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.

Objective: To investigate the influencing factors of overactive bladder (OAB) in college freshmen and the impacts of OAB on their mental health, quality of life and social interaction. Methods: An epidemiological questionnaire survey was conducted in an anonymous manner on the prevalence of OAB among 5300 freshmen aged 17 to 22 years enrolled in the 2023—2024 academic year in Xinxiang Medical University and Sanquan College of Xinxiang Medical University.The questionnaire included questions on basic information, history of urinary tract infection, constipation, smoking, history of alcohol consumption, history of coffee/strong tea drinking, history of carbonated beverage drinking, redundant prepuce, phimosis, holding urine, chronic insomnia, self-rating anxiety scale (SAS), quality of life score (QoL), and social avoidance and distress scale (SADS).The influencing factors of OAB were analyzed with multivariate logistic regression analysis.The subjects were grouped according to whether they had OAB, and the differences in SAS, QoL and SADS between the OAB group and non-OAB group were compared.The impacts of OAB on the anxiety level, quality of life, and social interaction were analyzed with multiple linear regression analysis. Results: The overall prevalence rate of OAB was 4.9% (244/5018).Multivariate logistic regression analysis showed that the history of urinary tract infection (OR=0.177), constipation (OR=0.636), smoking (OR=0.582), alcohol consumption (OR=0.685), coffee/strong tea drinking (OR=0.387), carbonated beverage drinking (OR=0.631), redundant prepuce (OR=0.673), phimosis (OR=0.311), urine holding (OR=0.593), and chronic insomnia (OR=0.256) were influencing factors for the occurrence of OAB (P＜0.05).The OAB group had higher SAS score [(41.18±6.54) vs. (38.61±6.36)], QoL score [(3.65±1.20) vs. (2.79±0.95)], social avoidance score [(6.25±1.86) vs. (5.86±1.51)], social distress score [(6.27±1.59) vs. (5.97±1.32)], and total SADS score [(12.51±2.35) vs. (11.84±2.01)] than the non-OAB group (P＜0.05).The results of multiple linear regression analysis showed that OAB could independently affect the scores of QoL, SAS, and SADS.The OAB group had higher scores of QoL, SAS, and SADS compared with the non-OAB group (P＜0.001). Conclusion: History of urinary tract infection, constipation, smoking, alcohol consumption, coffee/strong tea drinking, carbonated beverage drinking, redundant prepuce, phimosis, urine holding, and chronic insomnia are influencing factors for the occurrence of OAB in male college students.Moreover, OAB has negative impacts on their mental health, quality of life, and social interaction.

Aim To study the mechanism of quereetin (Que) inhibiting mitochondrial damage induced by Aβ

The coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which has led to serious worldwide economic burden. Due to the continuous emergence of variants, vaccines and monoclonal antibodies are only partial effective against infections caused by distinct strains of SARS-CoV-2. Therefore, it is still of great importance to call for the development of broad-spectrum and effective small molecule drugs to combat both current and future outbreaks triggered by SARS-CoV-2. Cathepsin L (CatL) cleaves the spike glycoprotein (S) of SARS-CoV-2, playing an indispensable role in enhancing virus entry into host cells. Therefore CatL is one of the ideal targets for the development of pan-coronavirus inhibitor-based drugs. In this study, a CatL enzyme inhibitor screening model was established based on fluorescein labeled substrate. Two CatL inhibitors IMB 6290 and IMB 8014 with low cytotoxicity were obtained through high-throughput screening, the half inhibition concentrations (IC₅₀) of which were 11.53 ± 0.68 and 1.56 ± 1.10 μmol·L^-1, respectively. SDS-PAGE and cell-cell fusion experiments confirmed that the compounds inhibited the hydrolysis of S protein by CatL in a concentration-dependent manner. Surface plasmon resonance (SPR) detection showed that both compounds exhibited moderate binding affinity with CatL. Molecular docking revealed the binding mode between the compound and the CatL active pocket. The pseudovirus experiment further confirmed the inhibitory effects of IMB 8014 on the S protein mediated entry process. In vitro pharmacokinetic evaluation indicated that the compounds had relatively good drug-likeness properties. Our research suggested that these two compounds have the potential to be further developed as antiviral drugs for COVID-19 treatment.

