Following the publication of the above article, an interested reader drew to the authors' attention that the control β‑actin western blots shown in Figs. 2C and 5A were strikingly similar, even though the experimental conditions reported in these figures were different. After having re‑examined the original data, the authors have realized that these western blots were inadvertently included in Fig. 2C erroneously. The revised version of Fig. 2, now incorporating the correct data for the β‑actin bands in Fig. 2C, is shown below. The authors confirm that the error associated with this figure did not have a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1778‑1788, 2019; DOI: 10.3892/ijmm.2019.4085].

This single-center retrospective study evaluated radiation pneumonitis (RP) in 209 treatment-naive EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving first-line third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) plus thoracic radiotherapy (TRT), with concurrent defined as any overlap of ≥ 1 day between EGFR-TKI and TRT, at Shandong Cancer Hospital and Institute between January 2019 and September 2024, excluding concurrent chemotherapy and anti-angiogenic therapy. RP was diagnosed by chest computed tomography (CT), clinical symptoms, and irradiated field concordance, while infectious pneumonia and tumor progression were excluded by laboratory tests and serial imaging. Grade ≥ 2 RP occurred in 43.54% of patients (22.01% grade 2, 21.53% grade 3; no grade 4/5 RP), with osimertinib showing the highest rates of grade ≥ 2 and grade 3 RP, followed by aumolertinib and furmonertinib. For grade ≥ 2 RP, patients receiving aumolertinib or furmonertinib had a lower observed risk than those receiving osimertinib, while ipsilateral lung V5 ≥ 35.93% and gross tumor volume (GTV) ≥ 12.62 mL were independent risk factors. For grade 3 RP, an inverse association between smoking history and RP risk was observed, whereas ipsilateral lung V30 ≥ 24.61% and GTV ≥ 14.56 mL were associated with increased risk. Median progression-free survival (PFS) was 26.70 months, with no significant difference among the three TKIs. In this cohort, first-line third-generation EGFR-TKI plus TRT was associated with frequent but generally manageable RP. TKI type, ipsilateral lung V5/V30, and GTV were key predictors of RP, although the dosimetric thresholds and drug-specific differences identified in this cohort require external validation.

Osteosarcoma (OS) is highly heterogeneous and often exhibits an immunosuppressive tumor microenvironment, contributing to poor outcomes. The cell-type-resolved role of the ATF/CREB stress-response network, particularly ATF4, remains unclear in OS. We integrated public OS single-cell RNA-seq and bulk transcriptome cohorts. Single-cell analyses included malignant program discovery (cNMF), regulon inference (SCENIC), and cell-cell communication (CellChat). Bulk cohorts (TARGET and GEO) were used to build and validate a prognostic model. ATF4-associated immune features were assessed using ESTIMATE, immune deconvolution, and TIDE-related metrics. WNT/β-catenin activity was evaluated by gene-set scoring. ATF4-related drugs were screened using DSigDB/Enrichr and assessed by docking. Sorafenib was selected for molecular dynamics simulation. ATF4 function was validated by siRNA knockdown (MG63, U2OS) and overexpression (HOS). A stress-associated malignant program showed enriched ATF/CREB activity and prominent signaling interactions. Intersecting its markers with ATF/CREB genes identified ATF3/ATF4/CREB5, which were used to construct an ATF/CREB-associated risk score (ACS) that stratified survival in TARGET and external cohorts. ATF4 showed the most consistent adverse prognostic association and remained an independent factor in multivariate analyses. ATF4-high tumors were associated with a more immunosuppressive profile and stronger WNT/β-catenin signaling, and these features tracked with the ACS. Among the compounds tested in silico, sorafenib ranked highest in docking, and subsequent molecular dynamics simulations suggested that the ATF4-sorafenib interaction can remain stable. In cell-based assays, silencing ATF4 curtailed proliferation, colony formation, and migration, accompanied by reduced β-catenin, CyclinD1, and c-MYC. By contrast, ATF4 overexpression led to the opposite pattern. Our results place ATF4 at the intersection of stress-related tumor programs, immune suppression, and WNT/β-catenin activation in OS, and this pattern is associated with poorer clinical outcomes. The ACS offers a practical way to stratify risk, and sorafenib warrants further evaluation as a potential ATF4-oriented therapeutic lead.

