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.

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 The benchmark dose (BMD) method calculates the dose associated with a specific change in response based on a specific dose-response relationship. Compared with the traditional no observed adverse effect level (NOAEL) method, the BMD method has many advantages, and the 95% lower confidence limit of benchmark dose lower limit (BMDL) is recommended to replace NOAEL in deriving biological exposure limits. No authority has yet published any health-based guideline for rare earth elements. Objective To evaluate genotoxicity threshold induced by acute exposure to neodymium nitrate in mice using BMD modeling through micronucleus test and comet assay. Methods SPF grade mice (n=90) were randomly divided into nine groups, including seven neodymium nitrate exposure groups, one control group (distilled water), and one positive control group (200 mg·kg⁻¹ ethyl methanesulfonate), 10 mice in each group, half male and half female. The seven dose groups were fed by gavage with different concentrations of neodymium nitrate solution (male: 14, 27, 39, 55, 77, 109, and 219 mg·kg⁻¹; female: 24, 49, 69, 97, 138, 195, and 389 mg·kg⁻¹) twice at an interval of 21 h. Three hours after the last exposure, the animals were neutralized by cervical dislocation. The bone marrow of mice femur was taken to calculate the micronucleus rate of bone marrow cells, and the liver and stomach were taken for comet test. Results The best fitting models for the increase of polychromatophil micronucleus rate in bone marrow of female and male mice induced by neodymium nitrate were the exponential 4 model and the hill model, respectively. The BMD and the BMDL of female mice were calculated to be 31.37 mg·kg⁻¹ and 21.90 mg·kg⁻¹, and those of male mice were calculated to be 58.62 mg·kg⁻¹ and 54.31 mg·kg⁻¹, respectively. The best fitting models for DNA damage induced by neodymium nitrate in female and male mouse hepatocytes were the exponential 5 model and the exponential 4 model, respectively, and the calculated BMD and BMDL were 27.15 mg·kg⁻¹ and 11.99 mg·kg⁻¹ for female mice, and 16.28 mg·kg⁻¹ and 10.47 mg·kg⁻¹ for male mice, respectively. The hill model was the best fitting model for DNA damage of gastric adenocytes in both female and male mice, and the calculated BMD and BMDL were 36.73 mg·kg⁻¹ and 19.92 mg·kg⁻¹ for female mice, and 24.74 mg·kg⁻¹ and 14.08 mg·kg⁻¹ for male mice, respectively. Conclusion Taken the micronucleus rate of bone marrow cells, DNA damage of liver cells and gastric gland cells as the end points of genotoxicity, the BMDL of neodymium nitrate is 10.47 mg·kg⁻¹, which can be used as the threshold of genotoxic effects induced by acute exposure to neodymium nitrate in mice.

Purpose::To identify the potential target genes of blast lung injury (BLI) for the diagnosis and treatment.Methods::This is an experimental study. The BLI models in rats and goats were established by conducting a fuel-air explosive power test in an unobstructed environment, which was subsequently validated through hematoxylin-eosin staining. Transcriptome sequencing was performed on lung tissues from both goats and rats. Differentially expressed genes were identified using the criteria of q ≤ 0.05 and |log 2 fold change| ≥ 1. Following that, enrichment analyses were conducted for gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathways. The potential target genes were further confirmed through quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay. Results::Observations through microscopy unveiled the presence of reddish edema fluid, erythrocytes, and instances of focal or patchy bleeding within the alveolar cavity. Transcriptome sequencing analysis identified a total of 83 differentially expressed genes in both rats and goats. Notably, 49 genes exhibited a consistent expression pattern, with 38 genes displaying up-regulation and 11 genes demonstrating down-regulation. Enrichment analysis highlighted the potential involvement of the interleukin-17 signaling pathway and vascular smooth muscle contraction pathway in the underlying mechanism of BLI. Furthermore, the experimental findings in both goats and rats demonstrated a strong association between BLI and several key genes, including anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4, which exhibited up-regulation.Conclusions::Anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4 hold potential as target genes for the prognosis, diagnosis, and treatment of BLI.