Objective To observe the effect of Shenfu injection on lung injury caused by hemor-rhagic shock(HS)in rats and explore the related potential mechanism.Methods Thirty-six SPF healthy male SD rats,aged 16-17 weeks,weighing 400-600 g,were randomly divided into three groups:sham op-eration group(group SH),HS group(group HS),and Shenfu injection group(group SF),12 rats in each group.In group SH,only the right femoral vein and femoral artery were separated after anesthesia,and ve-nous catheterization was not performed.HS model was established in groups SF and HS.In group HS,liquid resuscitation was performed through an intravenous catheter,and the resuscitation fluid consisted of the auto-blood lost and the compound sodium chloride injection equivalent to 1.5 times the blood loss and 10 ml/kg normal saline.In group SF,the resuscitation fluid consisted of the lost autoblood and the compound sodium chloride injection equivalent to 1.5 times the blood loss and Shenfu injection 10 ml/kg.The whole perfusion time was about 60 minutes.Six rats in the three groups were randomly anesthetized 24 and 48 hours after op-eration.The wet/dry weight ratio(W/D)of lung tissues was detected.The concentrations of interleukin-6(IL-6),IL-17,IL-10,and transforming growth factor-β(TGF-β)were detected by ELISA,the mRNA ex-pression of retinoic acid-related orphan nuclear receptor γt(RORγt),transcription factor forkhead box pro-tein 3(Foxp3),and hypoxia-inducible factor-1α(HIF-1α)in lung tissues were detected by PCR.The pro-tein contents of RORγt,Foxp3,HIF-1α,aquaporin 1(AQP1),and AQP5 in lung tissue were detected by Western blot.Pathological changesunder HE staining light microscope and lung injury scores were observed.Results Compared with 24 hours after operation,W/D,the concentrations of IL-6 and IL-17,mRNA ex-pression and protein content of RORγt and HIF-1α,and lung injury score were significantly decreased(P＜0.05),the concentrations of IL-10,and TGF-β,Foxp3 mRNA expression and protein content,and AQP1 protein content were significantly increased in group SF 48 hours after operation(P＜0.05).Compared with group SH,W/D,the concentrations of IL-6,IL-17,IL-10,and TGF-β,mRNA expression and protein content of RORγt,Foxp 3,and HIF-1α,and lung injury score were significantly increased(P＜0.05),AQP1 and AQP5 protein contents were significantly decreased in groups HS and SF 24 and 48 hours after operation(P＜0.05),and alveolar structure was damaged under light microscope and alveolar interstitium was filled with a large amount of edematous fluid,during which a large number of inflammatory cells infiltra-ted.Compared with group HS,W/D,the concentrations of IL-6 and IL-17,mRNA expression and protein content of RORγt and HIF-1α,and lung injury score were significantly decreased(P＜0.05),the concen-trations of IL-10 and TGF-β,Foxp3 mRNA expression and protein content,AQP1 and AQP5 protein con-tents were significantly increased in group SF 24 and 48 hours after surgery(P＜0.05),and the alveolar structure was improved under light microscope,and edema was reduced,and the number of inflammatory cells was reduced.Conclusion Shenfu injection can regulate the balance between pro-inflammatory factors IL-6 and IL-17,and anti-inflammatory factors IL-10 and TGF-β,increase the protein content of AQP1 and AQP5 in lung tissue,and decrease the W/D and injury score in lung tissue,thus alleviating lung injury in HS rats.The mechanism may be related to the regulation of HIF-1α-RORγt/Foxp3 balance.

Isocitrate dehydrogenase 1 (IDH1) R132H is the most common mutated gene in grade II-III gliomas and oligodendrogliomas. Instead of activating telomerase (a reverse transcriptase which using RNA as a template to extend telomere length), the majority of IDH1^R132H mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination (HR), which is known as alterative lengthening of telomere (ALT).The phenotype of ALT mechanism include: ALT associated promyelocytic leukemia protein (PML) bodies (APBs); extrachromosomal telomeric DNA repeats such as C- and T-loops; telomeric sister chromatid exchange (T-SCE), etc. The mechanism of ALT activation is not fully understood. Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways. Firstly, the IDH1^R132H mutation mediates RAP1 down-regulation leading to telomere dysfunction, thus ensuring persistent endogenous telomeric DNA damage, which is important for ALT activation. Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication (BIR)‑mediated ALT telomere lengthening, and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA, transcribed from telomeric DNA repeat sequences (TERRA) transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage, thereby inhibiting ALT telomere synthesis. Similarly, in ALT cells, knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation, which leads to increased replication pressure. Overexpression of RNaseH1, on the other hand, attenuates the recombination capacity of ALT telomeres, leading to telomere depletion, suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression. Secondly, the IDH1^R132H also alters the preference of the telomere damage repair pathway by down-regulating XRCC1, which inhibits the alternative non-homologous end joining (A-NHEJ) pathway at telomeres and alters cellular preference for the HR pathway to promote ALT. Finally, the IDH1^R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α ketoglutarate (α‑KG) and NADPH, so that the mutant IDH1^R132H catalyzes the hydrogenation of α‑KG to produce 2-hydroxyglutarate (2-HG)in a NADPH-dependent manner. Because 2-HG is structurally similar to α‑KG, which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α‑KG-dependent histone demethylase KDM4B, and recruits heterochromatin protein HP1α to heterochromatinize telomeres, and promote ALT phenotypes in cooperation with the inactivating of ATRX. In addition, it has been shown that APBs contain telomeric chromatin, which is essentially heterochromatin, and HP1α is directly involved in the formation of APBs. Based on these studies, this article reviews the mechanism of IDH1^R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT, which may provide references for clinical targeted therapy of IDH1^R132H mutant glioma.