Background Cancer patients will have an increased incidence of corona virus disease 2019 (COVID-19) infection. The severity of COVID-19 infection varies among cancer patients who have other complications and are being treated. Method This retrospective cohort study evaluated the impact of cancer treatments on COVID-19 incidence and outcomes in 603 cancer patients. Key objectives included assessing treatment-related risks, severity, and treatment efficacy, along with the effects of treatment interruptions on patient recovery and therapy resumption. Result This study included 603 cancer patients, of whom 68 (11.28%) were infected with COVID-19, and 398 (66%) were vaccinated. Logistic regression analysis revealed that underlying comorbidities, chemotherapy, and radiotherapy were significantly associated with an increased risk of COVID-19 infection ( P < 0.05 for chemotherapy and radiotherapy). Factors such as sex, smoking status, cancer pathology, and staging showed no significant correlation with COVID-19 incidence. Treatment disruptions during the pandemic were observed, with chemotherapy being most affected (42.86% suspension), while surgery and TKI therapy showed minimal interruption. Efficacy analysis indicated no significant difference in treatment outcomes between suspended and uninterrupted treatments ( P = 0.758). Treatment suspensions did not significantly alter toxicity profiles, with bone marrow suppression being the most frequent toxicity. Conclusion Chemotherapy and radiotherapy increased the risk of COVID-19 in cancer patients, with treatment interruptions not affecting efficacy or toxicity, underscoring the need for tailored management.

Objective: Synovial fibroblast migration and invasion are critical contributors to the progression of rheumatoid arthritis (RA). Acidification of local joint tissue exacerbates RA progression, but the underlying mechanisms remain unclear. This study aimed to investigate the role of acid-sensitive ion channel ASIC1a and its mediator, the RIPK3-MDH1 axis, in regulating the migration and invasion of RA fibroblast-like synoviocytes (RA-FLSs). Methods: The expression of ASIC1a, RIPK3, and MDH1 in synovial tissue from RA patients and arthritic mice was analyzed using immunofluorescence and Western blotting. RA-FLSs were stimulated with extracellular acidification (pH 6.8, mimicking local tissue conditions), and their migration and invasion were assessed via Transwell assays. The interaction between ASIC1a and RIPK3 was predicted using molecular docking and confirmed by co-immunoprecipitation (CO-IP). RIPK3-/- mice were used to establish a collagen antibody-induced arthritis (CAIA) model. Pharmacological inhibitors of ASIC1a (PcTX1) and RIPK3 (GSK-872) were employed to evaluate their therapeutic effects on migration and invasion in vitro and arthritis progression in vivo using the collagen-induced arthritis (CIA) model. Bioinformatics analyses, along with glucose, ATP, NAD+ and NADH assays, and oxygen consumption rate (OCR) measurements, were conducted to investigate the regulation of mitochondrial respiration by the RIPK3-MDH1 axis. Results: Extracellular acidification (pH 6.8) significantly enhanced the migration and invasion of RA-FLSs, effects that were abrogated by ASIC1a knockdown or pharmacological inhibition. ASIC1a activated RIPK3 through its kinase function, independent of its ion channel activity. RIPK3 activation promoted mitochondrial respiration and ATP production via MDH1-mediated malate shuttle activation. Furthermore, inhibition of the malate shuttle using Aminooxyacetic acid (Carboxymethoxylamine) hemihydrochloride (AOA) suppressed ASIC1a-mediated RA-FLSs migration and invasion. The RIPK3-MDH1 axis also maintained malate shuttle activity by enhancing glycolysis and glutamate metabolism through GLS1. Mechanistically, ASIC1a activated RIPK3, which in turn promoted MDH1-mediated malate shuttle activation, enhancing mitochondrial respiration and ATP synthesis, thereby driving RA-FLSs migration and invasion. In vivo, pharmacological inhibition of ASIC1a or RIPK3, as well as RIPK3 knockdown, significantly alleviated arthritis progression in CIA and CAIA mouse models. Conclusion: The RIPK3-MDH1 malate shuttle drives RA-FLSs migration and invasion in RA. Activation of the ASIC1a-RIPK3-MDH1 axis enhances mitochondrial respiration and ATP synthesis in RA-FLSs, highlighting this pathway as a potential therapeutic target for RA.

