = 7.52, 95% CI = 1.63-34.61, P = 0.0096). Numerically, gecacitinib had better TI. It also had significantly lower incidences of diarrhea, nausea, and AE-related treatment discontinuation. Hematologic AE profiles of gecacitinib varied by comparator cohort. Gecacitinib showed favorable efficacy and tolerability signals versus several comparators, suggesting it may be a valuable second-line option.

Parasitic plants can inflict significant damage to invasive plants and are considered biocontrol agents. Climate warming can affect the fitness of invasive plants and the efficacy of their biocontrol agents. However, the impact of climate warming on the responses of invasive plants to parasitism remains inadequately explored. To investigate this critical issue, we conducted a controlled warming experiment to assess the impact of a constant, continuous +2 °C temperature increase, consistent with projected global warming scenarios reported by the Intergovernmental Panel on Climate Change, on the responses of two common invasive plants in China, Solidago canadensis and Bidens pilosa to the parasitic plant Cuscuta gronovii. Our findings indicate that parasitism significantly reduces the growth of both invasive species irrespective of temperature increases. A significant interaction was observed between Cuscuta parasitism and the different host species, particularly affecting stem diameter, plant height, and root-to-shoot ratio of the host plants. Interestingly, while increased temperature independently did not significantly impact total biomass, aboveground biomass, or leaf number of the host plants, it exhibited marginal interactions with parasitism and the different hosts regarding belowground biomass of the hosts. Moreover, C. gronovii biomass was significantly influenced by host type; however, increased temperatures did not significantly affect the biomass of C. gronovii or its deleterious effects on host plants. Overall, these findings highlight the complex interplay among parasitism, host species, and environmental factors, which are crucial for comprehensively understanding invasive species dynamics and their ecological implications.

Subgroup analysis of (A) ORR, (B) DOR and (C) PFS confirmed by investigator

RUNX1-rearranged leukemia is one of the most common subtypes of leukemia associated with genetic abnormalities. Although the majority of patients respond to chemotherapy, relapse and long-term adverse effects remain significant challenges. RUNX1 fusions, resulting from chromosomal rearrangements, are pivotal oncogenic drivers, with over 70 distinct variants identified. Therefore, elucidating their regulatory mechanisms may help to develop novel therapeutic strategies. Herein, we identify a universal deubiquitinase, USP6, that stabilizes RUNX1 fusion proteins with different partners. Importantly, USP6 is specifically upregulated in RUNX1-rearranged leukemia and strongly correlates with poor patient outcomes. Mechanistically, USP6 stabilizes RUNX1 fusions to facilitate the formation of phase separation, leading to robust transcriptional activation of the fusions. Depletion of USP6 dramatically inhibits proliferation and induces differentiation of RUNX1-rearranged leukemic cells. The marketed drug auranofin is identified as a potential USP6 inhibitor, which induces degradation of different RUNX1 fusions, further triggering myeloid differentiation and arresting xenograft tumor growth. Notably, auranofin exhibits selective therapeutic efficacy in patient-derived leukemia blasts from RUNX1-rearranged cases. Together, we not only uncover a new biological function of USP6 in regulating the transcriptional activity of RUNX1 fusions but also validate USP6 as a promising drug target and auranofin as a candidate therapy for RUNX1-rearranged leukemia.

Cyclic GMP-AMP synthase (cGAS), a key mediator of the cGAS-STING DNA sensing pathway that triggers type-I interferon responses, plays a crucial role in innate immunity and has been implicated in the pathogenesis of various disease. Despite advances in the development of cGAS inhibitors, none have reached the market and there remains an unmet need for divergent chemical scaffolds with high selectivity, potency across species, and target-adaptive mechanisms of action to explore cGAS's potential as a therapeutic target. Here we report the structural, biochemical, cellular, and mechanistic characterization of the XL series of allosteric inhibitors, designed to engage an innovative allosteric site near the activation loop of cGAS. Among them, XL-3156 and XL-3158 emerge as potent, selective, cross-species cGAS inhibitors that simultaneously occupy allosteric and orthosteric sites, stabilizing the activation loop in a closed, inactive conformation and thereby attenuating the cGAS-DNA interactions. Moreover, these allosteric inhibitors, also known as protein condensation inhibitors (PCIs), significantly suppress cGAS-DNA condensate formation, triggering a morphological transition from liquid-solid phase separation (LSPS) to liquid-liquid phase separation (LLPS) at the molecular level while eliminating LLPS in cells. The distinct mechanism of action enables PCIs to achieve synergistic effects in combination with orthosteric inhibitors. These results establish a mechanism-driven pharmacological strategy to inhibit cGAS through PCIs that modulate phase separation primarily by engagement of the allosteric site.

