Leptin is abundant within marrow adipose tissue, yet its impact on acute myeloid leukemia (AML) therapy response is undefined. Here, we report that elevated bone-marrow leptin and blast-cell leptin-receptor (LEPR) levels strongly associate with poor cytarabine (Ara-C) clearance and reduced survival in newly diagnosed AML patients. Mechanistic and functional validation in human AML lines, primary blasts, and two syngeneic mouse models (MLL-AF9, AML1-ETO9a) shows that exogenous leptin markedly blunts Ara-C cytotoxicity, whereas the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukemia growth. Leptin up-regulates LEPR and triggers JAK2/STAT3 signaling that boosts mitochondrial complex Ⅰ activity, oxidative phosphorylation, and mitochondrial reactive oxygen species (mtROS); the resulting mtROS surge activates a compensatory antioxidant program that shields blasts from drug-induced oxidative damage. These data identify an adipokine-driven metabolic circuit governing AML chemoresistance and reveal LEPR blockade as a tractable strategy to improve outcomes, underscoring adipose–tumor crosstalk as a general therapeutic vulnerability.

In acute myeloid leukemia (AML), therapeutic resistance is intimately linked to vascular microenvironment remodeling; however, the initiating molecular determinants remain elusive. Here, we identified exosomal pyruvate kinase M2 (PKM2) as a pivotal mediator of this pathogenic process. PKM2 was abundantly present in AML-derived exosomes and transferred to human umbilical vein endothelial cells (HUVECs), eliciting metabolic reprogramming characterized by enhanced glycolysis and angiogenic activation. Mechanistically, PKM2 knockdown in AML cells substantially attenuated exosome-induced endothelial migration and tube formation, whereas ectopic PKM2 overexpression in endothelial cells potentiated pro-angiogenic phenotypes. In NOD/SCID mouse xenograft, AML-derived exosomes promoted microvascular remodeling and accelerated disease progression, effects that were abrogated by the angiogenesis inhibitor endostatin. This vascular remodeling coincided with diminished cytarabine (Ara-C) sensitivity, indicative of a chemoprotective microenvironment. Consistently, in a systemic AML model, pharmacological PKM2 inhibition disrupted the vascular niche, suppressed angiogenesis, and restored Ara-C chemosensitivity. Clinically, PKM2 expression correlated positively with VEGFA and HIF-1α levels, and exosomes derived from AML patients with elevated PKM2 conferred enhanced tube-forming capacity upon endothelial cells. Collectively, these findings establish exosomal PKM2 as a critical regulator of the chemoprotective vascular niche in AML and underscore its translational potential as a therapeutic target.

Acute myeloid leukaemia (AML) remains a therapeutically challenging malignancy owing to its high relapse rates and chemoresistance, often linked to elevated antioxidant defences. Here, we demonstrate that bone marrow stromal cells (BMSCs) confer chemoresistance in AML by upregulating the purinergic receptor P2RX7. Blocking P2RX7 restored chemosensitivity of AML cells. Mechanistically, BMSC-mediated P2RX7 overexpression induces calcium influx and mitochondrial calcium overload, triggering mitochondrial stress and a compensatory antioxidant response. This process involves mitochondrial phosphoglycerate mutase 5 (PGAM5) transducing reactive oxygen species signals, interfering with Keap1-Nrf2 complex formation and leading to Nrf2 stabilization, thereby enhancing cellular antioxidant defences. These findings identify a vital role of P2RX7 in the BMSC-driven redox adaptation programme that underlies AML chemoresistance and highlight P2RX7 signalling as a potential therapeutic target.