The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads to an increase in extracellular calcium influx, thereby exacerbating the degeneration of articular chondrocytes in rheumatoid arthritis (RA). It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53/NRF2/SLC7A11 pathway in its underlying mechanism. In vitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin-α (PFN-α), a p53 inhibitor, mitigated acidosis-induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx-1, an ASIC1a inhibitor, inhibited acidification-induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. In vivo experiments demonstrated that the ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics of ankle joints in collagen-induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification-induced ferroptosis in articular chondrocytes in RA, potentially via the p53/NRF2/SLC7A11 pathway.

Activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit hyperplasia that significantly contributes to rheumatoid arthritis (RA)-related joint destruction. Lactate, previously considered merely a byproduct of glycolysis, is now recognized as a critical regulator in the progression of RA from inflammation to bone degradation. Histone lactylation, an epigenetic modification dependent on lactate, serves as a link between glycolytic metabolism and chromatin remodeling. However, the role of lactate-dependent histone lactylation in the hyperplasia of RASFs remains insufficiently understood. Our findings revealed that elevated lactate levels in the synovial fluid of RA patients enhanced the proliferation of RASFs. Moreover, stimulation with extracellular lactate significantly increased the expression of histone H3 lysine 18 lactylation (H3K18la), while the inhibition of H3K18la through P300 silencing reduced the lactate-induced proliferation in RASFs. Furthermore, the Chromatin Immunoprecipitation-qPCR assay revealed that methyltransferase 1 (METTL1) was a downstream target gene of H3K18la, and silencing of METTL1 counteracted the lactate-induced suppression of ferroptosis and further diminished the proliferation in RASFs. Mechanistically, METTL1 facilitated m7G modification on NeuroD1 mRNA, thereby enhancing its stability. Subsequently, NeuroD1 bound to the glutathione peroxidase 4 (GPX4) promoter to augment its transcriptional activity, thereby inhibiting lipid peroxidation in a manner that conferred ferroptosis resistance. Additionally, intra-articular delivery of lentivirus encoding shMETTL1 or shNeuroD1 markedly alleviated arthritis severity and inhibited the hyperplasia of synovial fibroblasts in a collagen-induced arthritis (CIA) mouse model. Our findings demonstrate that lactate-induced H3K18la promotes ferroptosis resistance to facilitate the hyperplasia of RASFs through the activation of the METTL1/NeuroD1/GPX4 signaling pathway in RA.