For newly diagnosed acute myeloid leukemia (ND-AML), the traditional “3+7” induction is still the foundation of intensive chemotherapy. For certain subgroups, the combination of targeted drug can improve response rate and long-term survival. As previous reported in RJ-AML 2014 and 2016 trial [Am J Hematol. 2022;97(1):43-51; 65th ASH Annual Meeting and Exposition, San Diego, CA], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response. For patients in the D5-PBCR (+) group, addition of homoharringtonine can benefit favorable and intermediate risk groups. While for adverse-risk and FLT3-ITD mutated cases, other interventions were needed. IA+X 2024 is a multicenter, non-randomized, phase II clinical trial, conducted to evaluate the efficacy of targeted drug (drug “X”) in combination with “3+7” regimen for ND-AML (ClinicalTrials.gov NCT06652685). Patients receive IA-10 regimen (idarubicin 10mg/m2 on days 1–3 and cytarabine 100mg/m2 on days 1–7) as the initial induction. On day five of induction, D5-PBCR will be tested. Patients will be assigned to different arms according to the results of molecular tests and D5-PBCR. For CBF-AML patients, no interventions are needed. For FLT3-ITD mutated patients, a combination of gilteritinib is recommended (induction and consolidation: 80mg/d on days 8-21). All other D5-PRCR (+) patients will receive Venetoclax (VEN) addition (induction: 100mg on day 6, 200mg on day 7, and 400mg on days 8–13; consolidation: 400mg/d on days 8-14). The primary end point is composite complete remission (CRc) rate. We hypothesized that the CRc rate may increase by 15% (from 67% to 82%) with the addition of drug “X”. As designed using the single-arm, Simon two-stage model, twenty-nine patients were accrued in the first stage of analysis and if more than 20 CRc were observed, 31 additional patients will be included. The secondary end points include total CRc rate, overall survival (OS) and event-free survival (EFS). Consolidation therapy will be assigned according to the patients' ELN 2022 risk stratification. Here, we report the interim analysis. Between August 2024 and April 2025, a total of 115 patients underwent screening, 97 were included in the intention-to-treat (ITT) population and received IA-10 induction from 5 sites in China. Twenty-seven patients were classified as CBF-AML (14 cases with RUNX1::RUNX1T1 fusion, 13 with CBFβ::MYH11 fusion). The analysis of CBF-AML subgroup showed 100% CR rate after one cycle of induction with 50% and 100% MRD negativity by flow cytometry (<0.01%) in RUNX1::RUNX1T1 and CBFβ::MYH11 fusion groups, respectively. D5-PBCR were analyzed in 70 patients and 42 (60%) had D5-PBCR (+). Baseline characteristics, including age, sex, WBC, bone marrow blast counts, and cytogenetic parameters were similar between two groups. Patients with NPM1 mutation were more sensitive to IA-10, while TP53 mutation was more common in D5-PBCR (+) group. Of the 42 D5-PBCR (+) patients, 3 cases discontinued IA and 6 were unfit for drug “X” additional. Of the 28 D5-PBCR (-) patients, 2 patients discontinued IA and 2 were unfit for gilteritinib combination. The overall composite CR rate after one course of induction was 76.2% in the ITT cohort, and 87.7% in the Per-Protocol (PP) cohort. In PP population, CR rates were 95.8% and 81.8% for D5-PBCR (-) and D5-PBCR (+) groups, respectively. No early death events occurred within 60 days of induction. All patients in the 2022 ELN favorable-risk group obtained CR. FLT3-ITD mutated patients (15 in ITT and 12 in PP) showed high response with IA+gilteritinib, which is also observed in patients with NUP98 fusion. However, there is a certain degree of prolongation in the duration of bone marrow suppression. While subgroup analysis showed that only one patient with TP53 mutation achieved CR after one cycle of IA+VEN induction. Even after receiving the second course of induction, only 2 patients achieved remission, with the remaining 5 patients in non-remission. The IA+X 2024 protocol has currently met the requirements for the interim analysis as designed, and enrollment is planned to continue. All patients in the favorable-risk group achieved CR after one course of induction. And for patients with TP53 mutation, a new re-induction regimen needs to be designed.

Serum cytokine concentrations before and during treatment

Acute myeloid leukemia (AML) is a genetically complex and clinically heterogeneous hematopoietic malignancy. This study employs long-read transcriptome analysis using oxford nanopore technologies sequencing on 60 primary AML bone marrow samples. This approach delivers comprehensive isoform-level resolution of splicing abnormalities and overcomes limitations of short-read sequencing. We detect extensive AML-specific splicing anomalies and identify 119,278 previously unannotated transcript isoforms. Of these, 80,294 (67.31%) contain complete open reading frames, with 9,812 (12.22%) validated using liquid chromatography-tandem mass spectrometry. Quantitative analysis in 175 RNA sequencing samples enables non-negative matrix factorization clustering, defining distinct molecular subtypes. These isoform-defined subtypes exhibit strong correlations with patient prognosis, indicating their potential as biomarkers for clinical classification. The findings highlight alternative splicing as a major contributor to AML molecular heterogeneity and provide a valuable foundation for advancing precision medicine and developing innovative therapeutic strategies targeting splicing abnormalities in AML.

