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.

Diabetes-related cognitive impairment(DCI)is a major complication of type 2 diabetes melli-tus(T2DM).Although exercise is essential in alleviating DCI,the underlying mechanisms remain un-clear.The aim of this study is to investigate the role and mechanism of exosomal miR-126a-5p induced by exercise in ameliorating DCI.Twenty-four 16-week-old male db/db mice were randomly divided into dia-betes group(n=12;DM)and exercise intervention group(n=12;DE).The control group consisted of male m/m mice of the same age group(n=12;CON).The DE group underwent 8 weeks of moderate in-tensity treadmill training(10 m/min,5 days a week).In the MWM experiment,compared to the CON group,the DM group exhibited prolonged escape latency(P<0.01),reduced swimming speed and target quadrant time(P<0.001),and decreased expression of miR-126a-5p and EX-miR-126a-5p in hipp-ocampal tissue(P<0.001).After exercise intervention,the DE group showed improved performance with decreased escape latency(P<0.05),increased swimming speed and target quadrant time(P<0.05),and elevated levels of exosomal miR-126a-5p(P<0.001).Morphological staining revealed a de-crease in the expression and proportion of NeuN in hippocampal neurons and an increase in the expression and proportion of glial cells in the CA1 and CA3 regions of DM group mice compared to CON group mice(P<0.05),while DE group mice showed increased fluorescence intensity and proportion of neurons(P<0.05).Western blotting analysis revealed that the DM group also showed significant upregulation of amy-loid β(Aβ),high mobility group box 1(Hmgb1),and NF-κB in the hippocampus(P<0.05),which were reduced after exercise(P<0.05).Moreover,exosomal miR-126a-5p overexpression greatly de-creased the levels of Hmgb1,NF-κB,and amyloid precursor protein(APP)in HT22 cells and TNF-α,IL-1β in supernatant exposed to HG(P<0.05),while inhibition of miR-126a-5p led to increased levels of these proteins(P<0.05).In conclusion,eight weeks of treadmill exercise improved cognitive function in db/db mice,likely through the EXs-miR-126/HMGB1/NF-κB pathway to reduce inflammation in hip-pocampal tissue.

Objective To analyze the implementation of MPOWER tobacco control policies in different regions and populations in China,as well as the impact of perceptions of tobacco control policies on individual smoking behavior and quit intentions,to promote the fairness of policy implementation and protection for vulnerable groups.Methods A multivariable regression model was constructed utilizing raw data from the China Adult Tobacco Survey to analyze disparities in perceived MPOWER policy implementation among various social demographics and its impact on smoking behavior and quitting intentions.Results Regarding protection from tobacco smoke(P),local economic level,urban-rural divide were significantly correlated with awareness of comprehensive smoking bans.For offering help to quit smoking(O),local tobacco industry revenue and individual age were associated with the doctor's advice for quitting.As to the warning about the harm of tobacco(W),economic level,geography and urban-rural disparity were correlated with the visibility of health warnings.About the tobacco advertising,promotion and sponsorship(E),geography was related to the exposure to tobacco advertisements,local tobacco industry revenue was associated with the tobacco promotion.For tobacco taxes(R),education level and age were significantly correlated with tobacco affordability.People who perceived comprehensive smoking bans(OR=0.69,95%CI:0.59-0.81)was associated with less smoking behavior,while people perceiving tobacco promotional activities(OR=2.51,95%CI:2.00-3.17)were more likely to smoke.Additionally,people who perceived comprehensive smoking bans(OR=1.70,95%CI:1.25-2.31)and health warning(OR=2.09,95%CI:1.48-3.01)had higher intention to quit smoking.Conclusion In economically disadvantaged regions and among specific socially vulnerable groups(such as low-income individuals,rural residents,and the elderly)in China,the perception of tobacco control policy implementation is relatively low,the perception of tobacco control policies can influence smoking behavior and quitting intentions.Legislative and enforcement efforts should be increased targeting these groups with lower perceptions of the policies to enhance the fairness of tobacco control measures.

Objective To explore the impact of suture configuration and fixation type on the biome-chanical strength of rotator cuff repair,using a factorial design study.Methods Sixteen fresh-frozen porcine shoulder samples were randomized into an anchorless double-row suture bridge transosseous su-tures(DS)group,an anchored double-row suture bridge transosseous-equivalent(DE)group,an an-chorless X-BOX construct transosseous sutures(XS)group,and an anchored X-BOX construct transos-seous-equivalent(XE)group,each of four,according to suture configuration(double-row suture bridge,traditional X-BOX construct)and fixation type(suture anchors,transosseous sutures).Then,their fatigue resistance(first-cycle excursion,gap length difference ratio,and the percentage of ex-posed footprints)and the failure strength(the maximum failure load and the re-tear type)were mea-sured using a biomechanical material testing machine.Results Different suture configurations affected failure strength(F=39.559,P<0.001),with the double-row suture bridge groups(693.07±58.35 N,746.76±138.57 N)showing significantly higher failure strength,compared to the traditional X-BOX groups(462.90±18.91 N,421.43±90.76 N).However,the fixation type did not significantly im-pact failure strength(F=1.161,P=0.302).Moreover,the suture configuration influenced the gap differ-ence ratio(F=7.781,P=0.016),but had no significant correlation with other fatigue resistance indica-tors(P>0.05).Meanwhile,failure strength and fatigue resistance were not correlated with fixation type,and the interaction between suture and fixation type(P>0.05).The incidence of failure types for the four suture configurations was as follows:Type I tendon tear:XS>XE>DS=DE;type II tendon tear:DS>XE>XS=DE;fixing material-related failure:DE>DS=XE=XS.Conclusion The failure strength and gap formation ratio in rotator cuff repair under fatigue loading are influenced by suture configuration,whereas no significant association has been observed with respect to fixation method,whether using transosseous sutures or suture anchors.