PURPOSE:This study seeks to investigate the fundamental molecular processes through which histone deacetylase 9 (HDAC9) governs the proliferation of glomerular mesangial cells in the context of immunoglobulin A nephropathy (IgAN) and to identify novel targets for clinical research on IgAN. METHODS:Data from high-throughput RNA sequencing for IgAN were procured from the Gene Expression Omnibus database to assess the expression profiles and clinical diagnostic significance of histone deacetylase family proteins (HDACs). Blood samples from 20 IgAN patients were employed in RT-qPCR analysis, and the spearman linear regression method was utilized to analyze the clinical correlation. The proliferation of glomerular mesangial cells (GMCs) under the influence of HDAC9 was examined using the 5-ethynyl-2'-deoxyuridine (EdU) assay. Proteins interacting with HDAC9 were predicted utilizing the STRING database. Immunoprecipitation and protein immunoblotting employing anti-acetylated lysine antibodies were conducted to determine the acetylation status of calmodulin-like protein 6 (CALML6). RESULTS:Analysis of the GSE141295 dataset revealed a significant upregulation of HDAC9 expression in IgAN and the results of RT-qPCR demonstrated a substantial increase in HDAC9 expression in IgAN patients. Receiver operating characteristic (ROC) analysis indicated that the area under the curve (AUC) value for HDAC9 were 0.845 and Spearman correlation analysis showed that HDAC9 expression was positively correlated with blood levels of blood urea nitrogen (BUN) and serum creatinine (Crea). The EdU cell proliferation assay indicated that HDAC9 facilitated the excessive proliferation of GMCs. The STRING database and recovery experiments identified CALML6 as a downstream effector of HDAC9 in controlling abnormal GMC multiplication. Co-immunoprecipitation assays demonstrated that HDAC9 modulates CALML6 expression through acetylation modification. CONCLUSION:HDAC9 is markedly upregulated in IgAN, and it mediates the excessive proliferation of GMCs by regulating the deacetylation of CALML6.

Rationale: The death of chondrocytes triggered by extracellular acidification represents a critical factor in the degradation of cartilage tissue and bone, thereby exacerbating the progression of rheumatoid arthritis (RA). Our previous research demonstrated that acid-sensing ion channel 1a (ASIC1a) serves as a key acid sensor mediating the destruction of articular cartilage in RA, which is closely associated with mitochondrial damage of chondrocytes. However, its regulatory mechanism remains unclear. Methods: Cartilage samples from RA patients and collagen-induced arthritis (CIA) rat models were examined to determine the levels of mitophagy and PANoptosis. In parallel, primary rat articular chondrocytes were cultured and subjected to either ASIC1a activation or silencing. Mitochondrial function, mitophagy, and PANoptotic markers were evaluated using immunoblotting, immunofluorescence, and transmission electron microscopy. Additionally, the subcellular distribution of SIRT3 to clarify its role in maintaining mitochondrial homeostasis. Results: We observed a significant increase in the levels of mitophagy and PANoptosis within the cartilage tissue of both RA patients and collagen-induced arthritis (CIA) rat models. Activation of ASIC1a by extracellular acidification triggered mitophagy, ultimately resulting in PANoptosis of chondrocytes. The loss of ASIC1a protected chondrocytes from PANoptosis, thereby alleviating disease progression in CIA rats. Mechanistically, we demonstrated that the transport of SIRT3 from cytoplasm to mitochondria was inhibited upon ASIC1a activation. ASIC1a upregulated calcineurin (CaN) expression, which competitively bound to HSP70, disrupting the SIRT3-HSP70 complex and thereby impairing SIRT3 mitochondrial translocation. The reduced levels of SIRT3 in mitochondria induced mitochondrial dysfunction and excessive mitophagy in primary rat articular chondrocytes, ultimately leading to PANoptosis of chondrocytes. Restoration of SIRT3 improved mitochondrial dysfunction and inhibited excessive mitophagy in the process of ASIC1a-induced PANoptosis of chondrocytes. Conclusion: Our study demonstrated that ASIC1a induces the destruction of articular cartilage through the disruption of the equilibrium between mitochondrial quality control and cell fate. This suggests that ASIC1a is a promising therapeutic target to improve the clinical treatment of RA.

