S7. The effect of METTL3 on m6A-modified Bim mRNA.

S6. METTL14-mediated m6A methylation of Bim mRNA maintains its stability and increases Bim expression.

S4. METTL14 promotes osimertinib-induced cell apoptosis in NSCLC cells.

S1. The validation of resistance to third-generation TKIs osimertinib, furmonertinib and almonertinib in osimertinib-resistant NSCLC cells.

This report describes a 57-year-old male patient with metastatic breast cancer who experienced atrial fibrillation during the infusion of utidelone as palliative chemotherapy. All cardiological examinations conducted before treatment were normal. There was no evidence of thyroid dysfunction, nor any objective data indicating acute or chronic cardiovascular disease. Other combination drugs have been used in clinical practice for decades and rarely have proarrhythmic activity. The innovative drug utidelone, independently developed in China, was approved by the National Medical Products Administration (NMPA) of China in 2021 for the treatment of patients with metastatic breast cancer. Cardiotoxicity has not been prominently reported in prior clinical trials of utidelone. Although a definite causal relationship cannot be confirmed, the close temporal association and clinical course suggest that utidelone may have contributed to the arrhythmias. This case highlights the need for careful cardiac monitoring during treatment.

S2. The effect of METTL14 knockdown on cell proliferation of H1975 and PC9 cells.

S5. METTL14 promotes cell apoptosis in NSCLC cells.

S3. The effect of METTL3 on the osimertinib sensitivity of NSCLC cells.

Effective wound management remains a critical clinical challenge, with its inherent complexity posing a substantial burden on patient quality of life. Inadequate treatment can result in severe complications, including tissue infection, necrosis, and the loss of both localized and systemic physiological functions. Consequently, over the past decade, researchers have actively explored new approaches to accelerate wound healing. Here, we report the design of a multifunctional composite hydrogel dressing that simultaneously suppresses inflammation and promotes tissue regeneration by enhancing angiogenesis and modulating macrophage polarization. The hydrogel is crosslinked from amino-functionalized hyaluronic acid, aldehyde-functionalized dextran, and sulfonated chitosan, exhibiting excellent mechanical properties and biocompatibility, rendering it a highly suitable platform for controlled and sustained therapeutic delivery. Specifically, the hydrogel is engineered to incorporate exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSC-Exo), which encapsulate hexaminolevulinate hydrochloride (HAL). HAL@Exo regulates cell communication, enhances cellular migration and proliferation, facilitates collagen matrix deposition and angiogenesis, and produces anti-inflammatory bioactive substances through biometabolic processes, thereby alleviating the extent of local inflammatory response. In a rat full-thickness skin wound model, the hydrogel demonstrated a pronounced therapeutic effect, significantly accelerating the wound healing process.

A 36-year-old male patient presented to our hospital complaining of epistaxis for 3 months and persistent headaches with facial numbness for 3 days. After a series of exams, he was diagnosed with nasopharyngeal carcinoma (T4N2M1, stage IVB, AJCC 8th), with a biopsy consistent with non-keratinizing squamous cell carcinoma, and received a combination therapy of gemcitabine, cisplatin, and tislelizumab. Following the first dose, headaches and facial numbness were relieved. On the third day, however, he developed recurrent fever, with a peak body temperature of 39.2 °C, and developed severe paroxysmal stabbing pain in the right frontal region suggestive of trigeminal neuralgia, along with numbness on the right face. We considered multiple possibilities and provided symptomatic treatments, but with poor efficacy. Subsequently, given the emergence of prominent neurological symptoms and fever, we proceeded with a lumbar puncture for cerebrospinal fluid (CSF) analysis. Metagenomic next-generation sequencing (mNGS) of CSF detected the presence of Epstein-Barr virus (EBV) and cytomegalovirus (CMV), and acute intracranial viral infections were considered. After treatment with ganciclovir, the patient’s body temperature returned to normal, and headaches and facial numbness were alleviated, and no pathogens were detected in a follow-up examination. We report a case of trigeminal neuralgia emerging post-chemoimmunotherapy, accompanied by CSF positivity for EBV and CMV, where antiviral intervention with ganciclovir resulted in significant symptom alleviation.