Objective To investigate the therapeutic effect of transcutaneous auricular vagus nerve stimulation(taVNS)on overweight/obesity patients,and to explore its central mechanism.Methods Twenty-six overweight/obesity patients were randomly divided into two groups,12 cases in the taVNS test group(shortened as the taVNS group)and 14 cases in the lifestyle intervention control group(shortened as the control group).The patients in the control group were treated with online lifestyle intervention of calorie-restricted diet(CRD),and the patients in the taVNS group were treated with taVNS on the basis of the intervention for the control group.The taVNS was performed on unilateral acupoints of spleen and endocrine,twice(in the morning and at evening)per day,for five days a week.The treatment for the two groups covered four weeks.The obesity indicators such as body weight,body mass index(BMI)and waist circumference of the patients in the two groups were observed before and after treatment.Moreover,the resting-state cerebral functional magnetic resonance imaging(fMRI)data of the patients were collected after treatment,and then the regulatory effect of taVNS on the regional homogeneity(ReHo)of local cerebral area of the patients was observed.Results(1)During the trial,one case in each group dropped off,and a total of 24 patients(including 13 cases in the control group and 11 cases in the taVNS group)were finally included in the statistical analysis of the observation indicators.(2)After treatment,the body weight,BMI and waist circumference of patients in the taVNS group were decreased compared with those before treatment(P＜0.05),while the obesity indicators in the control group only showed a downward trend compared with those before treatment,the differences being not statistically significant(P＞0.05).The improvement of the obesity indicators of body weight,BMI,and waist circumference in the taVNS group was significantly superior to that in the control group,and there were statistically significant differences in the post-treatment indicators and in the pre-and post-treatment difference values of the indicators between the two groups(P＜0.05 or P＜0.01).(3)After treatment,the taVNS group had greater ReHo values in the left prefrontal lobe and medial frontal gyrus than the control group,and the control group had greater ReHo value in the right parietal lobe than the taVNS group,which indicated that compared with the control group,the ReHo of the left prefrontal lobe and medial frontal gyrus in the taVNS group was increased and the ReHo of the right parietal lobe was decreased(Pvoxel＜0.001,Pcluster＜0.05,corrected by FWE level).Conclusion As a non-invasive treatment method,taVNS exerts certain efficacy for the treatment of overweight/obesity patients.The central response mechanism for treatment of obesity is probably related with the modulation of taVNS on the functional areas of left prefrontal lobe,medial frontal gyrus,and right parietal lobe of the patients.

Objective To investigate the mechanism of nootkatone(NKT)in mitigating depression-like behavior caused by blast traumatic brain injury(TBI).Methods The rat bTBI depression-like model was established by simulating the shock wave parameters of blast overpressure(BOP of 60 kPa,90 kPa,and 120 kPa)with a biological shock wave tube.After 14 days of exposure,we evaluated the depression-like behavior of rats using the tail suspension test and forced swimming test.We identified that the BOP(120 kPa)condition caused the most noticeable depressive behavior and used this condition for subsequent experiments.Thirty male SD rats were randomly divided into sham operation group,bTBI group(BOP of 120 kPa),and bTBI+NKT group[at 1 d after exposure to BOP of 120 kPa,giving NKT 10 mg/(kg·d)orally for 14 days],10 in each group.After 14 days of exposure,the depression-like behavior of rats was evaluated by tail suspension test and forced swimming test.The expression levels of protein kinase A(PKA),phosphorylated cyclic adenosine monophosphate effector binding protein(pCREB),and brain-derived neurotrophic factor(BDNF)in the hippocampus of rat were determined by Western blotting.Immunohistochemistry was used to detect the generation of proliferating cell nuclear antigen(PCNA)-labeled neurons in the hippocampal dentate gyrus(DG).Results BOP of 90 kPa can cause depression-like in rats and BOP of 120 kPa can cause the most noticeable depressive behavior(P<0.05).Therefore,we selected the BOP exposure of 120 kPa for subsequent experiments.After 14 days of BOP exposure,compared with sham operation group,the immobility time of tad suspension test in bTBI group was prolonged(P<0.05),the latency of for ced swimming test was shortened,the immobility time was prolonged(P<0.05),the expression levels of PKA,pCREB and BDNF protein in hippocampus were lowered(P<0.05),and the number of PCNA-labeled neurons in hippocampal DG area was reduced(P<0.05);compared with the bTBI group,the immobility time of tail suspension test in bTBI+NKT group was shortened(P<0.05),the latency of forced swimming test was prolonged,the immobility time was shortened(P<0.05),the expression levels of PKA,pCREB and BDNF protein in hippocampus were increased(P<0.05),and the number of PCNA-labeled neurons in hippocampal DG area was increased(P<0.05).Conclusions Early treatment with NKT can improve depression-like behavior in mild bTBI rats.The mechanism may be related to the up-regulation of the PKA-CREB-BDNF signaling pathway and increased expression levels of pCREB and BDNF in the hippocampus,which results in increased neuron numbers in the DG region of the hippocampus.