Tissue acidosis is a key characteristic of RA. It remains unclear whether acidosis promotes the formation of the complex adaptive immune landscape mainly characterized by T cell activation in RA by influencing synovial fibroblasts. This study aims to investigate the influence of acidosis on the immune microenvironment of RA by exploring the cytokine secretion and expression of co-stimulatory factors of RA synovial fibroblasts. The Bulk RNA-seq dataset (GSE89408, Normal = 23, RA = 150) was utilized for cytokine screening and the immune state assessment based on disease stage. RNA-seq was employed to investigate cytokine and co-stimulatory molecule expression following 6 h of acid stimulation, combined with Bulk RNA-seq data to evaluate contributions to RA. Human cytokine arrays were used to confirm cytokine accumulation in supernatants after 12 h of acid stimulation. Proteomics was applied to explore cellular functional states in RASFs under 6 h of acid stress, with joint RNA-seq analysis elucidating transcription factor activation. Validation of select high-throughput data was performed using qRT-PCR and immune-based assays. Bulk RNA-seq and RNA-seq identified 56 differentially expressed cytokines at their intersection. Functional enrichment analysis demonstrated that acid stimulation enhanced cytokine secretion and T cell chemotaxis in RA synovial fibroblasts (RASFs). Cytokine array revealed that acid exposure increased the accumulation of growth factors (e.g., FGF, VEGF) by over twofold and promoted the expression of multiple inflammatory and chemotactic factors. Immune state analysis indicated that acid stimulation induced a complex immune landscape by upregulating co-stimulatory and antigen-presenting molecules. Proteomics showed that acid stress enhanced mitochondrial function and triggered metabolic reprogramming in RASFs. Integrated transcriptomic and proteomic analyses revealed that AP1 regulates gene expression in RASFs, with its activation further confirmed by Western blotting and immunofluorescence.

Metal-microplastic complexes (m-MPs) represent an emerging environmental health concern. However their presence and pathological implications in lung adenocarcinoma (LUAD) remain underexplored. This study employed a multimodal approach to characterize m-MPs in 15 LUAD patients, integrating several techniques, including laser direct infrared imaging (LDIR), pyrolysis gas chromatography-mass spectrometry (Py-GCMS), inductively coupled plasma analysis (ICP), and Sequencing at the transcriptome level. Totally, 34 distinct microplastic types were identified in lung tissues, with polyvinyl chloride (PVC) predominant in tumor tissues. Notably, the levels of aluminum (Al) and calcium (Ca) exhibited strong positive correlations with microplastics (MPs) content in tumors (p < 0.05). In this study, a novel approach was applied to assess the influences of m-MPs on tumor, through which we found that m-MPs accumulation could activate pro-tumorigenic pathways, leading to reduced overall survival (HR=1.59, p = 0.002) and disease-specific survival (HR=1.64, p = 0.01). Moreover, SYNE1 and RORA genes were identified as diagnostic/prognostic biomarkers for the assessment of m-MPs exposure in LUAD. Our findings revealed that m-MPs have the capacity for promoting metal ion deposition and oncogenic signaling, thereby involved in LUAD progression. This work also provides evidence using human tissue to demonstrate the association of m-MPs with lung cancer outcomes and advocate the development and application of therapeutic strategies targeting m-MPs.

Activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit tumor-like properties, which play a significant role in joint degradation in RA. The prevalence of N6-methyladenosine (m6A) as a modification in mRNA is involved in diverse biological processes; however, its specific implications in the pathogenesis of RA have yet to be fully elucidated. This study seeks to explore the impact and underlying mechanisms of m6A methylation on the proliferation, migration, and invasion of RASFs. Our study revealed an upregulation of METTL3 expression in synovium and SFs from patients with RA. Moreover, knockdown of METTL3 resulted in decreased proliferation, migration, and invasion of RASFs. Mechanistically, METTL3 mediated m6A modification in the SLC7A11 mRNA, enhancing its stability through interaction with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Furthermore, knockdown of METTL3 accelerated erastin-induced ferroptosis and further inhibited tumor-like characteristics in RASFs. Additionally, intra-articular injection of lentivirus-shMETTL3 showed promising results in reducing arthritis severity and inhibiting aggressive behaviors of SFs in a CIA mouse model. Our findings indicate that the METTL3-mediated m6A modification plays a critical role in the pathogenesis of synovial hyperplasia and invasion in RA. Therapeutic interventions aimed at targeting METTL3 may offer a novel approach for the treatment of RA.