Background:Primary squamous cell carcinoma of the thyroid is a rare, highly lethal malignancy, comprising less than 1% of all thyroid cancers. It is associated with poor prognosis due to its rapid progression, resistance to conventional therapies, and frequent presentation at an advanced stage. The preferred treatment approach combines surgical resection with adjuvant radiotherapy or chemotherapy, yet outcomes remain unsatisfactory. Case Description:We report a case involving a 69-year-old female who presented with a progressively enlarging mass in the anterior neck. Computed tomography (CT) scans identified a right thyroid nodule measuring 4.0 cm × 4.7 cm × 5.3 cm. Subsequent fine needle aspiration biopsy confirmed thyroid squamous cell carcinoma, with molecular analysis revealing a positive BRAF (exon15:c.1801A>G:p.K601E) mutation. Given the substantial size of the neck mass and the unsuitability for surgical resection, neoadjuvant therapy was initiated. This included a combination of tislelizumab immunotherapy, chemotherapy, and anlotinib targeted therapy, which significantly reduced the size of tumor. The patient subsequently underwent a total thyroidectomy and remained disease-free for 2 years. Conclusions:The present case demonstrates the potential of a multimodal treatment regimen encompassing chemotherapy, immunotherapy and targeted therapy, followed by surgical excision, for primary thyroid squamous cell carcinoma. Further studies are needed to validate the efficacy and safety of this combined treatment modality in larger patient populations.

Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR. N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assays showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and that elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.Implications: This study offers more evidences for the involvement of METTL14-mediated N6-methyladenosine modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.

Background:Primary malignancies of the cervical lymph nodes with special pathological characteristics are relatively uncommon in clinical settings, and there have been few reports on these tumors. The precise basis for their pathogenesis is poorly understood, and their diagnosis can be challenging. In addition, no clinically validated treatments have been established to date for affected patients. Case Description:Here, we describe a case of a 65-year-old male patient who exhibited the enlargement of several lateral and supraclavicular lymph nodes on the right side of his neck that presented as a large mass associated with a high fever and benign leukocytosis. He did not exhibit any relevant prior history. Radiological assessment revealed that this lesion was the primary tumor and that it has since spread to the liver. Histological assessment was unable to definitively classify the pathological characteristics of this tumor. Without any relevant morphological findings, immunohistochemical outcomes were not sufficiently specific to clarify the origin of these cells. When distinguishing it from similar sarcomas of the lymphohematopoietic system, it was found to not be typical of a histiocytic or dendritic cell tumor. Treatment to this patient was performed following multidisciplinary consultation and consisted of one course of a cyclophosphamide plus doxorubicin, vincristine, and dexamethasone regimen and two courses of the cyclophosphamide plus pirarubicin, vincristine, and dexamethasone regimen. However, the tumor exhibited minimal response to such treatment. While radiotherapy was proposed, the patient lacked confidence in the approach and declined treatment. He eventually developed severe tumor-associated complications. In the discussion section of this report, we detail and analyze the pathogenesis, diagnosis, and referential treatments of this rare malignancy. Conclusions:This is the first report describing such a malignancy, and we hope that the publication of these findings can lead to the recognition of this tumor while supporting efforts to acquire greater experience in the diagnosis and treatment of affected patients.

Abstract We aimed to investigate the quality of life of nasopharyngeal carcinoma (NPC) patients during treatment and association with radiation-induced oral mucositis (ROM). A prospective study of 173 patients with nasopharyngeal carcinoma was initiated. Quality of life (QoL) was evaluated using the self-reported quality of life questionnaire for Head and Neck (QLQ-H&N 35) and ROM was evaluated before treatment and weekly with the Common Terminology Criteria for Adverse Events dictionary (CTCAE 4.0). Patients were divided into three groups (mild, moderate, severe groups) according to the duration of ≥ 3 grade ROM. The ANOVA analysis was performed to investigate the change in life quality and its association with ROM. During the treatment process, there was a significant decrease in patient QoL from T0 to T1-6. There were also significant differences (p < 0.05) observed in most scales at several time points (especially between T4 and T6), between the groups (mild vs. severe group). The QoL for NPC patients deteriorated during treatment and was associated with ROM. Patients with severe ROM were likely to develop the poorest QoL. More supportive intervention should be carried out early particularly for those with severe ROM.

