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N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics. Leukemia: Key component of disease progression identified Inhibiting a protein that is overexpressed in the bone marrow of acute myeloid leukemia patients may prove valuable in treating the disease. Recent research has demonstrated the important role played by epigenetics in cancers – for example, disruption to a common mRNA modification known as m6A can result in cancer initiation and progression. Jianchuan Deng and co-workers at Chongqing Medical Universit0y, China, examined the role of an m6A-related protein called IGF2BP3 in mice models and samples from leukemia patients. IGF2BP3 was overexpressed in patients’ bone marrows, the levels of the protein correlating with extent of proliferation of leukemia cells and poor prognosis. IGF2BP3 stabilises the activity of a known cancer-related protein, promoting leukemia progression. Blocking IGF2BP3 expression reduced cell proliferation and impaired activity of leukemic cells, suggesting the protein may be a useful therapeutic target.

Background Systemic inflammation and nutritional status play critical roles in determining clinical outcomes across multiple disease entities, particularly malignancies. Significantly, these two pathophysiological factors exhibit dynamic interplay through shared pathobiological mechanisms. This study sought to investigate the independent and combined prognostic capacity of the systemic inflammatory response index (SIRI) and prognostic nutritional index (PNI) in predicting all-cause, cancer-specific, and non-cancer mortality among cancer survivors. Methods Utilizing the National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018, 3,289 adult cancer survivors (weighted population: 20,795,493) were analyzed. Restricted cubic splines (RCS) delineated mortality risk nonlinearity. Survival trajectories were assessed via Kaplan-Meier (KM) analysis with complex survey adjustments. Weighted Cox proportional hazards models quantified independent and joint associations. Results Eight hundred seventy-four deaths were identified over a median follow-up of 6.5 years. By RCS analyses, SIRI exhibited a linear association with all-cause mortality, whereas PNI demonstrated a nonlinear relationship with all-cause mortality. Weighted Cox regression analysis demonstrated increased all-cause, cancer-specific, and non-cancer mortality risks in cancer survivors with high-SIRI or with undernutrition (PNI ≤ 48). Joint analysis showed that cancer survivors with concurrent high-SIRI and undernutrition had the highest risk for all-cause (HR 3.169, 95%CI 2.324–4.321), cancer-specific (HR 2.578, 95%CI 1.308–5.080) and non-cancer (HR 2.197, 95%CI 1.480–3.261) mortality, respectively, relative to the reference group with concurrent low-SIRI and PNI > 48. Subgroup and interaction analysis confirmed the stability of the core results. Conclusion SIRI and PNI emerged as independent prognostic predictors with synergistic mortality prediction capacity in cancer survivors. Cancer survivors with concurrent high level of systemic inflammation and poor nutritional status was associated with the highest mortality risk for all-cause, cancer-specific, and non-cancer.

Background Effective treatment options are limited for elderly patients with acute myeloid leukemia (AML). A prospective phase II study was conducted to investigate the safety and efficacy of pegylated liposomal doxorubicin (PLD) combined with low-dose cytarabine (LDAC) and granulocyte colony-stimulating factor (G-CSF) in newly diagnosed older and unfit AML patients. Methods Twenty-two patients were enrolled and deemed evaluable. The study included one cycle of induction and four cycles of consolidation, followed by maintenance therapy. Results The median age of enrolled patients was 71.5 years (range, 63 to 82 years), and 16 patients (72.7%) were over 70 years of age. The overall response rate (ORR) was 77.3% (n = 17) and the complete remission (CR)/complete remission with incomplete recovery (CRi) rate was 63.6% (n = 14) after the first induction cycle. With a median follow-up of 12.4 months, eight patients (57.1%) relapsed, with a median time to relapse of 12.3 months. The median duration of response (DOR) was 11.9 months (95% CI, 6.4 to NA months), the median overall survival (OS) was 15 months (95% CI, 8.4 to 21.6 months), and the median progression-free survival (PFS) was 7.5 months (95% CI, 4.6 to 15.1 months). Common grade 3 or greater adverse events included febrile neutropenia (77.8%) and infection (63.6%), with pneumonia being the most common (10, 45.5%). There was one death (4.5%) within 30 days. Conclusion The combination of PLD, LDAC, and G-CSF is well-tolerated and exhibits high rates of CR/CRi and low early mortality, providing an attractive treatment option for newly diagnosed elderly and unfit AML patients.