Our previous study showed that acidic stimuli activate acid-sensitive ion channel 1a (ASIC1a), resulting in chondrocyte destruction associated with rheumatoid arthritis (RA). However, the exact underlying processes remain unclear. Recent evidence suggests that the production of reactive oxygen species (ROS) mediated by succinate dehydrogenase (SDH), contributes to chondrocyte damage. The objective of this study was to investigate the involvement of SDH in ASIC1a-induced chondrocyte destruction in RA and to explore the associated mechanisms both in vivo and in vitro. Our findings revealed that the cartilage of mice with collagen-induced arthritis (CIA) and acid-treated chondrocytes exhibited a substantial increase in SDH expression. Furthermore, SDH inhibition attenuates acidosis-induced pyroptosis in chondrocytes. Notably, ASIC1a activation through acid stimuli increases SDH activity and pyroptosis through the Ca2+/CaMKK2/AMPK pathway in chondrocytes. Mechanistically, SDH assembly factor 2 (SDHAF2) was identified as a key modulator of SDH activity induced by ASIC1a in acid-stressed chondrocytes. Moreover, the expression of SDH in CIA mouse chondrocytes decreased and the histological characteristics of ankle joint damage were reduced by the ASIC1a-particular blocker PcTx-1. Overall, these observations suggest that ASIC1a activation under acidic conditions increases SDH activity and modulates SDHAF2, thereby promoting chondrocyte pyroptosis through the Ca2+/CaMKK2/AMPK pathway.

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

Sepsis-induced acute lung injury (ALI) is a leading cause of death among septic complications. Tao-Hong-Si-Wu decoction (TSD), a classical recipe from traditional Chinese medicine used for treating ischemic stroke, has been recently reported to alleviate inflammation and inflammation-stimulated injuries related to the pathology of ALI. Here, we first observed the therapeutic effect of TSD on sepsis-induced ALI. Based on integrated metabolomics and network pharmacology analysis (NPA) techniques, we aim to understand the mechanism of TSD alleviating ALI. TSD’s effects were observed in rats modeled by cecal ligation and puncture (CLP) and rat macrophages stimulated by lipopolysaccharide (LPS). Metabolomics analyses were applied to determine the ingredients in the medicine and key metabolites correlated to the NPA for the prediction of TSD targets. Gene and protein expressions of the key predicted targets were evaluated in the lung tissue and macrophages of septic model rat by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays, respectively. TSD improved survival rate and protected against lung injury in CLP rats. Eleven endogenous metabolites were related to TSD’s actions. TSD significantly suppressed IL-6 and TNF-α secretions and their gene expressions both in the lung tissue of the model rats and in LPS-stimulated macrophages. TSD also restored decreased lung protein expression of VEGFA in septic model rats. Targeted proteins and their affecting metabolites were finally validated in an external test set of rats. This study shows that metabolomics coupled with NPA is a promising approach to explore potential targets of medicine with complex compositions.

Backgrounds and aims: Carcinogenesis is characterized by an unlimited growth of cells exacerbated by Cox-2 overexpression. Cox-2 inhibitors have been proven effective in preventing and treating tumors. In our previous studies, we found that 4-Amino-2-Trifluoromethylphenyl Retinate (ATPR) induces cell apoptosis and inhibits cell proliferation to exhibit anti-cancer properties. The use of ATRA as well as Cox-2 inhibitors in clinical settings can cause adverse reactions. It is unknown what the effects and mechanisms of co-administration of ATPR and Cox-2 inhibitors are. Results: A combination of ATPR and Cox-2 inhibitors, Celecoxib, inhibited pharyngeal cancer cell proliferation in vitro and induced apoptosis. The cell cycle was arrested at G0/G1 by activating P53 and CDNA1. By activating MAPK/JNK pathways, ATPR and Celecoxib led to intrinsic and extrinsic apoptosis in pharyngeal cancer cells. ATPR/Celecoxib combined treatment suppressed tumor growth in the pharyngeal cancer cell-derived xenograft mouse model by increasing the number of apoptotic cells. The expression of the RARA and PTGS2 genes was significantly increased in tumor tissue compared to non-tumor tissue in the clinical analysis of the head and neck squamous cell carcinoma dataset. An association was found between this and the level of intrinsic apoptotic signals. Furthermore, a survival analysis conducted over a period of five years indicated that higher levels of RARA expression were associated with a better clinical outcome. Conclusion: ATPR and celecoxib inhibit the proliferation of cancer cells as well as induce apoptosis. Co-administration of ATPR and Cox-2 inhibitors has the potential to be a novel treatment plan for cancer.