Oxidative stress refers to the process of reactive oxide species (ROS) increase in human body due to various factors, which leads to oxidative damage in human tissues. Current studies have confirmed that sustained oxidative stress is one of the distinctive features throughout the development of tumors. Numerous reports have shown that lncRNAs can regulate the process of oxidative stress through multiple pathways. However, the relationship between glioma-associated oxidative stress and lncRNAs is not clearly investigated. RNA sequencing data of GBM (glioblastoma) and LGG (low grade glioma) and corresponding clinical data were retrieved from the TCGA database. Oxidative stress related lncRNAs (ORLs) were identified by Pearson correlation analysis. Prognostic models for 6-ORLs were structured in the training cohort by univariate Cox regression analysis, multivariate Cox regression analysis and LASSO regression analysis. We constructed the nomogram and verified its predictive efficacy by Calibration curves and DCA decision curves. The biological functions and pathways of 6-ORLs-related mRNAs were inferred by Gene Set Enrichment Analysis. Immune cell abundance and immune function associated with risk score (RS) were estimated by ssGSEA, CIBERSORT and MCPcounter synthetically. External validation of the signature was completed using the CGGA-325 and CGGA-693 datasets. 6-ORLs signature—AC083864.2, AC107294.1, AL035446.1, CRNDE, LINC02600, and SNAI3-AS1—were identified through our analysis as being predictive of glioma prognosis. Kaplan–Meier and ROC curves indicated that the signature has a dependable predictive efficacy in the TCGA training cohort, validation cohort and CGGA-325/CGGA-693 test cohort. The 6-ORLs signature were verified to be independent prognostic predictors by multivariate cox regression and stratified survival analysis. Nomogram built with risk scores had strong predictive efficacy for patients' overall survival (OS). The outcomes of the functional enrichment analysis revealing potential molecular regulatory mechanisms for the 6-ORLs. Patients in the high-risk subgroup presented a significant immune microenvironment of macrophage M0 and cancer-associated fibroblast infiltration which was associated with a poorer prognosis. Finally, the expression levels of 6-ORLs in U87/U251/T98/U138 and HA1800 cell lines were verified by RT-qPCR. The nomogram in this study has been made available as a web version for clinicians. This 6-ORLs risk signature has the capabilities to predict the prognosis of glioma patients, assist in evaluating immune infiltration, and assess the efficacy of various anti-tumor systemic therapy regimens.

目的:比较3个非共面全弧容积旋转调强放射治疗(VMAT)与9野共面调强放射治疗(IMRT)在脑转移患者全脑照射保护海马和下丘脑-垂体轴计划中的剂量分布.方法:选取在医院进行放射治疗的12例肺癌脑转移患者图像资料.其中8例患者预防性颅脑照射(PCI)为36 Gy/18次,脑转移病灶推量(SIB)照射总剂量为54 Gy/18次;另4例患者只做了总剂量为36 Gy/18次的PCI治疗.每例患者分别设计3个非共面全弧VMAT(3A-VMAT)及9共面野IMRT(9F-IMRT)两种治疗计划,模拟设计海马和下丘脑-垂体(HT-P)轴区域的保留方法.放射治疗计划未实施到患者体内.评价两种计划适形性指数(CI)、均匀性指数(HI)、靶区覆盖(TC)、γ通过率、海马、下丘脑及垂体剂量.结果:①VMAT计划剂量SIB照射的CI、HI和TC分别为0.972、0.059和97.19％;IMRT计划剂量分别为0.955、0.083和95.45％,两种计划的HI比较差异有统计学意义(Z=3.524,P<0.05);②VMAT计划剂量全脑放射治疗(WBRT)的CI、HI和TC与IMRT计划比较,差异均有统计学意义(t=-5.007,t=-4.056,t=10.025;P<0.05);③VMAT计划左侧海马和右侧海马剂量最大辐射剂量(Dmax)、平均辐射剂量(Dmean)和等效2 Gy剂量(EQD2)与IMRT计划比较,差异均有统计学意义(Z左侧海马=-2.432,Z=-3.059,Z=2.432;Z右侧海马=-3.059,Z=2.353,Z=-2.589;P<0.05);④VMAT计划HT-P Dmax、HT-P Dmean和机器跳数(MU)值与IMRT计划比较,差异有统计学意义(Z=-3.059,Z=2.904,Z=-3.059;P<0.05).VMAT计划与IMRT计划的γ通过率比较差异无统计学意义.结论:3个非共面全弧VMAT计划靶区剂量分布明显优于9野共面IMRT,对海马和下丘脑-垂体轴的保护VMAT也有较大优势.两种IMRT技术在全脑放射治疗同时保护海马和下丘脑-垂体轴均具有可行性,但需要进行前瞻性的神经系统、内分泌结果和安全性分析.

肝癌是我国发病率和死亡率最高的癌种之一,大多数患者在确诊时已处于中晚期.中晚期肝癌异质性大且治疗选择众多,建立多学科协助诊治模式,选择针对病情的个体化治疗能为患者带来最大的获益.近年来的研究发现,放疗在肝癌中具有较高的安全性以及可观的治疗效果.然而,单独接受放疗的肝癌患者,其生存期主要受限于放疗野外的肿瘤复发,而将放疗与全身治疗策略相结合可能会产生更好的效果.本文将综述外照射放疗(EBRT)联合系统治疗在中晚期肝癌中的研究进展.