Objective To investigate the clinical characteristics of female migraine patients with patent foramen ovale(PFO)and design a risk prediction model for PFO in female migraine patients(migraineur patients PFO risk prediction model,MPRPM).Methods Female migraine patients who visited Zhongshan Hospital,Fudan University from Jun 1,2019 to Dec 31,2022 were included.Preoperative information and follow-up results after discontinuation of medication were collected.Patients were divided into PFO-positive and PFO-negative groups based on transesophageal echocardiography results.A multivariate Logistic regression model and a random forest model were constructed,and the random forest model was validated multidimensionally.Key features were selected based on the mean decrease accuracy(MDA)to construct MPRPM.Results A total of 305 female patients were included in the study,with 204 patients in the PFO-positive group and 101 patients in the PFO-negative group.Multivariate Logistic regression analysis showed that age at migraine onset,attack frequency,severe impact on life during attacks,exercise-related headaches,menstruation-induced headaches,aura migraines,and a history of cryptogenic stroke were predictive factors for PFO positivity.The random forest model effectively predicted the incidence of PFO in female migraine patients,with an AUC of 0.895(95%CI:0.847-0.943).MPRPM demonstrated a sensitivity of 71.6%and specificity of 91.1%(AUC:0.862,95%CI:0.818-0.906,P<0.001).The optimal cut-off value was 2.5 points.Patients correctly classified by the model showed a higher rate of symptom improvement compared to incorrectly classified patients(94.3%vs.82.0%,P=0.023).Conclusion We identified predictive factors for PFO in migraine patients.MPRPM can provide guidance in the diagnostic process and therapeutic decision-making for female migraine patients,assist in patient triage,and reduce the healthcare burden.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

The incidence of osteoporotic thoracolumbar vertebral fracture (OTLVF) in the elderly is gradually increasing. The kyphotic deformity caused by various factors has become an important characteristic of OTLVF and has received increasing attention. Its clinical manifestations include pain, delayed nerve damage, sagittal imbalance, etc. Currently, the definition and diagnosis of OTLVF with kyphotic deformity in the elderly are still unclear. Although there are many treatment options, they are controversial. Existing guidelines or consensuses pay little attention to this type of fracture with kyphotic deformity. To this end, the Lumbar Education Working Group of the Spine Branch of the Chinese Medicine Education Association and Editorial Committee of Chinese Journal of Trauma organized the experts in the relevant fields to jointly develop Clinical guidelines for the diagnosis and treatment of osteoporotic thoracolumbar vertebral fractures with kyphotic deformity in the elderly ( version 2024), based on evidence-based medical advancements and the principles of scientificity, practicality, and advanced nature, which provided 18 recommendations to standardize the clinical diagnosis and treatment.