Background Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is a component of mitochondrial respiratory chain complex CIII. Its relationship with human cancer has been less studied. Pathomics uses artificial intelligence algorithms to collect histopathological image features and perform joint analysis by combining gene and transcriptome data. In this study, a pathomics prediction model was established based on UQCRH expression and histopathological images of lung adenocarcinoma (LUAD). Prognostic value and other analyses were conducted based on this model. Methods The expression level of UQCRH in 33 types of human cancers was measured. Its relationship with the survival of the primary LUAD samples with complete pathological images, gene expression data, and clinical information were divided into high and low expression groups based on the expression level threshold of the UQCRH gene (Table S1). LUAD patients was studied. Pathomic prediction model was established by using machine learning algorithms according to the UQCRH expression level and the characteristics of LUAD histopathological images. Based on this prediction model, survival analysis, molecular pathways, immune infiltration, immunological subtypes, ICI treatment prediction, and drug sensitivity analyses were performed. Results UQCRH is highly expressed in various cancers, including LUAD. In addition, we verified that UQCRH is overexpressed in human LUAD tissues. High expression of UQCRH is worse prognostic factor for LUAD patients. A pathomic prediction model was constructed based on the UQCRH expression level and histopathology image features. The pathomic score showed good correlation with the UQCRH expression level. Patients in the high-risk group of the pathomic prediction model had worse prognosis and higher tumor proliferation ability, but may have better response to immune checkpoint inhibitors (ICIs) therapy. Conclusion We have established a pathomic prediction model for LUAD based on gene expression values and according to histopathological image features, which can predict patient survival prognosis and has potential guiding value for ICIs therapy.

Background:The red cell distribution width-to-albumin ratio (RAR) is a biomarker reflecting systemic inflammation and oxidative stress, and has been associated with outcomes in multiple diseases. However, its value for predicting postoperative recurrence or progression in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains undetermined. Methods:We retrospectively reviewed 1 011 HBV-HCC patients who underwent surgical treatment at three tertiary centres. Patients were divided into training, internal validation and external validation cohorts. The performance of RAR for predicting progression-free survival (PFS) was assessed using receiver operating characteristic (ROC) analysis, and restricted cubic spline (RCS) modelling was used to explore its nonlinear association with progression risk. Independent prognostic factors were identified by multivariate Cox regression and incorporated into a nomogram and an interactive web-based calculator, which were validated in all cohorts. Results:RAR achieved an area under the ROC curve (AUC) of 0.662 for predicting PFS. RCS analysis revealed a nonlinear increase in progression risk with rising RAR values, with the curve plateauing at higher levels. Multivariate Cox analysis confirmed RAR as an independent predictor of postoperative PFS (hazard ratio [HR] = 4.40; 95% CI, 1.74-11.12). The nomogram-integrating RAR, tumour size, alpha-fetoprotein, TNM stage and portal vein tumour thrombus (PVTT)-demonstrated Satisfactory discrimination, excellent calibration and consistent net clinical benefit across data sets. Conclusion:RAR independently predicts postoperative recurrence or progression in HBV-HCC. The RAR-based nomogram offers a practical tool for individualised estimation of PFS, facilitating more precise postoperative risk stratification and management.

Mucosa-associated invariant T (MAIT) cells are associated with tumor immunity. However, their role in diffuse large B-cell lymphoma (DLBCL) remains unclear. Therefore, this study aimed to elucidate frequency and functional characteristics of circulating MAIT cells in DLBCL patients. The findings revealed a significant reduction in the frequency of circulating MAIT cells in DLBCL patients compared to age-matched healthy controls. Moreover, circulating MAIT cells from DLBCL patients exhibited proapoptotic and senescent phenotypes and demonstrated dysfunction, as evidenced by elevated expression of activation and exhaustion markers, including CD69, CD25, HLA-DR, PD-1, and Tim-3. MAIT cells derived from DLBCL produced lower levels of crucial anti-tumor cytokines, such as interferon-gamma, interleukin-17, tumor necrosis factor-α and granzyme B, suggesting impaired anti-tumor immunity. Additionally, MAIT cells from DLBCL patients showed diminished cytotoxicity against DLBCL cells compared to those from healthy donors. Notably, a lower frequency of circulating MAIT cells in patients with DLBCL was associated with poor prognosis. In summary, this study reveals reduced and impaired circulating MAIT cells in DLBCL patients, suggesting their importance in anti-lymphoma immunity.

