Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Oral cancer is one of the most common malignancies in the head and neck regions. few patients benefit from current clinical therapy. Zinc finger proteins (ZNFs) are one of the largest transcription factor family proteins in the human genome. ZNFs bind to DNA, RNA, and proteins through their unique three-dimensional structure created by zinc ions to regulate gene transcription, RNA packaging, and protein folding. In recent years, the number of studies focused on the functional mechanism of ZNFs in regulating the progression of oral cancer has been increasing, with focuses on: ① ZNF677, ZNF460, ZNF154, ZNF132, ZNF281, Kaiso, and ZNF582, which regulate the invasion and metastasis of tumor cells; ② ZNF750 and PEST-containing nuclear protein (PCNP), which regulate the cell cycle; ③ ZNFs, which are involved in forming the tumor immune microenvironment, such as ZNF71 and myeloid zinc finger 1 (MZF1). For example, methylation modification modulates the reduction of ZNF677 in oral cancer and reduces the proliferation, migration, and invasion of oral cancer cells by inhibiting the protein kinase B/forkhead box O3a (AKT/FOXO3a) pathway; and ZNF460 promotes the proliferation, migration, and invasion of oral cancer cells by regulating microRNA-320a/alpha thalassemia/mental retardation, X-linked (ATRX) axis. In addition, ZNF750 inhibits the growth and metastasis of oral cancer by suppressing cell cycle transcription factor activity. Further, ZNF71 promotes the progression of oral cancer by reducing the infiltration of tumor immune cells. In this review, we will summarize the molecular mechanism, regulatory meshwork, and pro-tumor and anti-tumor roles of ZNFs in the pathogenesis of oral cancer. Our study may provide a new strategy for the diagnosis and treatment of oral cancer.

Electromagnetic fields can regulate the fundamental biological processes involved in bone remodeling. As a non-invasive physical therapy, electromagnetic fields with specific parameters have demonstrated therapeutic effects on bone remodeling diseases, such as fractures and osteoporosis. Electromagnetic fields can be generated by the movement of charged particles or induced by varying currents. Based on whether the strength and direction of the electric field change over time, electromagnetic fields can be classified into static and time-varying fields. The treatment of bone remodeling diseases with static magnetic fields primarily focuses on fractures, often using magnetic splints to immobilize the fracture site while studying the effects of static magnetic fields on bone healing. However, there has been relatively little research on the prevention and treatment of osteoporosis using static magnetic fields. Pulsed electromagnetic fields, a type of time-varying field, have been widely used in clinical studies for treating fractures, osteoporosis, and non-union. However, current clinical applications are limited to low-frequency, and research on the relationship between frequency and biological effects remains insufficient. We believe that different types of electromagnetic fields acting on bone can induce various “secondary physical quantities”, such as magnetism, force, electricity, acoustics, and thermal energy, which can stimulate bone cells either individually or simultaneously. Bone cells possess specific electromagnetic properties, and in a static magnetic field, the presence of a magnetic field gradient can exert a certain magnetism on the bone tissue, leading to observable effects. In a time-varying magnetic field, the charged particles within the bone experience varying Lorentz forces, causing vibrations and generating acoustic effects. Additionally, as the frequency of the time-varying field increases, induced currents or potentials can be generated within the bone, leading to electrical effects. When the frequency and power exceed a certain threshold, electromagnetic energy can be converted into thermal energy, producing thermal effects. In summary, external electromagnetic fields with different characteristics can generate multiple physical quantities within biological tissues, such as magnetic, electric, mechanical, acoustic, and thermal effects. These physical quantities may also interact and couple with each other, stimulating the biological tissues in a combined or composite manner, thereby producing biological effects. This understanding is key to elucidating the electromagnetic mechanisms of how electromagnetic fields influence biological tissues. In the study of electromagnetic fields for bone remodeling diseases, attention should be paid to the biological effects of bone remodeling under different electromagnetic wave characteristics. This includes exploring innovative electromagnetic source technologies applicable to bone remodeling, identifying safe and effective electromagnetic field parameters, and combining basic research with technological invention to develop scientifically grounded, advanced key technologies for innovative electromagnetic treatment devices targeting bone remodeling diseases. In conclusion, electromagnetic fields and multiple physical factors have the potential to prevent and treat bone remodeling diseases, and have significant application prospects.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Objective To investigate the mechanism behind the protective effects of gastrodin against microglia-mediated inflammatory responses following hypoxic-ischemic brain damage(HIBD)in neonatal mice.Methods Thirty-six 10-day-old C57BL/6J mice were randomized into sham-operated group,HIBD(induced by ligation of the left common carotid artery followed by hypoxia for 40 min)group,and HIBD with gastrodin treatment groups(n=12).In gastrodin treatment group,100 mg/kg gastrodin was injected intraperitoneally 1 h before and at 2 and 12 h after hypoxia.After the treatments,the expressions of CCR5,AKT,p-AKT,and TNF-α and the co-expression of IBA1 and CCR5 in the corpus callosum of the mice were detected with Western blotting and immunofluorescence double staining.In a BV2 microglial cell model of oxygen-glucose deprivation(OGD),the effects of pretreatment with gastrodin and Maraviroc(an CCR5 antagonist)on protein expressions of CCR5,AKT,p-AKT,TNF-α and IL-1β were evaluated using Western blotting and immunofluorescence double staining.Results The neonatal mice with HIBD showed significantly increased expressions of CCR5 and TNF-α with lowered p-AKT expression in the brain tissues,and GAS treatment obviously reversed these changes.HIBD also significantly increased the co-expression of IBA1 and CCR5 in the corpus callosum of the mice,which was obviously lowered by gastrodin treatment.In BV2 cells,OGD significantly increased the expressions of CCR5,TNF-α,and IL-1β and decreased the expression of p-AKT,and these changes were inhibited by treatment with gastrodin,Maraviroc or their combination;the inhibitory effect of the combined treatment did not differ significantly from that of gastrodin or Maraviroc alone.Conclusion Gastrodin can produce neuroprotective effects in neonatal mice with HIBD by inhibiting inflammatory cytokine production and activate AKT phosphorylation via inhibiting CCR5.