Acute myeloid leukemia (AML) remains a biologically heterogeneous disease with high morbidity and mortality under the existing treatment strategies. Our previous study showed that E2A might be a potential therapeutic target for AML, but the underlying mechanism was unclear. Here, we found that SDCBP2 might be a target gene of E2A through RNA-seq combined ChIP-seq screening. This was also demonstrated by Co-IP experiment. Furthermore, the expression of E2A and SDCBP2 were increased in both AML cell lines and patient samples. Downregulation of SDCBP2 expression suppressed proliferation and induced differentiation of AML cells. In human xenograft mouse leukemia model, inhibiton of SDCBP2 expression delayed AML progression. Overall, the above results confirmed that SDCBP2 might be a target gene of E2A and a potential therapeutic target for AML.

As one of the common complications of radiotherapy, radiation pneumonia (RP) limits the prognosis of patients. Therefore, better identifying the high-risk factors that lead to RP is essential to effectively prevent its occurrence. However, as lung cancer treatment modalities are being replaced and the era of immunotherapy has arrived, literature that reviews the parameters and mode of radiotherapy, chemotherapy drugs, targeted drugs and current hot immune checkpoint inhibitors related to RP is lacking. This paper summarizes the risk factors for radiation pneumonia by retrieving and analysing previously published literature and the results of large clinical trials. The literature primarily included retrospective analyses, including clinical trials in different periods and a part of the literature review. A systematic literature search of Embase, PubMed, Web of Science, and Clinicaltrials.gov was performed for relevant publications up to 6 Dec. 2022. Search keywords include, but are not limited to, "radiation pneumonia", "pneumonia", "risk factors", "immunotherapy", etc. The factors related to RP in this paper include physical parameters of radiotherapy, including V5, V20, and MLD; chemoradiotherapy mode and chemotherapy drugs, including paclitaxel and gemcitabine; EGFR-TKI; ALK inhibitors; antiangiogenic drugs; immune drugs and the underlying disease of the patient. We also introduce the possible mechanism of RP. In the future, we hope that this article not only sounds the alarm for clinicians but also helps to identify a method that can effectively intervene and reduce the occurrence of RP, significantly improve the quality of life and prognosis of patients, and more effectively improve the therapeutic effect of radiation therapy.

目的 利用ASIC1基因敲除小鼠构建佐剂性关节炎(AA)模型,探讨敲除ASIC1对关节炎发病程度及关节软骨损伤的影响.方法 将野生型小鼠和基因敲除小鼠分别分为:正常组、模型组.通过观察足爪炎症情况进行关节炎评分,并测定继发侧足爪肿胀度;通过HE染色、免疫组化、TUNEL法、ELISA法检测关节软骨损伤及关节炎炎症情况.结果 基因敲除小鼠模型组的关节炎评分及足爪肿胀度低于野生型小鼠模型组;HE结果显示敲除ASIC1可减轻AA小鼠关节软骨的破坏情况;免疫组化结果显示敲除ASIC1可提高AA小鼠关节软骨中Ⅱ型胶原的表达;TUNEL法结果显示基因敲除小鼠模型组中软骨细胞的凋亡水平低于野生型小鼠模型组;ELISA法结果表明,敲除ASIC1可下调AA小鼠血清中高表达的促炎细胞因子IL-1β、TNF-α的水平.结论 敲除ASIC1可降低佐剂性关节炎发病程度及关节软骨的破坏水平.

Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3- ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical down-stream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.