BACKGROUND:Myeloid-derived suppressor cells (MDSCs) are a subset of immature myeloid cells with immunosuppressive properties. Evidence suggests that abnormal immune system can lead to immune dysfunction and increase the risk of developing diffuse large B-cell lymphoma (DLBCL). This study investigated the abnormality of MDSCs in the peripheral blood of patients with DLBCL. METHODS:Expression, apoptosis, and proliferation of MDSCs was measured in the peripheral blood DLBCL patients and healthy donors (HDs) via flow cytometer. The co-culture groups included the MDSCs and DLBCL cells line and MDSCs and T cells. Using flow cytometry detected MDSCs and T cells proliferation, apoptosis, T cells activation and function in the co-culture groups. RNA transcriptome sequencing analysis was conducted on DLBCL-MDSCs and HDs-MDSCs. Combined with the clinicopathological data of DLBCL patients, the correlation between MDSCs and DLBCL progression was analyzed. RESULTS:The expression of MDSCs in patients newly diagnosed with DLBCL was elevated. DLBCL tumor cells could stimulate MDSCs growth. DLBCL-MDSCs showed stronger immunosuppressive ability to T cells proliferation, activation and secretion of cytokines and associated with several clinical indicators such as Ann Arbor stage, serum LDH level, and lymphoma IPI score. CONCLUSION:This study investigated the abnormality of MDSCs and underscored the critical role of MDSCs in suppressing T cell function in DLBCL patients. It provides certain laboratory evidence for MDSCs as biomarkers of disease progression and treatment response in DLBCL.

The specific function of NR4A1 as a transcriptional regulator in cancer remains unclear. Here we report the biological effect of NR4A1 in suppressing breast cancer (BC) growth. We found that NR4A1 deficiency was correlated with BC progression in the clinic. Genetic deletion of NR4A1 in BC cells significantly promoted cellular proliferation and tumor growth. Moreover, global metabolome screening indicated that the deletion of NR4A1 resulted in tumor lipid remodeling and phospholipid accumulation, which was accompanied by increases in fatty acid and lipid uptake. In addition, NR4A1 knockout induced oxidative stress that aggravated redox balance disruption. Mechanistically, transcriptomic and epigenomic analyses revealed that NR4A1 restrained BC cell proliferation by directly interacting with c-Fos and competitively inhibiting c-Fos binding to the promoter of the target gene PRDX6, which is involved in lipid and redox homeostasis. Notably, we confirmed that the treatment of BC cells with the selective NR4A1 agonist cytosporone B significantly activated the expression of NR4A1, followed by increased interaction between NR4A1 and c-Fos, thereby interfering with c-Fos-mediated transcriptional regulation of BC cell growth. Thus, NR4A1 plays a vital role in reducing the c-Fos-induced activation of downstream signaling cascades in BC, suggesting that agents that activate NR4A1 may be potential therapeutic strategies.

Background: The prognostic significance of the red blood cell distribution width to albumin ratio (RAR) spans various diseases, yet its utility as a biomarker for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains unclear. Methods: We retrospectively studied 1,413 patients with HBV-HCC. Receiver operating characteristic curves identified optimal RAR cut-offs, stratifying patients into H-RAR and L-RAR groups. Propensity score matching helped balance baseline characteristics. We further evaluated the incremental predictive value of RAR by incorporating it into established conventional models. Results: Overall, 906 patients with HBV-HCC were enrolled (H-RAR group, 600 (66.2%); L-RAR group, 306 (33.8%)). After propensity score matching, 209 patients were included in each group with balanced baseline characteristics (all p > 0.05). RAR demonstrated superior prognostic discrimination compared to red blood cell distribution width, albumin, total bilirubin, and Child-Pugh scores alone, with an area under the curve (AUC) of 0.751. The risk of all-cause mortality increased progressively within a specific RAR range. High RAR was identified as an independent risk factor for long-term overall survival in patients with HBV-HCC (hazard ratio = 1.707, 95% confidence interval [CI]: 1.338-2.176). Stratification by tumour stage revealed substantially lower overall survival for H-RAR than for L-RAR across Tumour, Node, Metastasis I-IV stages. Incorporating RAR into traditional HCC staging systems substantially improved the ability to predict overall mortality risk. Conclusion: RAR is a novel and valuable prognostic indicator for patients with HBV-HCC.