Objective:To explore the characteristics and changes of cardiac injury with age in Duchenne muscular dystrophy (DMD) and its clinical significance.Methods:A prospective cohort study was conducted. The 215 patients diagnosed with DMD in West China Second Hospital from January 2019 to November 2022 and aged from 6 to 18 years were enrolled. Their clinical data, myocardial injury markers, routine electrocardiogram, cardiac magnetic resonance (CMR) and echocardiography were collected. The patients were divided into five age groups: 6-<8, 8-<10, 10-<12, 12-<14 and 14-18 years of age, and matched with healthy boys respectively. Independent sample t test or Mann-Whitney U test was used to compare the clinical data and CMR indexes between DMD patients and controls in all age subgroups, and to compare the value of left ventricular ejection fraction (LVEF) measured by echocardiography and CMR in each subgroup of DMD patitents. Pearson correlation analysis or Spearman correlation analysis was used to explore the relation between the CMR indexes and age in DMD patients. Results:A total of 215 patients with DMD (all male) and 122 healthy boys were included in the study. There were 75 DMD patients and 23 controls in 6-<8 years of age group, 77 DMD and 28 controls in 8-<10 years of age group, 39 DMD and 23 controls in 10-<12 years of age group, 10 DMD and 31 controls in the 12-<14 years of age group, and 14 DMD and 17 controls in 14-18 years of age group. In the DMD patients, the older the age, the lower the levels of creatine kinase (CK) and creatine kinase isoenzyme (CK-MB). In the 6-<8 years of age group, the CK level was 10 760 (7 800, 15 757) U/L, while in the group of 14-18 years of age, it was 2 369 (1 480, 6 944) U/L. As for CK-MB, it was (189±17) μg/L in the 6-<8 years of age group and (62±16) μg/L in the 14-18 years of age group. Cardiac troponin I remained unchanged in <12 years of age groups, but significantly increased in 12-<14 years of age group, reaching the highest value of 0.112 (0.006, 0.085) μg/L. In the DMD patients, the older the age, the higher the proportion of abnormal electrocardiogram (ECG). In the 6-<8 years of age group, the proportion is 29.3% (22/75), while in the 14-18 years of age group, it was 10/14. Correlation analysis showed that the left ventricular end-diastolic volume index was positively related with age ( r=0.18, P=0.015), and the left ventricular stroke volume index and cardiac output index were negatively related with age ( r=-0.34 and -0.31, respectively, both P<0.001). In the DMD patients, the older the age, the lower LVEF, with the LVEF decreasing to (49.3±3.1)% in the 14-18 years of age group. The LVEF of DMD cases was significantly lower than that of controls in the age subgroups of 8-<10, 10-<12, 12-<14 and 14-18 years of age groups ((57.9±5.2) % vs. (63.6±0.8)%, 60.7% (55.9%, 61.9%) vs. 63.7% (60.2%, 66.0%), 57.1% (51.8%, 63.4%) vs. 62.1 % (59.5%, 64.5)%, (49.3±3.1) % vs. (61.6±1.3)%, respectively; all P<0.01). In the DMD patients, the older the age, the higher the proportion of positive late gadolinium enhancement (LGE). In the 6-<8 years of age group, it was 22% (11/51), in the 12-<14 years of age group, it was 13/14, and in the 14-18 years of age group, all DMD showed positive LGE. The value of LVEF of DMD cases measured by echocardiography was significantly higher than that measured by CMR in 6-<8 years of age group and 8-<10 years of age group (63.2% (60.1%, 66.4%) vs. 59.1 % (55.4%, 62.9%), and (62.8±5.2) % vs. (57.9±5.2)%, all P<0.001). Conclusion:DMD patients develop cardiac injury in the early stage of the disease, and the incidence of cardiac damage gradually increases with both age and the progression of disease.

