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With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.

In this study, two districts, Erdaojiang District and Dongchang District, in Tonghua City, Jilin Province, were evaluated for their geological environment carrying capacity. A total of 14 evaluation indicators were selected from the three aspects of the geological environment, ecological environment, and social environment to make it more comprehensive to evaluate the carrying capacity of the geological environment. Using the AHP and CRITIC methods, the subjective weight and objective weight of each evaluation index are obtained, and the combined weight is calculated by game theory. When combined with the GIS and combined weights, the distribution map of the geological environment carrying capacity is obtained, and it is classified into four grades: excellent, good, medium, and poor. A comprehensive evaluation of the carrying capacity of the geological environment is carried out. The following conclusions are drawn: the overall carrying capacity of the geological environment in the study area is good, and the carrying capacity of individual areas is poor. The comparative analysis of the good and poor areas provides a scientific basis for future environmental governance and urban planning and provides a scientific basis for geological disasters and mines.

Patients with haematological malignancies are immunocompromised and prone to respiratory infections, but identification of causative pathogens is challenging. The aim of this study was to analyse the ability of targeted next-generation sequencing (tNGS) to detect pathogens in immunocompromised patients. tNGS and conventional microbiological tests (CMT) were performed on samples from the respiratory tract of 99 patients with suspected respiratory infections. Metagenomic next-generation sequencing (mNGS) was conducted in parallel in 43 patients. Comparative analysis was conducted using the Pearson χ2 test and Fisher's exact test, as appropriate. The overall microbial detection rates for tNGS were 100% (23/23) in the upper respiratory tract and 96.1% (99/103) in the lower respiratory tract. Microorganism colonization was detected by tNGS in 80.8% (97/120) of cases. The sensitivity of tNGS was approximately 30% higher than that of CMT (87.7% vs. 52.5%; < 0.001), but tNGS had a lower specificity (33.3% vs. 83.3%;  = 0.242). tNGS improved the overall treatment success rate by 69.7% (69/99 cases) in CMT true-negative or CMT-partially matched cases. In the paired respiratory tNGS and mNGS cases, tNGS verified 73.3% (11/15) cases of infection, while mNGS only verified 40% (  = 0.139). Most immunosuppressed patients are colonized by microorganisms, and require prompt identification of the cause of any infections. tNGS has promising diagnostic potential and offers valuable information for optimizing antibiotic therapy, especially when compared to CMT.

Based on the data from two field surveys in 2015 and 2022, this paper calculates the weight of values using the entropy weight method and the variation coefficient method, and evaluates risk using the information quantity method. The information quantities of four levels of criteria (hazards, exposure, vulnerability, emergency responses, and capability of recovery) were extracted and inputted into a random forest model. After optimizing the hyperparameters of the random forest using GridSearchCV, the risk assessment was performed again. Finally, the accuracy of the two evaluation results was verified using an ROC curve, and the model with the higher AUC value was selected to create a risk map. Compared with previous studies, this paper considers the factors of emergency responses and recovery capability, which makes the risk assessment more comprehensive. Our findings show that the evaluation results based on the coupling model are more accurate than the evaluation results of the information method, as the coupling model had an AUC value of 0.9329. After considering the indices of emergency responses and capability of recovery, the risk level of the highest-risk area in the study area decreased.

In recent years, the volcanic activity of Changbai Mountain has been accompanied by several earthquakes, and the frequent human engineering activities have led to a gradual increase in the number of collapses in the region, which severely impacts residents’ lives and property safety. In northeastern China, the Changbai Mountain area in the southeastern Jilin Province is a typical mountain environment. This paper selects 12 evaluation indicators to build a hazard assessment system, including slope, aspect, elevation, curvature, lithology, NDVI, land use type, distance from the fault, the river from the road, volcanic earthquake, and annual average precipitation. Using emotional weight (G1 method) and objective weight (WOE-CV method), the hazard due to collapses in the study area is evaluated too. Among them, the transcendence probability of volcanic earthquakes greater than VI degree represents the relationship between Changbai Mountain volcanic earthquakes and the assessment of geological collapse hazard. The results show that high- and very high-hazard areas are mainly distributed in densely populated areas and national and provincial trunk lines, with apparent spatial agglomeration characteristics. The low-hazard area, medium-hazard area, high-hazard area and very high-hazard area accounted for 19.33%, 44.19%, 33.85% and 2.63% of the total area of the study area, respectively. By comparing the previous geological hazard survey reports in the area with the collapse hazard zoning map in this paper, 87.72% of the known collapse hazard areas are distributed within high and very high hazard zones, indicating that the conclusions of the article are more accurate and in line with the actual situation. Results from collapse-related hazards can provide relevant guidance for preventing and controlling geological risks posed by volcanic earthquakes affecting Changbai Mountain.

Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive T-cell activation remains incomplete. To address this, we studied transcriptional activation of carbohydrate, nucleotide, tricarboxylic acid (TCA) cycle, and amino acid metabolism of T cells before aGvHD onset by mining the Gene Expression Omnibus (GEO) datasets. Glycolysis had the most extensive correlation with other activated metabolic sub-pathways. Through Pearson correlation analyses, we found that glycolytic activation was positively correlated with activated CD4 memory T-cell subset and T-cell proliferation and migration. T-cell receptor (TCR), mechanistic target of rapamycin complex 1 (mTORC1), myelocytomatosis oncogene (MYC) signaling pathways and E2F6 might be “master regulators” of glycolytic activity. aGvHD predictive model constructed by glycolytic genes ( PFKP , ENO3 , and GAPDH ) through logistic regression showed high predictive and discriminative value. Furthermore, higher expressions of PFKP , ENO3 , and GAPDH in alloreactive T cells were confirmed in our pre-aGvHD patient cohort. And the predictive value of the aGvHD risk model was also validated. In summary, our study demonstrated that glycolytic activation might play a pivotal function in alloreactive T-cell activation before aGvHD onset and would be the potential target for aGvHD therapy.