Objective:To investigate the relationship between heart rate variability(HRV), deceleration capacity(DC) and cardiovascular metabolic disease(CMD) in children and adolescents with normal weight obesity(NWO).Methods:A total of 200 children and adolescents aged 6-17 who underwent normal physical examination in Chengdu Women′s and Children′s Central Hospital from December 2022 to June 2023 were included in this retrospective case-control study.They were divided into the NWO group, normal weight lean(NWL) group, and overweight-obesity(OW-OB) group according to their body mass index(BMI) and body fat percentage(BF%).Fifty children were enrolled into the NWO group; fifty-one children were enrolled into the NWL group; and 99 children were enrolled into the OW-OB group.All the subjects received 24-hour heart monitoring, and their HRV indexes, such as the standard deviation of N-N interval in normal sinus(SDNN), the standard deviation of the mean value N-N intervals every 5-minute(SDANN), the mean of the standard deviations of all N-N intervals for each 5-minute segment of 24 hours(SDNNindex), the root mean square of successive N-N interval difference(rMSSD), the proportion of N-N 50(the successive N-N interval differences>50 ms) in the total number of N-N intervals(pNN50), and DC were automatically calculated.Blood pressure, fasting blood glucose and blood lipids were measured, and the cardiometabolic risk score(CRS) was obtained through the accumulation of relevant factors.The general data, SDNN, SDANN, SDNNindex, rMSSD, pNN50, DC and CRS of the three groups were compared by variance analysis.Spearman correlation and multivariate Logistic regression were used to analyze the risk factors affecting CRS.Results:There was no significant difference in age, gender and other general information among the three groups(all P>0.05).SDNN in the NWO, NWL, and OW-OB groups were(120.88±16.36) ms, (129.07±16.36) ms, and(109.29±16.38) ms, respectively( F=26.231, P<0.001); SDANN were(64.44±11.61) ms, (66.25±8.34) ms, and(61.70±6.85) ms, respectively( F=5.048, P=0.007); rMSSD were(27.02±3.87) ms, (27.51±5.92) ms, and(25.12±6.78) ms, respectively( F=3.328, P=0.038); pNN50 were(12.62±4.04)%, (13.39±2.26)%, and(11.22±2.93)%, respectively( F=9.099, P<0.001); DC were(4.83±0.20) ms, (4.94±0.33) ms, and(4.63±0.28) ms, respectively( F=23.496, P<0.001)and CRS was 0.94±0.87, 0.69±0.19 and 1.57±1.07, respectively( P<0.01).The differences between the three groups were statistically significant.Spearman correlation analysis showed that BMI( r=0.211, P=0.003) and BF%( r=0.558, P<0.001) were significantly positively correlated with CRS, while SDNN( r=-0.258, P<0.001) and DC( r=-0.499, P<0.001) were significantly negatively correlated with CRS.Multivariate Logistic regression analysis showed that BF%(95% CI: 0.098-0.265, P<0.001) and DC(95% CI: -3.962--1.391, P<0.001) were independent risk factors for predicting CMD. Conclusions:Increased BF% and decreased DC are independent risk factors for CMD.Analysis of body composition and HRV in children and adolescents can help to identify potentially high-risk groups more accurately, intervene early, and reduce the risk of CMD.

OBJECTIVE To establish the specific chromatogram of Qianghuo Shengshi Tang(QHSS) reference sample, clarify the key quality attributes of QHSS, providing reference for the quality evaluation of QHSS reference sample. METHODS The SilGreen C18 column(4.6 mm×250 mm, 5 μm) was used. The mobile phase consisted acetonitrile and 0.2% formic acid aqueous solution. The detection wavelength was 328 nm. Established an HPLC characteristic spectrum analysis method for the reference sample of QHSS. A variety of chromatographic columns and different instruments were applied to investigate the adaptability of the system. HPLC-LTQ-Orbitrap MS was used to identify the specific peaks of the QHSS reference samples in positive ion mode. RESULTS There were 14 peaks in the specific chromatogram, which belonged to Notopterygii Rhizoma Et Radix, Angelicae Pubescentis Radix, Ligustici Rhizoma Et Radix, Chuanxiong Rhizome, Viticis Fructus, respectively. Ferulic acid(peak 3) was reference peak. A total of 22 compounds were identified by mass spectrometry, including coumarin and flavonoids. CONCLUSION The established specific chromatogram method of QHSS is simple, stable and reproducible. The material basis of QHSS reference sample is basically determined, providing a reference for the development and quality control of QHSS.