Purpose:Hepatitis B virus-related hepatocellular carcinoma poses a significant global health challenge. This study aimed to develop and validate a novel prognostic nomogram integrating the red blood cell distribution width-to-albumin ratio for predicting patients' overall survival. Patients and Methods:A retrospective cohort of 1403 patients was divided into training, internal validation, and external validation cohorts. A multivariate Cox regression model selected variables to construct a nomogram and an online calculator, which were subsequently validated. Results:The ratio emerged as an independent risk factor for long-term survival (hazard ratio: 5.808, 95% confidence interval: 1.721-19.599). A prognostic nomogram incorporating nine variables based on the ratio was developed. Calibration curves demonstrated high concordance between the predicted and actual 3-year survival rates. Decision curve analysis indicated that the nomogram significantly increased the net benefit of predicting 3-year survival. Based on the area under the receiver operating characteristic curves, the nomogram outperformed traditional models in predicting survival across the three cohorts. Patients were stratified into low-, intermediate-, and high-risk groups based on risk scores calculated from the nomogram. In all cohorts, the median survival time of the high-risk group was significantly shorter than that of the intermediate- and low-risk groups. An online calculator, deployed via a web-based platform, facilitated convenient mortality risk prediction for these patients. Conclusion:The ratio-based nomogram we developed can accurately predict the survival of patients with hepatitis B virus-related hepatocellular carcinoma, serving as an effective auxiliary tool for clinical personalized treatment and prognostic assessment.

ABSTRACT:In acute myeloid leukemia (AML), elevated interleukin 6 (IL-6) levels in the bone marrow (BM) are linked to poor prognosis. However, the mechanisms driving this elevation and its role in chemoresistance remain unclear. Using the Prrx1-Cre system, we selectively deleted Il6 in BM mesenchymal stromal cells (MSCs) and established an AML mouse model. Our results show that MSCs are a major source of IL-6 in AML BM. Importantly, Il6 deletion in MSCs reduced oxidative phosphorylation (OXPHOS) activity in AML cells, slowed disease progression, and enhanced chemosensitivity to cytarabine (Ara-C). Similarly, the OXPHOS inhibitor IACS-010759 improved chemosensitivity in AML mice. Exogenous recombinant IL-6 reversed the chemosensitivity gains from Il6 deletion, confirming its role in chemoresistance. We further demonstrated that Il6 absence in MSCs inhibits mitochondria transfer to AML cells, dampening OXPHOS and enhancing Ara-C efficacy. In summary, our study underscores the critical role of Il6 from MSCs in AML progression and chemoresistance. Targeting IL-6 in MSCs may offer a promising therapeutic strategy for AML. This trial was registered at www.clinicaltrials.gov as #NCT06486350.

Background:This study challenges the prevailing view that hemolytic diseases of the newborn (HDN) associated with the Rh blood group system are more severe than those caused by the ABO system. The objective was to assess the effectiveness of exchange transfusion (ET) in managing HDN, with a focus on comparing treatment outcomes between ABO and Rh incompatibility cases. Methods:A study enrolled 125 neonates diagnosed with hyperbilirubinemia, comprising 66 males and 59 females. The gestational age of the neonates ranged from 33 to 41 weeks, and their birth weights varied between 2.11 to 4.3 kilograms. Based on the etiology of hemolysis, the study categorized 73 cases as ABO group and 52 as Rh group. Results:Post- ET, there was a significant reduction in serum total bilirubin (STB), serum indirect bilirubin (SIB), and platelet (PLT) counts (P<0.001). Pre- ET, differences in SIB and PLT were noted between neonates with ABO and Rh incompatibilities (P<0.05). There was no statistically significant disparities in the therapeutic effects of ET on STB, SIB, and PLT levels when comparing male and female neonates across both the ABO and Rh incompatibility groups. Conclusion:Our study demonstrated that ET is efficacious in reducing bilirubin levels and platelet counts in neonates presenting with ABO and Rh blood group incompatibilities. Notably, the effectiveness of ET was found to be independent of the neonates' gender, a finding that underscores the universal applicability of this treatment approach. Our study observation contradicts the prevalent belief that HDN associated with the Rh system is inherently more severe than that linked to the ABO system. This revelation underscores the imperative for the swift implementation of ET in managing cases of severe hyperbilirubinemia.

Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.

Background Chimeric antigen receptor (CAR) T cells have shown significant activity in B-lineage malignancies. However, their efficacy in myeloid leukemia has not been successful due to unclear molecular mechanisms. Methods We conducted in vitro and in vivo experiments to investigate whether myeloid leukemia cells directly induce CAR down-regulation. Furthermore, we designed a CD33 CAR KR in which all lysines in the cytoplasmic domain of CAR were mutated to arginine and verified through in vitro experiments that it could reduce the down-regulation of surface CARs and enhance the killing ability. Transcriptome sequencing was performed on various AML and ALL cell lines and primary samples, and the galectin-1-specific inhibitory peptide (anginex) successfully rescued the killing defect and T-cell activation in in vitro assays. Results CAR down-regulation induced by myeloid leukemia cells under conditions of low effector-to-tumor ratio, which in turn impairs the cytotoxicity of CAR T cells. In contrast, lysosomal degradation or actin polymerization inhibitors can effectively alleviate CAR down-regulation and restore CAR T cell-mediated anti-tumor functions. In addition, this study identified galectin-1 as a critical factor used by myeloid leukemia cells to induce CAR down-regulation, resulting in impaired T-cell activation. Conclusion The discovery of the role of galectin-1 in cell surface CAR down-regulation provides important insights for developing strategies to restore anti-tumor functions.

AbstractChimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1–2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.

The tumor suppressor Lkb1 is known to regulate the expression of forkhead box P3 (Foxp3), thereby maintaining the levels of Foxp3 + regulatory T cells (Treg) that play a crucial role in self‐tolerance. However, the effect of Lkb1 in Treg on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains obscure. Here, we demonstrated that conditional deletion of Lkb1 in Treg causes loss of Treg in the BM, which leads to failure of HSC homeostasis and the abnormal expansion. Moreover, the loss of BM Treg results in dysregulation of other developing progenitors/stem cell populations, leading to the defective differentiation of T cells and B cells. In addition, HSC from the BM with Treg loss exhibited poor engraftment efficiency, indicating that loss of Treg leads to irreversible impairment of HSC. Collectively, these results demonstrated the essential role of Lkb1 in Treg for maintaining HSC homeostasis and differentiation in mice. These findings provide insight into the mechanisms of HSC regulation and guidance for a strategy to improve the outcomes and reduce complications of HSC transplantation.

The effect of STAT3 knockout on the IL-6 regulation of MFN1.

Background: In addition to being secreted into the intercellular spaces by exocytosis, insulin-like growth factor binding protein 5 (IGFBP5) may also remain in the cytosol or be transported to the nucleus. Depending on the different cellular context and subcellular distribution, IGFBP5 can act as a tumor suppressor or promoter through insulin-like growth factor -dependent or -independent mechanisms. Yet, little is known about the impacts of IGFBP5 on acute myeloid leukemia (AML) and its underlying mechanism. Methods: Here we investigated the roles of IGFBP5 in human AML by using recombinant human IGFBP5 (rhIGFBP5) protein and U937 and THP1 cell lines which stably and ectopically expressed IGFBP5 or mutant IGFBP5 (mtIGFBP5) with the lack of secretory signal peptide. Cell counting kit-8 and flow cytometry assay were conducted to assess the cell viability, cell apoptosis and cell cycle distribution. Cytotoxicity assay was used to detect the chemosensitivity. Leukemia xenograft model and hematoxylin-eosin staining were performed to evaluate AML progression and extramedullary infiltration in vivo. Results: In silico analysis demonstrated a positive association between IGFBP5 expression and overall survival of the AML patients. Both IGFBP5 overexpression and extrinsic rhIGFBP5 suppressed the growth of THP1 and U937 cells by inducing cell apoptosis and arresting G1/S transition and promoted the chemosensitivity of U937 and THP1 cells to daunorubicin and cytarabine. However, overexpression of mtIGFBP5 failed to demonstrate these properties. An in vivo xenograft mouse model of U937 cells also indicated that overexpression of IGFBP5 rather than mtIGFBP5 alleviated AML progression and extramedullary infiltration. Mechanistically, these biological consequences depended on the inactivation of insulin-like growth factor 1 receptor -mediated phosphatidylinositol-3-kinase/protein kinase B pathway. Conclusions: Our findings revealed secreted rather than intracellular IGFBP5 as a tumor-suppressor and chemosensitizer in AML. Upregulation of serum IGFBP5 by overexpression or addition of extrinsic rhIGFBP5 may serve as a suitable therapeutic approach for AML.