Arbuscular mycorrhizal fungi (AMF) are considered crucial for the survival of many endangered plant species. However, the dynamics of AMF communities in the roots and rhizosphere soil of Heptacodium miconioides, particularly along elevation gradients, remain underexplored. This study investigates AMF colonization, spore density, and community structure in the root and rhizosphere soil of H. miconioides across an elevation range from 306 to 1028 m a.s.l., employing high-throughput sequencing. Our results show that AMF colonization and spore density in H. miconioides increased with elevation. Glomus was the dominant genus in both root and rhizosphere samples. Elevation significantly influenced the AMF community structure and diversity in the root, with alpha diversity decreasing linearly with elevation. In contrast, no significant elevation-related changes were observed in the rhizosphere soil alpha diversity. The difference in AMF beta diversity between the root and rhizosphere soil was lowest at the highest elevation. Compared to the rhizosphere soil, the degree and degree centralization of AMF community co-occurrence networks in the root showed a significant increase at higher elevations. Variations in soil properties, particularly soil pH, available phosphorus, and total nitrogen levels strongly influenced AMF communities in rhizosphere soil, while nitrate nitrogen, available potassium, and acid phosphatase were correlated with AMF communities in the root. These findings highlight the impact of elevation on AMF communities in both root and rhizosphere soil, providing valuable insights for the habitat restoration and conservation efforts for this species.

Introduction: Acute promyelocytic leukemia (APL) has been highly cured with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), but they still bring differentiation syndrome (DS) in about 25% of cases. Patients with intermediate-to-high-risk APL are more prone to severe DS, which is closely associated with early mortality. The mechanism of DS remains unclear, besides current prevention methods are limited and unsatisfactory. This study aims to optimize prophylaxis strategy of DS among patients with intermediate-to-high-risk APL. Patients and Methods: The APL2022 study was a prospective, single-arm clinical trial in patients with newly diagnosed intermediate-to-high-risk APL (according to Sanz risk model, white blood cell (WBC) count > 10 × 109/L or platelet (PLT) count < 40 × 109/L) aged between 14 and 75. From June 2023 to July 2025, 114 eligible patients were treated with ATRA and ATO based induction therapy, combining limited dosage of chemotherapy if WBC count > 10 × 109/L. Seventeen of them were excluded from the study because of initially fatal bleeding, PLT count < 10 × 109/L, or refusal. And 98 patients received Ruxolitinib 5mg bid and dexamethasone 10mg per day for prophylaxis of DS after the initiation of ATRA. DS scores were measured by the following 7 clinical manifestations, each for 1 point: unexplained fever, dyspnea, pleural or pericardial effusion, pulmonary infiltration, renal failure, hypotension, and a weight gain of ≥ 5 kg. Mild DS was measured as 1-2 points, moderate DS as 3 points, and severe DS ≥ 4 points. When the DS score continued to be 0 and the WBC count less than 5 × 109/L for more than 3 days, Ruxolitinib should be discontinued and the dosage of dexamethasone gradually reduced. If symptoms reoccurred, they could be reused. If the DS score was ≥ 3, ATRA was suspended and dexamethasone should be added up to 10mg q12h. For safety concern, when PLT count was less than 10 × 109/L or any other grade III-IV adverse effect which was considered possibly related to Ruxolitinib occurred, it should be discontinued. Results: The median use of Ruxolitinib was 13 days (range 1 - 23). Among the 98 per-protocol intermediate-to-high-risk patients, 15 (15.3%) developed DS, which was significantly reduced compare to the rate in our historical study (26.3% (169 of 642), P = 0.019). High-risk patients were remarkably benefited from this strategy, with the incidence of DS reduced from 30.6% to 12.2% (P = 0.015). Dyspnea (67%), fever (67%), pleural or pericardial effusion (60%), and weight gain (53%) were the most common symptoms of DS. Once acute renal dysfunction or hypotension occurred, patients all developed severe DS. Mild-to-moderate DS occurred in 12 patients, while severe DS in 3 (3.1%) patients. Seven patients died within 30 days from diagnosis, with an early death rate of 7.1%. Only 1 died from severe DS, 4 from cerebral bleeding, 1 from hemoptysis, and 1 from infection. The following factors at diagnosis were analyzed through univariate analysis to evaluate the risk for DS (P < 0.05): age, gender, FLT3-ITD, FLT3-TKD, NRAS, WT1, WBC count, hemoglobin, PLT count and fibrinogen. Only NRAS mutation was significantly related to the onset of DS (OR = 5.319, 95% CI = 1.381-19.126, P = 0.015). We collected the data of cytokines or receptors at different time points after ATRA treatment and fitted the dynamic trajectory through Locally Weighted Regression (LOESS). Multivariate Logistic regression showed that IL-2R was the only independent predictive marker for DS (P = 0.021) among all the 13 detectable cytokines or receptors, and not affected by the infection status (using mixed effect model, P = 0.222). Patients with IL-2R elevation greater than 2.5 times the upper limit of normal within 7 days of ATRA treatment had a significantly increased risk of DS (OR = 7.31, 95% CI = 1.13-47.70, P = 0.032). Moreover, NRAS mutation would accelerate the risk of DS, manifested as an increased trend in DS risk when IL-2R reached a 1.5-fold upper limit within 5 days (OR=10.00, p=0.086), and a significantly increased risk if reaching a 2.5-fold upper limit within 5 days (OR = 34.00, P = 0.043). Conclusion: Ruxolitinib and dexamethasone combination strategy could be an effective and safe recommendation for preventing DS during ATRA-ATO induction therapy for APL patients. NRAS mutation and changes in IL-2R after ATRA treatment might serve as risk predictors for DS under this protocol. (www.chictr.org.cn, ChiCTR2300072086)