Electrochemiluminescence(ECL)refers to the process of luminescence triggered by high-energy electron transfer between intermediate products during the oxidation-reduction reaction on the electrode surface.In the co-reactants involved ECL process,the presence of co-reaction accelerators can effectively catalyze the decomposition of co-reactants,leading to the generation of abundant free radical intermediates,thereby significantly enhancing the ECL signals.This plays a critical role in constructing simple,sensitive,and efficient ECL sensing platforms.This review focused on the novel co-reaction accelerators developed in recent years.Based on different types of co-reaction accelerator materials,including single atom catalysts,metal-based nanomaterials,polymers and other materials,the ECL reaction process and signal enhancement mechanisms,as well as their relevant applications in constructing ECL sensing platforms,were elucidated.Furthermore,the current research challenges and development prospect of co-reaction accelerators were also discussed.

The assessment of adverse drug events is an important basis for clinical safety evaluation and post-marketing risk control of drugs,and its causality assessment is gaining increasing attention.The existing methods for assessing the causal relationship between drugs and the occurrence of adverse reactions can be broadly classified into three categories:global introspective methods,standardized methods,and probabilistic methods.At present,there is no systematic introduction of the operational details of the various methods in the domestic literature.This paper compares representative causality assessment methods in terms of definition and concept,methodological steps,industry evaluation and advantages and disadvantages,clarifies the basic process of determining the causality of adverse drug reactions,and discusses how to further improve the adverse drug reaction monitoring and evaluation system,with a view to providing a reference for drug development and pharmacovigilance work in China.

Objective:To investigate the associations of onset age, diabetes duration, and glycated hemoglobin (HbA1c) levels with ischemic stroke risk in type 2 diabetes patients.Methods:The participants were from Comprehensive Research on the Prevention and Control of the Diabetes in Jiangsu Province. The study used data from baseline survey from December 2013 to January 2014 and follow-up until December 31, 2021. After excluding the participants who had been diagnosed with stroke at baseline survey and those with incomplete information on onset age, diabetes duration, and HbA1c level, a total of 17 576 type 2 diabetes patients were included. Cox proportional hazard model was used to calculate the hazard ratio ( HR) and 95% CI of onset age, diabetes duration, and HbA1c level for ischemic stroke. Results:During the median follow-up time of 8.02 years, 2 622 ischemic stroke cases were registered. Multivariate Cox proportional risk regression model showed that a 5-year increase in type 2 diabetes onset age was significantly associated with a 5% decreased risk for ischemic stroke ( HR=0.95, 95% CI: 0.92-0.99). A 5-year increase in diabetes duration was associated with a 5% increased risk for ischemic stroke ( HR=1.05, 95% CI: 1.02-1.10). Higher HbA1c (per 1 standard deviation increase: HR=1.17, 95% CI: 1.13-1.21) was associated with an increased risk for ischemic stroke. Conclusion:The earlier onset age of diabetes, longer diabetes duration, and high levels of HbA1c are associated with an increased risk for ischemic stroke in type 2 diabetes patients.