目的 从血常规炎症指标和血清肿瘤标志物中寻找能诊断肺癌的血液学指标组合.方法 收集2018年1月至2021年4月在福建医科大学附属协和医院就诊的289例肺癌患者(肺癌组)、93例肺良性病变患者(肺良性病变组)和89例健康体检人员(体检组)的血液检验数据,包括血小板计数(PLT)、血小板分布宽度(PDW)、平均血小板体积(MPV)、血小板压积(PCT)、粒细胞绝对值(Neu#)、粒细胞百分比(Neu％)、淋巴细胞绝对值(Lym#)、淋巴细胞百分比(Lym％)、中性粒细胞与淋巴细胞比值(NLR)、红细胞体积分布宽度变异系数(RDW-CV)和红细胞体积分布宽度标准差(RDW-SD)等血常规炎症指标,癌胚抗原(CEA)、糖类抗原19-9(CA19-9)、甲胎蛋白(AFP)、细胞角蛋白19的可溶性片段(CYFRA)、神经元特异性烯醇化酶(NSE)、胃泌素释放肽前体(pro-GRP)、总前列腺特异性抗原(tPSA)、游离前列腺特异性抗原(fPSA)和CA125等血清肿瘤标志物,以及乳酸脱氢酶(LD H).采用秩和检验比较这些指标在3组间的差异,选取组间差异有统计学意义的指标用于下一步的ROC曲线诊断分析,再选择曲线下面积(AUC)较大的指标用于进一步的联合诊断分析,最后应用二分类Logistic回归联合ROC曲线综合分析不同指标联合模式对肺癌的诊断能力.结果(1)PLT、MPV、PCT、Lym#、RDW-CV、RDW-SD、LDH、Neu％、CEA、CYFRA在3组间的水平差异均有统计学意义(P<0.05).(2)ROC曲线分析PLT、MPV、PCT、Lym#、RDW-CV、RDW-SD、LDH、Neu％、CEA、CYFRA对肺癌的诊断效能,结果显示仅PCT、RDW-CV、CYFRA、LDH诊断肺癌的AUC>0.6,分别为0.626、0.603、0.707、0.630.(3)将PCT、RDW-CV、CYFRA、LDH相互联合,进行二分类Logistic回归和ROC曲线综合分析,结果显示,各种联合模式中,RDW-CV+LDH+CYFRA诊断肺癌的AUC最大,为0.823,而PCT+RDW-CV+LDH+CYFRA诊断肺癌的AUC为0.821,PCT+RDW-CV诊断肺癌的特异度最高(92.0％);PCT+RDW-CV+LDH+CYFRA诊断肺癌的灵敏度最高(76.5％).结论 在所检测的血液指标中,诊断肺癌效能最高的单项指标为CYFRA,CYFRA与RDW-CV、PCT、LDH中的一项或多项联合诊断肺癌的效能优于单项指标,其中RDW-CV+LDH+CYFRA及PCT+RDW-CV+LDH+CYFRA模式的诊断效能较大.

Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-CreERT2;Mettl3fl/+ mice with Mettl3fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.