N1-methyladenosine(m1A)RNA methylation is critical for regulating mRNA translation;however,its role in the development,progression,and immunotherapy response of head and neck squamous cell carcinoma(HNSCC)remains largely unknown.Using Tgfbr1 and Pten conditional knockout(2cKO)mice,we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels.Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis.Mechanistically,TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis,upregulating programmed death-ligand 1(PD-L1)expression.Moreover,m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus(oHSV),contributing to reactive PD-L1 upregulation.Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth,representing a promising strategy to alleviate resistance.These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression,providing a mutually reinforcing combination immunotherapy approach.

Objective:To investigate the relationship between cerebrovascular variation and the occurrence and recurrence of cerebral infarction, and provide a theoretical basis for the precise prevention and treatment of cerebral infarction.Methods:Totally 13 939 patients who underwent magnetic resonance imaging(MRI) and magnetic resonance angiography(MRA) examination at the Second Affiliated Hospital of Shandong First Medical University from January 2020 to December 2021 were grouped according to clinical symptoms combined with the imaging report, including 4 412 cases in the cerebral infarction group and 9 527 cases in the control group.2 048 patients in the cerebral infarction group were eventually enrolled in the study according to the inclusion and exclusion criteria, including 1 479 cases of initial cerebral infarction and 569 cases of recurrent cerebral infarction.SPSS 25.0 statistical software was used for data analysis.The χ2 test was used to compare the incidence of cerebral infarction with different cerebrovascular variations.Univariate analysis of suspected risk factors for recurrent cerebral infarction was performed with χ2 test, nonparametric test and t test.The binary logistic regression was used to analyze independent risk factors of recurrent cerebral infarction. Results:The incidence of cerebral infarction in the dual-system cerebrovascular variant patients, the single-system cerebrovascular variant patients, and the non-cerebrovascular variant patients were 40.9%, 30.7% and 31.8% respectively.The incidence of cerebral infarction in the dual-system cerebrovascular variant patients was the highest compared with those in the single-system cerebrovascular variant patients and the non-cerebrovascular variant patients (both P<0.05). The incidence rates of embryonic posterior cerebral artery, vertebral artery dominance, and bilateral common origin anterior cerebral arteries were 14.09%, 10.76% and 5.32%, respectively.The incidence of bilateral common origin anterior cerebral arteries in the cerebral infarction group was significantly higher than that in the control group and the difference was statistically significant.Patients with cerebral infarction who were familial aggregation ( OR=2.207, 95% CI=1.591-3.062), hyperhomocysteinemia ( OR=1.262, 95% CI=1.014-1.570), hypertension ( OR=1.461, 95% CI=1.114-1.918), diabetes mellitus ( OR=1.348, 95% CI=1.072-1.694), coronary heart disease ( OR=1.491, 95% CI=1.196-1.858) were more likely to recurrent cerebral infarction ( P<0.05), and patients with cerebral infarction had a significantly increased risk of recurrent cerebral infarction with age ( OR=1.031, 95% CI=1.020-1.042, P<0.05). Conclusion:Dual-system cerebrovascular variation and bilateral common origin anterior cerebral arteries are risk factors for cerebral infarction.

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.
Humans ; Autophagy ; Carcinoma, Squamous Cell/pathology* ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 beta/metabolism* ; Head and Neck Neoplasms/pathology* ; Neoplastic Stem Cells/pathology* ; Squamous Cell Carcinoma of Head and Neck/pathology* ; Lysosome-Associated Membrane Glycoproteins