Breast cancer is the leading cause of cancer-related mortality among women worldwide and has drawn extensive research attention.Owing to its molecular heterogeneity,drug resistance,and low therapeutic response,single-modality treatments often fail to achieve satisfactory efficacy or broad applicability.Combination therapy,designed based on the pathophysiological characteristics,related signaling pathways,and biomarkers of breast cancer,has emerged as a promising approach for improving therapeutic outcomes.With the advancement of research on combination strategies,the understanding of their molecular mechanisms—particularly key signaling pathways and biomarkers—has become increasingly important.However,comprehensive reviews addressing these molecular mechanisms and synergistic strategies remain scarce.This article summarizes recent advances in combination therapy for breast cancer,providing a comprehensive review of recent combination therapies for breast cancer and their underlying molecular mechanisms,and focusing on key signaling pathways involved in combination therapy and synergistic strategies,thereby providing theoretical insights and reference for researchers,graduate students,and clinicians engaged in the development of novel combination therapeutic strategies for breast cancer and related malignancies.

Objective:To investigate the clinical application effect of Zishen Yutai Pill in patients with repeated implantation failure (RIF) undergoing frozen-thawed embryo transfer (FET) cycles.Methods:A retrospective case-control study was conducted, selecting 744 cycles of patients with RIF at the Department of Female Reproductive Medicine,State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University from October 2017 to April 2023. The patients were divided into experimental group (treated with Zishen Yutai Pill, n=279) and control group (treated without Zishen Yutai Pill, n=465) based on whether Zishen Yutai Pill was added to luteal support. The pregnancy outcomes between the two groups were compared. Based on the different endometrial preparation protocols in the FET cycles, the patients were used down-regulation protocol ( n=271) or non-down-regulation protocol ( n=473). The pregnancy outcomes of the two groups in each protocol were compared. Results:There were no statistically significant differences between the two groups in terms of biochemical pregnancy rate, clinical pregnancy rate, embryo implantation rate, early miscarriage rate, late miscarriage rate, and live birth rate (all P>0.05). However, the biochemical pregnancy rate [69.0% (58/84)], clinical pregnancy rate [59.5% (50/84)], and embryo implantation rate [59.4% (57/96)] in the experimental group of the down-regulated protocol were significantly higher than those in control group [56.1% (105/187), P=0.045; 46.5% (87/187), P=0.048; 44.9% (92/205), P=0.019], with statistically significant differences. In the non-down-regulated protocol, there were no statistically significant differences in pregnancy outcomes between the two groups (all P>0.05). Conclusion:In the FET down-regulated protocol, Zishen Yutai Pill can significantly improve the clinical pregnancy rate and the embryo implantation rate in patients with RIF, thereby improving pregnancy outcomes.

Objective To investigate the effect of tissue-resident memory T cells(TRM)on imiquimod-induced psoriatic-like skin lesions in mice,and to elucidate the underlying mechanisms of TRM involvement in this process.Methods Forty female BALB/c mice were procured and randomly allocated into four groups:ten in the blank control group,and thirty for the establishment of a psoriasis mouse model.Following successful modeling,the thirty mice were further randomized into three groups:the model control group,the methotrexate-treated group,and the imiquimod-treated group,with ten mice in each group.Mice in the blank control group and model control group were uniformly treated with Vaseline for intervention.The methotrexate group and the imiquimod group were treated with 62.5mg of 5％imiquimod cream.The methotrexate group was administered by gavage at a dose of 1 mg/kg,and the gavage volume of each group was 10 mL/kg.The model control group,blank group and imiquimod group were gavaged with the same volume of normal saline.Treatment was conducted over six consecutive days.Subsequently,comparisons were made across groups regarding the psoriasis area and severity index(PASI),histopathological findings,inflammatory cytokine levels,and TRM cell levels.Results(1)The imiquimod group exhibited signifi-cantly lower scores for erythema(2.54±0.32),skin thickening(2.59±0.25),and scaling(2.52±0.29)compared to the methotrexate group,model control group,and blank control group(P<0.05).Additionally,the methotrexate group demonstrated reduced scores for erythema,skin thickening,and scaling compared to the model control group(P<0.05).(2)Hematoxylin-eosin(HE)staining revealed that the epidermis in the methotrexate group became thin-ner,with fewer parakeratotic cells and increased hair follicles.Conversely,the imiquimod group displayed abnor-mal cell morphology and relatively thicker white skin after modeling.(3)The imiquimod group showed significantly lower levels of TNF-α(51.63±4.39 pg/mL),IL-1β(35.53±4.15 pg/mL),IFN-γ(23.43±3.41 pg/mL),and IL-23(15.24±2.95 pg/mL)compared to the methotrexate and model control groups(P<0.05).Similarly,the methotrexate group exhibited reduced levels of TNF-α,IL-1β,IFN-γ,and IL-23 compared to the model control group(P<0.05).(4)The imiquimod group had significantly lower levels of CD8+CD103+cells(15.39±2.31)than the methotrexate and model control groups(P<0.05).Furthermore,the methotrexate group demonstrated lower levels of CD8+CD103+cells compared to the model control group(P<0.05).Conclusion Miquimod induces heavier skin lesions,faster response,and more epidermal thickening in psoriasis like mice.CD8+CD103+TRM cells and inflammatory factors may be involved in the recurrence of psoriasis.