By hetero atom doping, a nitrogen-doped porous carbon was synthesized and applied to catalytic oxidation removal of NO. The synthesis conditions and NO removal process conditions of the modified carbon material were investigated, including calcination temperatures, impregnation amount, NO inlet concentration (100–500 ppm) and catalytic reaction temperature. The results showed that the dicyandiamide impregnation solution concentration of 0.5 M, and the calcination temperature of 600 °C performed the best in the preparation of structurally stable nitrogen-modified carbon. Due to the formation of a large number active centers of pyridine nitrogen (N-6) groups and graphitic nitrogen (N-Q) groups, the optimal conversion rate of NO could reach 67.2%. Graphic Abstract

Metabolic reprogramming disrupts energy homeostasis and promotes tumor cell proliferation. In the present study, high expression of adipose triglyceride lipase (ATGL) in patients with acute myeloid leukemia (AML) predicted a poor clinical prognosis. Furthermore, the aberrant upregulation of ATGL was confirmed to promote the malignant progression of AML through gene ablation, overexpression, and pharmacological inhibition of ATGL, particularly in FLT3-ITD-mutated AML. RNA sequencing, lipid peroxidation, cellular iron, and ROS assays were performed to confirm the association of ATGL with ferroptosis. Mechanistically, ATGL is positively correlated with stearoyl-CoA decarboxylase 1 (SCD1) and promotes the malignant progression of AML by inhibiting ferroptosis through the CEBPα/SCD1 axis. We established gilteritinib-resistant MOLM-13 and MV4-11 cell lines and collected cells from patients with FLT3 -ITD mutations to confirm that ATGL inhibitors increased the efficacy of gilteritinib. Consequently, we constructed an AML xenograft model using cells derived from patients with FLT3 -ITD-mutated AML to confirm the efficacy of combining ATGL inhibitors with gilteritinib in vivo. This study provides novel therapeutic targets and monitoring indicators for AML, along with new treatment strategies for patients with FLT3 -ITD-mutated AML and those with relapsed/refractory FLT3 -ITD-mutated AML.

Background Asthma, a chronic allergic condition, is commonly associated with elevated eosinophil levels. However, the relationship between the neutrophil percentage and the high-density lipoprotein ratio (NHR) in asthma remains poorly defined. This study aims to clarify the association between NHR and asthma in the elderly population in the US. Methods Leveraging data from the national health and nutrition examination survey (NHANES) from 2015 to 2018, this study investigated the association between NHR and asthma among individuals aged 60–80 years in the US. Logistic regression models, adjusted for multiple covariates, were employed to evaluate these associations. In addition, smooth curve fitting was applied to identify potential nonlinear relationships and threshold effects. Subgroup analyses were further conducted to assess variations across different population groups. Results The study included 1,514 participants, with a median age of 70.0 years and an asthma prevalence of 14.53%. After adjustment for relevant covariates in Model III, a statistically significant negative association between NHR and asthma was observed (OR = 0.130, 95% CI: 0.040–0.360, p  < 0.001). This relationship was nonlinear, with an inflection point at NHR = 1.637. Beyond this threshold, the negative association remained significant (OR = 0.160, 95% CI: 0.040–0.680, p  = 0.013). Receiver operating characteristic (ROC) curve analysis demonstrated a predictive value of NHR for asthma, with an area under the curve (AUC) of 0.615 when NHR was ≥ 1.430. Conclusion This study reveals a significant association between NHR and asthma among individuals aged over 60 in the US, indicating that as NHR increases beyond 1.637, the likelihood of asthma decreases.

