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.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Intestinal microorganisms and their metabolites are involved in the pathogenesis and progression of various cardiovascular diseases,especially in the progression of heart failure.This paper mainly discussed the gut microbial metabolites trimethylamine oxide(TMAO)participated in the pathological process of heart failure,and application value of TMAO in heart failure patients.This paper introduced the change characteristics of intestinal flora and its metabolites in heart failure patients,illu-minated the TMAO-mediated inflammatory response,and the related signal pathways and mechanism of myocardial hypertrophy and heart failure.High levels of TMAO are associated with poor outcomes in patients with heart failure indicating a good predictive value for the prognosis of heart failure.Regulating TMAO levels through diet,probiotics and prebiotics,antibiotics,fecal transplan-tation,and other pathways is expected to be a potential treatment for heart failure.

Objective To analyze the current situation and characteristics of risk factors in antithrombotic therapy(in-cluding antiplatelet and anticoagulant treatments)at home and abroad,and to provide a theoretical basis for the prevention and treatment of thrombosis or bleeding associated with antithrombotic therapy.Methods The literature on risk factors of an-tithrombotic therapy published in Chinese databases(China Journal Full-text Data,Wanfang Database,VIP Database)and Eng-lish databases(PubMed,Web of Science,MEDLINE)from January 2011 to November 2021 was searched and bibliometric analy-sis was performed.The visualization analysis was performed using VOS viewer software.Results A total of 595 publications were included in the analysis.The top three countries for English publications were the USA,China,and Japan.The type of stud-ies were predominantly cohort studies,with sample sizes mostly being below 1 000.Risk factors for antithrombotic therapy are cat-egorized into those affecting antiplatelet drugs,warfarin,and new oral anticoagulants.Age,gender,renal function,and combination of antithrombotic drugs are common risk factors,and different risk factors of antithrombotic drugs also have their characteristics.Conclusion While there is substantial research on risk factors in antithrombotic therapy globally,the sample size needs to be improved.Pharmacists should provide individualized medication services based on different drugs and different groups to ensure medication safety for patients.

Synthetic cannabinoids(SCs)are synthetic psychoactive substances that can pose a public health risk.The SCs are structurally variable and susceptible to structural modification.The rapid emergence of structurally unknown synthetic cannabinoids has led to new challenges in their identification.In recent years,machine learning has made great progress and has been widely applied to other fields,providing new strategies for the identification of unknown synthetic cannabinoids and the inference of possible sources.This paper describes the principles of commonly used machine learning methods and the application of machine learning techniques to mass spectrometry,Raman spectroscopy,metabolomics and quantitative conformational relationships of synthetic cannabinoids,aiming to provide new ideas for the identification of unknown synthetic cannabinoids.

Objective To construct a new type of glucosamine/DNA composite nanostructure(NTGlcN)assembled without magnesium,verify whether or not glucosamine can mediate the assembly of DNA nanotubes(NT)and assess its effect on the function of Raw264.7 cells.Methods Utilizing the gradient annealing method with 3 DNA single strands Y1,Y2,and Y3,glucosamine(GlcN)was employed to mediate the assembly of DNA NT,resulting in the formation of glucosamine/DNA composite nanostructures.Atomic force microscopy(AFM)was used to observe the surface structure of the nanomaterial and dynamic light scattering(DLS)was used to measure its size.RAW264.7 cells were used in cell experiments.The cytotoxicity of GlcN and NTGlcN was assessed using CCK-8 assay.Flow cytometry and laser confocal microscopy were employed to investigate the cellular uptake efficiency of the nanostructures.The effects of NTGlcN and NTMg(Mg2+-assembled of DNA NT)on the expression levels of inflammatory cytokines(IL-1β,IL-6)in macrophages induced by lipopolysaccharides(LPS)were evaluated using RT-qPCR.Results GlcN successfully mediated the synthesis of NTGlcN,which exhibited good stability.AFM characterization results revealed that NTGlcN formed tubular particles that were uniformly distributed on the surface of mica.DLS measurements indicated that the diameter of NTGlcN was approximately 15.26±3.86 nm.Cell experiments demonstrated that,compared to NTMg,macrophages exhibited a higher cellular uptake efficiency for NTGlcN,with a higher cell survival rate following treatment with NTGlcN(P＜0.05).After NTGlcN treatment,the expression of inflammatory cytokines in LPS-induced macrophages was reduced(P＜0.05).Conclusion The glucosamine/DNA composite nanostructures have been successfully developed,possessing excellent stability,biocompatibility and cell uptake efficiency.NTGlcN is capable of reducing the cytotoxicity of GlcN and can suppress cellular inflammatory responses by decreasing the expression of inflammatory cytokines in RAW264.7 cells.