Objective:To analyze the clinical features and genetic background of adrenoleukodystrophy(ALD).Methods:In this study, we reported a rare case of ALD who initially presented with progressive bilateral lower limb weakness. The clinical data of the patient and his family members were collected and the ABCD1 gene was sequenced for the patient and his three daughters by a high-throughput sequencing method.Results:The proband had a later onset of symptoms, a prolonged course of the disease, and initially exhibited bilateral lower limb weakness and nocturnal muscle spasms. The disease progressed to spastic quadriplegia, aphasia, dementia, swallowing difficulties, and urinary and fecal incontinence. Serum very-long-chain fatty acid concentrations were elevated. Subclinical cortisol secretion abnormalities were observed. Cranial imaging indicated symmetrical reduction in density around the lateral ventricles and white matter degeneration. The proband′s ABCD1 gene analysis revealed a novel heterozygous mutation c. 1367G>A, p. R456H. His three daughters carried the same nucleotide heterozygous mutation.Conclusion:This study investigates the clinical characteristics of ALD, providing additional clinical evidence for the diagnosis and treatment of this condition. Additionally, a novel mutation in the ABCD1 gene was identified, contributing to the genetic variation database.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Objective:To construct a scientific and complete competency evaluation index system for postgraduate tutors of clinical medicine.Methods:Based on literature research, group discussion and expert interviews, the research used the competency model theory, and conducted twice expert consultation by Delphi method, then the index weight was determined by mathematical analysis method and precedence diagram method. SPSS 22.0 was used for data statistical analysis.Results:According to the characteristics of the competency model and expert opinions, 4 first-level indicators, 12 second-level indicators, and 40 third-level indicators were finally determined, and the tutor evaluation index system was constructed.Conclusion:The system is highly scientific and reliable, which will provide a reference for the comprehensive evaluation of postgraduate tutors at medical colleges and will be of great significance for strengthening the construction of tutors and ensuring the cultivation quality of postgraduate.

Medical humanistic literacy education is important in modern medical education. In the United States, Britain, Japan and other countries, many medical schools have incorporated medical humanistic literacy education into compulsory courses and attached great importance to its value. However, the humanistic literacy education in domestic colleges has not yet formed a systematic development. This article analyzes the current status and deficiencies of domestic medical humanistic literacy education by comparing the development stages and characteristics of foreign medical humanistic literacy education. This paper puts forward reasonable suggestions on the integration of medical humanistic literacy curriculum from three aspects: medical education structure and modes, teaching methods and the importance attached to medical literacy education, aiming to provide a reference for our country's reform of medical education.

With the increasing incidence of breast cancer, the relationship between tumor and immune function has attracted more and more attention. This article reviews the relationship between breast cancer and T lymphocyte subsets, in order to explore the changes of immune function before and after operation in breast cancer patients, so as to select appropriate surgical methods, radiotherapy, chemotherapy and immunotherapy for the patients.

Objective There are few researches for the serum betatrophin level and diabetic nephropathy (DN) recently.The aim of this study was to investigate the change of serum betatrophin level and the correlation of serum betatrophin and urinary albumin-to-creatintine ratio (UACR) in patients with type 2 diabetes mellitus (T2DM).Methods A total of 150 Chinese subjects from Mar 2013 to Jul 2016 were enrolled in the study, including 90 patients with type 2 diabetes and 60 healthy controls.According to the level of UACR, the diabetic patients were divided into two groups:normal UACR group (UACR<30 mg/g, n=60) and abnormal UACR group(UACR>30 mg/g, n=30).Serum betatrophin was measured by enzyme linked immunosorbent assay (ELISA).UACR was measured by turbidimetric inhibition immune assay.Blood glucose blood lipid were measured simultaneously.Results The serum betatrophin level was significantly higher in abnormal UACR group than that in normal UACR group[677.37±59.02 vs 486.13±41.22 pg/mL, P<0.05];Serum betatrophin level in T2DM patients was positively correlated with age (r=0.246), waist hip ratio (WHR) (r=0.240), fasting blood glucose (FPG) (r=0.234), 2 hour plasma glucose (2hPG) (r=0.363), glycosylated hemoglobin (HbA1c) (r=0.346), fasting insulin (FINS) (r=0.249), insulin resistance index (HOMA-IR) (r=0.309), blood urea nitrogen (BUN) (r=0.223), creatinine (CREA) (r=0.277) and UACR (r=0.244) (P<0.05),and negatively correlated with glomerular filtration rate (GFR) (r=0.308) (P<0.01).Serum betatrophin level in normal UACR group was positively correlated with age, HbA1c and UACR (P<0.05);Serum betatrophin level in abnormal UACR group was positively correlated with WHR (r=0.504), 2hPG (r=0.600), HbA1c (r=0.449), HOMA-IR (r=0.395) (P<0.05).The WHR, HbA1c, HOMA-IR and GFR were the influential factors of the serum betatrophin level.Conclusion The level of serum betatrophin was significantly increased in T2DM patients with albuminuria, which suggests that the betatrophin might play an important role in the pathogenesis of DN.