Acute myeloid leukemia (AML) with KMT2A rearrangement ( KMT2A -r) is associated with poor prognosis, but the benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for KMT2A -r AML is unclear. We reviewed adult AML patients treated within the TROPHY group and identified 292 cases of KMT2A -r AML, 254 (87.0%) of whom achieved first complete remission (CR1) and 192 (75.6%) of CR1 patients underwent allo-HSCT. We show that allo-HSCT is an independent favorable prognostic factor in CR1 patients for both overall survival (OS) (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.45–0.69, P  < 0.001) and cumulative incidence of relapse (CIR) (HR = 0.01, 95% CI: 0.005–0.04, P  < 0.001). Among allo-HSCT recipients, survival outcomes were comparable between patients with KMT2A::MLLT3 and those with other 11q23/ KMT2A rearrangements (3-year OS: 74.3% vs. 77.5%, P  = 0.97; 3-year event-free survival [EFS]: 55.2% vs. 62.2%, P  = 0.34; 3-year CIR: 24.4% vs. 20.8%, P  = 0.32). Both multiparameter flow cytometry-based measurable residual disease (MFC-MRD) and KMT2A -r MRD determined by quantitative PCR prior to allo-HSCT were associated with worse transplant outcomes. Multivariable analysis identified detectable KMT2A -r MRD at allo-HSCT as a significant risk factor for reduced EFS (HR = 2.46, 95% CI: 1.32–4.60, P  = 0.005). These findings confirm the survival benefit of allo-HSCT in adult patients with KMT2A -r AML and underscore the prognostic value of KMT2A -r MRD prior to transplantation. Highlights Patients with KMT2A -rearranged ( KMT2A -r) acute myeloid leukemia (AML) benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). While KRAS mutations are novel adverse prognostic factors in KMT2A -r AML, allo-HSCT mitigates their adverse effects on survival. PCR-based quantification of KMT2A -r measurable residual disease (MRD) prior to allo-HSCT is a superior surrogate for transplant prognosis than multiparameter flow cytometry-based MRD assessment.

Introduction: Immunosuppression predisposes allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients to infection. Prompt and accurate identification of pathogens is crucial to optimize treatment strategies. This multi-center retrospective study aimed to assess the ability of metagenomic next-generation sequencing (mNGS) to detect causative pathogens in febrile allo-HSCT recipients and examined its concordance with conventional microbiological tests (CMT).Methods: We performed mNGS and CMT on samples obtained from 153 patients with suspected infection during allo-HSCT. Patients were grouped based on their neutropenic status at the time of sampling.Results: The mNGS test was more sensitive than CMT (81.1% vs. 53.6%, P<0.001) for diagnosing clinically suspected infection, especially in the non-neutropenia cohort. mNGS could detect fungi and viruses better than bacteria, with a higher sensitivity than CMT. Immune events were diagnosed in 57.4% (35/61) of the febrile events with negative mNGS results, and 33.5% (48/143) with negative CMT results (P=0.002). The treatment success rate of the targeted anti-infection strategy was significantly higher when based on mNGS than on empirical antibiotics (85% vs. 56.5%, P=0.004).Conclusion: The mNGS test is superior to CMT for identifying clinically relevant pathogens, and provides valuable information for anti-infection strategies in allo-HSCT recipients. Additionally, attention should be paid to immune events in patients with negative mNGS results.

Letermovir is an antiviral agent that significantly decreases the frequency of cytomegalovirus (CMV) infections following allogeneic hematopoietic stem cell transplantation (allo-HCT); however, its impact on Epstein-Barr virus (EBV) infection remains unclear. This multicenter, retrospective study involved 565 patients aged ≥ 18 years, who underwent allo-HCT between January 2021 and December 2023, with 284 receiving letermovir prophylaxis (letermovir group) and 281 not (control group). Cumulative incidences of clinically significant CMV infection (cs-CMVi), EBV DNAemia, EBV-disease and post-transplant lymphoproliferative disorder (PTLD) were compared between the groups. The 1-year cumulative incidence of EBV DNAemia did not differ significantly between the letermovir and control groups (58.1% vs. 52.7%, P  = 0.3). However, letermovir prophylaxis was associated with a significantly higher incidence of PTLD within the first year post-HCT (7.39% vs. 1.80%, P = 0.00059). Multivariate analysis identified letermovir prophylaxis as an independent risk factor for PTLD (HR [95% CI]: 4.619 [1.458–10.278], P = 0.007). Letermovir altered the early reconstitution trajectory after allo-HCT, particularly in CD8 + T cells. Our findings emphasized that although letermovir prophylaxis did not increase the risk of EBV DNAemia in allo-HCT recipients, it was associated with a higher incidence of PTLD. Further studies focusing on immune reconstitutiom dynamics are warranted to elucidate the underlying pathophysiology of EBV-PTLD under letermovir pressure.