Objective To evaluate the efficacy of double U-stitch and modified"double U-stitch pancreaticojejunostomy"in pancreaticoduodenectomy.Methods We retrospectively analyzed the clinical information of 150 patients who underwent pancreaticoduodenectomy between January 2022 and September 2023 in Wang Wei's team in department of pancreatic surgery,Fudan University Shanghai Cancer Center.The patients were divided into two groups according to the pancreaticojejunostomy method:the double U-stitch 1.0 group(70 cases before modification)and the double U-stitch 2.0 group(80 cases after modification).The postoperative complications of the two groups were compared.Results The overall postoperative complications were significantly lower in the double U-stitch 2.0 group as compared with the double U-stitch 1.0 group(13.8％vs.38.6％,P=0.001).The incidence of clinically relevant pancreatic fistula was 18.6％in the double U-stitch 1.0 group,while this was significantly decreased in the double U-stitch 2.0 group(6.3％)(P=0.021).Postoperative extraluminal hemorrhage occurred in 5 patients in the double U-stitch 1.0 group,while in the double U-stitch 2.0 group,only one patient experienced postoperative intraluminal hemorrhage,the difference was statistically significant between two groups(P=0.007).The median postoperative length of hospital stay was significantly shorter in the double U-stitch 2.0 group than that in the double U-stitch 1.0 group(11d vs.14 d,P=0.001).Conclusions The modified"double U-stitch pancreaticojejunostomy"can significantly reduce the incidence of clinically relevant pancreatic fistula and other relevant severe complications,which helps improve the safety of the procedure.

Objective:To investigate the perioperative impact of closure of mesenteric fissure in laparoscopic right hemicolectomy.Methods:The prospective randomized controlled trial was conducted. The clinical data of 320 patients who underwent laparoscopic right hemicolectomy in 11 medical centers, including The First Affiliated Hospital of China Medical University et al, from November 2022 to August 2023 were selected. Based on block randomization, patients were alloca-ted into the mesenteric fissure non-closure group and the mesenteric fissure closure group. Observa-tion indicators: (1) grouping of the enrolled patients; (2) intraoperative conditions; (3) postopera-tive conditions. Measurement data with skewed distribution were represented as M( Q1, Q3) and com-parison between groups was conducted using the Mann-Whitney U test. Count data were represen-ted as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher's exact probability. Comparison of ordinal data was conducted using the rank sum test. Comparison of visual analog scores was analyzed using generalized estimating equations. Results:(1) Grouping of the enrolled patients. A total of 320 patients with colon cancer were screened for eligibility, including 156 males and 164 females, aged 68(59,73)years. All the 320 patients were allocated into the mesenteric fissure non-closure group with 164 cases and the mesenteric fissure closure group with 156 cases. There was no significant difference in the age, body mass index, American Society of Anesthesiologist score, maximum tumor diameter, anastomosis location, anastomosis method, surgical approach, range of lymph node dissection, tumor staging between the two groups ( P>0.05) and there was a significant difference in the sex between them ( P<0.05). (2) Intraoperative conditions. There was no significant difference between the mesenteric fissure closure group and the mesenteric fissure non-closure group in the volume of intraoperative blood loss, operation time, conversion to laparotomy, intraoperative complication ( P>0.05). Three patients in the mesenteric fissure non-closure group were converted to laparotomy. One patient in the mesenteric fissure closure group was converted to laparotomy, and 2 cases with intraoperative complication were mesenteric hematoma. (3) Postoperative conditions. There was no significant difference between the mesenteric fissure non-closure group and the mesenteric fissure closure group in the overall postoperative complications ( χ2=0.28, P>0.05). There was no significant difference in the occurrence of postoperative intestinal obstruction, abdominal distension, ascites, pleural effusion, gastric paralysis, anastomotic bleeding, anastomotic leakage, or surgical wound infection between the two groups ( P>0.05). There was no significant difference between the two groups in the reoperation, postoperative gastric tube replacement. There was no significant differ-ence in time to postoperative first flatus, time to postoperative initial liquid food intake, time to post-operative resumption of bowel movements, duration of postoperative hospital stay, total hospital expenses between the two groups ( Z=-0.01, 0.43, 1.04, -0.54, -0.36, P>0.05). One patient in the mesenteric fissure non-closure group received reoperation. No perioperative internal hernia or death occurred in either group. The visual analog score decreased with time in both groups. There was no significant difference in the visual analog score between the mesenteric fissure closure group and the mesenteric fissure non-closure group [ β=-0.20(-0.53,0.13), P>0.05]. Conclusion:Compared with closure of mesenteric fissure, non-closure of mesenteric fissure during laparoscopic right hemi-colectomy dose not increase perioperative complications or postoperative management risk.