Background: Lung cancer is a leading cause of cancer death globally. Platinum-based chemotherapeutic medications are essential for treating advanced NSCLC, despite that drug resistance severely limits its effectiveness. Objective: In this study, we investigated the cytotoxic effect of metformin on cisplatin-resistant NSCLC cells (A549/DDP) and its potential mechanisms. Methods: Anti-lung cancer efficacy of metformin, cisplatin, and metformin combined with cisplatin was examined in A549 and A549/DDP cells. The cell counting kit-8 (CCK-8) assay was applied for measuring cell proliferation. CalcuSyn software was used to calculate the combination index and estimate the synergistic effect of metformin and cisplatin on cell proliferation. The cell apoptosis was analyzed by flow cytometry and the expression of apoptosis-related proteins, Bcl-2, Bax and caspase-3 were analyzed using Western blot. Futhermore, the expression of key nucleotide excision repair (NER) proteins, ERCC1, XPF, and XPA, was also analyzed using Western blot. Results: We found that metformin had dose-dependent antiproliferative effects on A549/DDP and A549 cells. The combination of metformin and cisplatin had higher effectiveness in inhibiting A549/DDP and A549 cell growth than either of the two drugs alone. Flow cytometry analysis indicated that the combined treatment could cause more cell apoptosis than the single-drug treatment. Consistently, the combined treatment decreased the expression of Bcl-2 protein and elevated the expression of Bax, and cleaved caspase-3 proteins. The expression level of ERCC1, XPF, and XPA proteins were lower in the combined treatment than in either of metformin and cisplatin treatment alone. Conclusions: Our study suggested that metformin and cisplatin had synergistic antitumorigenic effects in A549/DDP cells. The combination of cisplatin and metformin could be promising drug candidates to sensitize cisplatin-induced apoptosis through regulating nucleotide excision repair pathways in lung cancer.

Background: Autophagy plays an important role in the development of cancer. However, the prognostic value of autophagy-related genes (ARGs) in cervical cancer (CC) is unclear. The purpose of this study is to construct a survival model for predicting the prognosis of CC patients based on ARG signature. Methods: ARGs were obtained from the Human Autophagy Database and Molecular Signatures Database. The expression profiles of ARGs and clinical data were downloaded from the TCGA database. Differential expression analysis of CC tissues and normal tissues was performed using R software to screen out ARGs with an aberrant expression. Univariate Cox, Lasso, and multivariate Cox regression analyses were used to construct a prognostic model which was validated by using the test set and the entire set. We also performed an independent prognostic analysis of risk score and some clinicopathological factors of CC. Finally, a clinical practical nomogram was established to predict individual survival probability. Results: Compared with normal tissues, there were 63 ARGs with an aberrant expression in CC tissues. A risk model based on 3 ARGs was finally obtained by Lasso and Cox regression analysis. Patients with high risk had significantly shorter overall survival (OS) than low-risk patients in both train set and validation set. The ROC curve validated its good performance in survival prediction, suggesting that this model has a certain extent sensitivity and specificity. Multivariate Cox analysis showed that the risk score was an independent prognostic factor. Finally, we mapped a nomogram to predict 1-, 3-, and 5-year survival for CC patients. The calibration curves indicated that the model was reliable. Conclusion: A risk prediction model based on CHMP4C, FOXO1, and RRAGB was successfully constructed, which could effectively predict the prognosis of CC patients. This model can provide a reference for CC patients to make precise treatment strategy.

Objective: The aim of the present study was to construct a prognostic model based on the peptidyl prolyl cis – trans isomerase gene signature and explore the prognostic value of this model in patients with hepatocellular carcinoma. Methods: The transcriptome and clinical data of hepatocellular carcinoma patients were downloaded from The Cancer Genome Atlas and the International Cancer Genome Consortium database as the training set and validation set, respectively. Peptidyl prolyl cis – trans isomerase gene sets were obtained from the Molecular Signatures Database. The differential expression of peptidyl prolyl cis – trans isomerase genes was analyzed by R software. A prognostic model based on the peptidyl prolyl cis – trans isomerase signature was established by Cox, Lasso, and stepwise regression methods. Kaplan–Meier survival analysis was used to evaluate the prognostic value of the model and validate it with an independent external data. Finally, nomogram and calibration curves were developed in combination with clinical staging and risk score. Results: Differential gene expression analysis of hepatocellular carcinoma and adjacent tissues showed that there were 16 upregulated genes. A prognostic model of hepatocellular carcinoma was constructed based on three gene signatures by Cox, Lasso, and stepwise regression analysis. The Kaplan–Meier curve showed that hepatocellular carcinoma patients in high-risk score group had a worse prognosis ( p < 0.05). The receiver operating characteristic curve revealed that the area under curve values of predicting the survival rate at 1, 2, 3, 4, and 5 years were 0.725, 0.680, 0.644, 0.630, and 0.639, respectively. In addition, the evaluation results of the model by the validation set were basically consistent with those of the training set. A nomogram incorporating clinical stage and risk score was established, and the calibration curve matched well with the diagonal. Conclusion: A prognostic model based on 3 peptidyl prolyl cis – trans isomerase gene signatures is expected to provide reference for prognostic risk stratification in patients with hepatocellular carcinoma.