Acute myeloid leukemia (AML), a hematologic malignancy, is an important public health issue. It is a result of the abnormal proliferation of immature myeloid cells. Despite advancements in diagnostic procedures, the early identification of AML remains a significant clinical challenge, marking a distinctive niche for newer theranostic approaches to ameliorate diagnosis and treatment. Aptamers are single-stranded oligonucleotides capable of specific binding with high target affinity that have emerged as a promising candidate for molecular recognition in diagnostics and targeted therapy. In this study, we aimed to select and characterize a high-affinity aptamer for C-type lectin-like molecule-1 (CLL-1), an important cell surface marker for AML. CLL-1-specific aptamers were enriched in the context of iterative positive and negative rounds of selection in a systematic evolution of ligands by exponential enrichment (SELEX) approach. In the following, flow cytometry assessment demonstrated the progression of enrichment and then confirmed their performance. The high-throughput sequencing supported the enrichment of five candidate aptamers. In addition, flow cytometry and specificity assays determined that aptamer-2 specifically bound to CLL-1 with an exceedingly high degree of specificity (94.3%) compared with negative controls and other aptamers. The surface plasmon resonance (SPR) valuation revealed that aptamer-2 has a K d of 1.55 × 10 −8 M, which indicates a high affinity of binding to CLL-1. Docking analysis reveals a stable and specific interaction between aptamer-2 and CLL-1, highlighting key binding regions and molecular contacts that may underpin targeted recognition. Taken together, the results put forward aptamer-2 as a highly specific and high-affinity candidate for targeting CLL-1. This study opens the prospect of using this aptamer for diagnostic approaches for AML. Further in vivo and translational studies on its efficacy and efficiency are needed to elucidate its performance in real-world scenarios.

BackgroundChimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies in recent years. However, a considerable proportion of patients would experience tumor recurrence and deterioration. Insufficient CAR-T cell persistence is the major reason for relapse. Multiple strategies to enhance the long-term antitumor effects of CAR-T cells have been explored and developed. In this study, we focused on tyrosine kinase inhibitors (TKIs), which have emerged immunomodulatory potential besides direct tumoricidal effects.MethodsHere, we screened 50 approved TKIs drugs and identified that afatinib (AFA) markedly enhanced the expressing of CD62L and inhibited reactive oxygen species level in T cells. And the underlying mechanisms of AFA medicating T cells were explored by detecting signal transduction, and metabolism pattern. Furthermore, we co-cultured AFA with CAR-T cells during the preparation stage and multianalyses of differentiation characteristics, metabolic profiling, and RNA sequencing revealed that AFA induce comprehensive metabolism remodeling and fate reprogramming. Based on it, we finally identified the antitumor efficacy of AFA-pretreatment CAR-T compared with negative-control CAR-T.ResultsWe identified that AFA blocked the T-cell receptor (TCR) and phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, induced metabolic reprogramming and modulated T-cell differentiation. When combined with CAR-T cells, AFA inhibited the exhaustion and enhanced the persistence and cytotoxicity. Our results revealed that the pretreatment of AFA enables to boost CAR-T cells with strong antitumor cytotoxicity in leukemia mouse model.ConclusionsOur study systematically demonstrated that AFA pretreatment effectively enhanced CAR-T cells antitumor performance, which presents a novel optimization strategy for potent and durable CAR-T cell therapy.

Background Chronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells. Methods GS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan–Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1 . RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS. Results GS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635 . Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1 / miR-635 /GS/Gln/mTOR signaling pathway. Conclusions Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway. Graphic Abstract

Acute myeloid leukemia (AML) is a malignant clonal disorder. Despite enormous progress in its diagnosis and treatment, the mortality rate of AML remains high. The aim of this study was to identify prognostic biomarkers by using the gene expression profile dataset from public database, and to improve the risk-stratification criteria of survival for patients with AML. The gene expression data and clinical parameter were acquired from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. A total of 856 differentially expressed genes (DEGs) were obtained from the childhood AML patients classified into first complete remission (CR1) group (n=791) and not CR group (n=249). We performed a series of bioinformatics analysis to screen key genes and pathways, further comprehending these DEGs through Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Six genes ( and ) identified by univariate, Kaplan-Meier survival and multivariate Cox regression analyses were used to develop the prognostic model. Further analysis showed that the survival estimations in the high-risk group had an increased risk of death compared with the low-risk group based on the model. The area under the curve of the receiver operator characteristic curve in the prognostic model for predicting the overall survival was 0.729, confirming good prognostic model. We also performed a nomogram to provide an individual patient with the overall probability, and internal validation in the TARGET cohort. We identified a six-gene prognostic signature for risk-stratifying in patients with childhood AML. The risk classification model can be used to predict CR markers and may assist clinicians in providing realize the individualized treatment in this patient population.