Objective:To investigate the inhibitory effect and mechanism of puerarin(Pue)on hydrogen peroxide(H2 O2)induced ferroptosis in the rat Schwann cell derived cell line RSC96.Methods:The RSC96 cells were incuba-ted with H2 O2 to establish a cellular injury model,while a subset of cells were co-incubated with H2 O2 and Pue.The vi-ability of cells was examined using the CCK-8 assay.The intracellular levels of glutathione(GSH),total superoxide dismutase(T-SOD),reactive oxygen species(ROS),malondialdehyde(MDA),and ferrous ions(Fe2+)levels were quantified using commercial kits.Western blot was employed to detect the protein expression level of glutathione peroxi-dase 4(GPX4),cyclooxygenase-2(COX-2),solute carrier family 7 member 11(SLC7A11),nuclear factor erythroid 2-related factor 2(Nrf2),and heme oxygenase-1(HO-1).Immunofluorescence assay was performed to examine the expression and nuclear distribution of Nrf2.Results:Pue pretreatment significantly increased the survival rate of H2 O2-treated RSC96 cells,increased the intracellular content of GSH and T-SOD,and inhibited the concentration of ROS and MDA.It also activated the nuclear translocation of Nrf2 and upregulated GPX4,SLC7A11,HO-1,and Nrf2 proteins in RSC96 cells;This effect was abolished by the Nrf2 inhibitor ML385.Conclusion:Pue treatment alleviated the H2 O2-induced ferroptosis of RSC96 cells via the Nrf2/SLC7A11/GPX4 signaling pathway.

Objective:To investigate the inhibitory effect and mechanism of puerarin(Pue)on hydrogen peroxide(H2 O2)induced ferroptosis in the rat Schwann cell derived cell line RSC96.Methods:The RSC96 cells were incuba-ted with H2 O2 to establish a cellular injury model,while a subset of cells were co-incubated with H2 O2 and Pue.The vi-ability of cells was examined using the CCK-8 assay.The intracellular levels of glutathione(GSH),total superoxide dismutase(T-SOD),reactive oxygen species(ROS),malondialdehyde(MDA),and ferrous ions(Fe2+)levels were quantified using commercial kits.Western blot was employed to detect the protein expression level of glutathione peroxi-dase 4(GPX4),cyclooxygenase-2(COX-2),solute carrier family 7 member 11(SLC7A11),nuclear factor erythroid 2-related factor 2(Nrf2),and heme oxygenase-1(HO-1).Immunofluorescence assay was performed to examine the expression and nuclear distribution of Nrf2.Results:Pue pretreatment significantly increased the survival rate of H2 O2-treated RSC96 cells,increased the intracellular content of GSH and T-SOD,and inhibited the concentration of ROS and MDA.It also activated the nuclear translocation of Nrf2 and upregulated GPX4,SLC7A11,HO-1,and Nrf2 proteins in RSC96 cells;This effect was abolished by the Nrf2 inhibitor ML385.Conclusion:Pue treatment alleviated the H2 O2-induced ferroptosis of RSC96 cells via the Nrf2/SLC7A11/GPX4 signaling pathway.

Deutetrabenazine(DTBZ)is a selective oral small molecule inhibitor of vesicular monoamine transporter 2(VMAT2).Its pharmacological action works by inhibiting VMAT2,thereby reducing the release of presynaptic dopamine and alleviating tardive dyskinesia symptoms caused by long-term use of dopamine receptor antagonists.Compared with tetrabenazine,DTBZ has longer half-life,lower peak plasma concentration,and smaller plasma concentration fluctuations.Clinical studies demonstrate that DTBZ significantly improves abnormal involuntary movement in patients with tardive dyskinesia and has a favourable safety profile.Based on available clinical evidence and practical experience,this paper discuss the common questions about DTBZ including the suitable population,dose,duration of treatment,combination administration with antipsychotics,efficacy assessment and application in special populations.This article aimed to provide guidance and recommendations on clinical application of DTBZ for clinicians.