List of participating hospitals for the clinical trial NCT04370405

Background:Acute myeloid leukemia (AML) poses a significant global health burden. This study evaluates long-term trends in AML burden from 1990 to 2021, focusing on global and Chinese patterns using Global Burden of Disease (GBD) data. Methods:We extracted AML-related mortality, incidence, prevalence, and disability-adjusted life years (DALYs) from the GBD 1990-2021 dataset. Age-standardized rates (ASRs) were analyzed using Joinpoint regression to calculate annual percentage change (APC) and average APC (AAPC). Contributions of smoking, high body mass index (BMI), and occupational exposures were also evaluated. Results:Globally, AML deaths rose by 73.8%, with a 17.45% increase in ASMR. Conversely, China's ASMR declined by 14.76%. DALYs showed a global AAPC of -0.83%, with a sharper decline in China (-2.40%). Males and older adults (>65 years) bore a disproportionate burden. Smoking remained the top risk factor, while high BMI showed the fastest growth in attributable burden. Conclusion:While AML's absolute burden is increasing worldwide, age-adjusted metrics are stabilizing or declining in China, likely due to healthcare improvements. Targeted prevention, risk control, and geriatric-oriented AML strategies are urgently needed.

ABSTRACT:Integration of torque teno mini virus (TTMV) generating the TTMV::RARA (retinoic acid receptor α) fusion represents a newly recognized subtype of acute promyelocytic leukemia (APL) that merits detailed investigation. We present, to our knowledge, the first comprehensive characterization of its epidemiologic profile, clinical presentation, virologic characteristics, and underlying molecular mechanisms. Our findings indicate that TTMV::RARA is more prevalent in pediatric patients and represents the second most common retinoic acid receptor fusion after PML::RARA. Affected patients exhibit a high incidence of extramedullary involvement, particularly myeloid sarcoma. Cytogenetic abnormalities involving i(17)(q10) or 7q22 were identified in 52.0% of cases, largely in a mutually exclusive manner. Co-occurring mutations in epigenetic regulators were present in 76.9% of patients. Although most patients achieved initial remission, relapse was common and associated with rapid acquisition of all-trans retinoic acid (ATRA)-resistant mutation and secondary chemoresistance. Venetoclax-containing regimens demonstrated encouraging clinical efficacy. Phylogenetic analysis indicated that patient-derived TTMV strains clustered into a distinct clade. TTMV integration consistently occurred within RARA intron 2, involving a consensus fragment of 510 to 610 base pairs encompassing the viral promoter and open reading frame 2 (ORF2) N terminus, likely mediated by microhomology-driven recombination. Tandem RUNX1-binding motifs within the integrated viral promoter may underlie the myelotropism of these TTMV strains and facilitate transcriptional activation of TTMV::RARA. The chimeric protein retains at least the first 56 N-terminal residues of ORF2 and remains transcriptionally responsive to pharmacological concentrations of ATRA. These findings establish TTMV::RARA-APL as a distinct leukemia entity, laying the foundation for future studies on virus-mediated leukemogenesis and therapeutic strategies.

Detailed inclusion and exclusion criteria for the clinical trial (NCT04370405)