Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis through the transport of microRNA-29a

BACKGROUND Knee osteoarthritis(KOA)is a common orthopedic condition with an uncertain etiology,possibly involving genetics and biomechanics.Factors like changes in chondrocyte microenvironment,oxidative stress,inflammation,and immune responses affect KOA development.Early-stage treatment options primarily target symptom relief.Mesenchymal stem cells(MSCs)show promise for treatment,despite challenges.Recent research highlights microRNAs(miRNAs)within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA progression.This suggests exosomes(Exos)as a promising avenue for future treatment.While these findings emphasize the need for effective KOA progression management,further safety and efficacy validation for Exos is essential.AIM To explore miR-29a’s role in KOA,we’ll create miR-29a-loaded vesicles,testing for early treatment in rat models.METHODS Extraction of bone marrow MSC-derived extracellular vesicles,preparation of engineered vesicles loaded with miR-29a using ultrasonication,and identification using quantitative reverse transcription polymerase chain reaction;after establi-shing a rat model of KOA,rats were randomly divided into three groups:Blank control group injected with saline,normal extracellular vesicle group injected with normal extracellular vesicle suspension,and engineered extrace-llular vesicle group injected with engineered extracellular vesicle suspension.The three groups evaluation,histological detection,and immunohistochemical detection to compare and evaluate the progress of various forms of arthritis.RESULTS General behavioral observation results showed that the extracellular vesicle group and engineered extracellular vesicle group had better performance in all four indicators of pain,gait,joint mobility,and swelling compared to the blank control group.Additionally,the engineered extracellular vesicle group had better pain relief at 4 wk and better knee joint mobility at 8 wk compared to the normal extracellular vesicle group.Imaging examination results showed that the blank control group had the fastest progression of arthritis,the normal extracellular vesicle group had a relatively slower progression,and the engineered extracellular vesicle group had the slowest progression.Gross histological observation results showed that the blank control group had the most obvious signs of arthritis,the normal extracellular vesicle group showed signs of arthritis,and the engineered extracellular vesicle group showed no significant signs of arthritis.Using the Pelletier gross score evaluation,the engineered extracellular vesicle group had the slowest progression of arthritis.Results from two types of staining showed that the articular cartilage of rats in the normal extracellular vesicle and engineered extracellular vesicle groups was significantly better than that of the blank control group,and the engineered extracellular vesicle group had the best cartilage cell and joint surface condition.Immunohistochemical detection of type II collagen and proteoglycan showed that the extracellular matrix of cartilage cells in the normal extracellular vesicle and engineered extracellular vesicle groups was better than that of the blank control group.Compared to the normal extracellular vesicle group,the engineered extracellular vesicle group had a better regulatory effect on the extracellular matrix of cartilage cells.CONCLUSION Engineered Exos loaded with miR-29a can exert anti-inflammatory effects and maintain extracellular matrix stability,thereby protecting articular cartilage,and slowing the progression of KOA.

Long non-coding RNA H19 regulates neurogenesis of induced neural stem cells in a mouse model of closed head injury

Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.

Identification of cell surface markers for acute myeloid leukemia prognosis based on multi-model analysis

Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and progression.In the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression analysis.By using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML patients.The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels.Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients.The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores.Notably,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance.Furthermore,PI3K inhibitors were identified as potential treatments for these high-risk patients.In conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

Suppressive effects of exercise-conditioned serum on cancer cells:A narrative review of the influence of exercise mode,volume,and intensity

Cancer is a major cause of morbidity and mortality worldwide,and the incidence is increasing,highlighting the need for effective strategies to treat this disease.Exercise has emerged as fundamental therapeutic medicine in the management of cancer,associated with a lower risk of recur-rence and increased survival.Several avenues of research demonstrate reduction in growth,proliferation,and increased apoptosis of cancer cells,including breast,prostate,colorectal,and lung cancer,when cultured by serum collected after exercise in vitro(i.e.,the cultivation of cancer cell lines in an experimental setting,which simplifies the biological system and provides mechanistic insight into cell responses).The underlying mechanisms of exercise-induced cancer suppressive effects may be attributed to the alteration in circulating factors,such as skeletal muscle-induced cytokines(i.e.,myokines)and hormones.However,exercise-induced tumor suppressive effects and detailed information about training interventions are not well investigated,constraining more precise application of exercise medicine within clinical oncology.To date,it remains unclear what role different training modes(i.e.,resistance and aerobic training)as well as volume and intensity have on exercise-condi-tioned serum and its effects on cancer cells.Nevertheless,the available evidence is that a single bout of aerobic training at moderate to vigorous intensity has cancer suppressive effects,while for chronic training interventions,exercise volume appears to be an influential candidate driving cancer inhibitory effects regardless of training mode.Insights for future research investigating training modes,volume and intensity are provided to further our understanding of the effects of exercise-conditioned serum on cancer cells.

Model reduction of fractional impedance spectra for time–frequency analysis of batteries, fuel cells, and supercapacitors

Joint time–frequency analysis is an emerging method for interpreting the underlying physics in fuel cells,batteries,and supercapacitors.To increase the reliability of time–frequency analysis,a theoretical correlation between frequency-domain stationary analysis and time-domain transient analysis is urgently required.The present work formularizes a thorough model reduction of fractional impedance spectra for electrochemical energy devices involving not only the model reduction from fractional-order models to integer-order models and from high-to low-order RC circuits but also insight into the evolution of the characteristic time constants during the whole reduction process.The following work has been carried out:(i)the model-reduction theory is addressed for typical Warburg elements and RC circuits based on the continued fraction expansion theory and the response error minimization technique,respectively;(ii)the order effect on the model reduction of typical Warburg elements is quantitatively evaluated by time–frequency analysis;(iii)the results of time–frequency analysis are confirmed to be useful to determine the reduction order in terms of the kinetic information needed to be captured;and(iv)the results of time–frequency analysis are validated for the model reduction of fractional impedance spectra for lithium-ion batteries,supercapacitors,and solid oxide fuel cells.In turn,the numerical validation has demonstrated the powerful function of the joint time–frequency analysis.The thorough model reduction of fractional impedance spectra addressed in the present work not only clarifies the relationship between time-domain transient analysis and frequency-domain stationary analysis but also enhances the reliability of the joint time–frequency analysis for electrochemical energy devices.

Exosomes derived from tendon stem/progenitor cells enhance tendon-bone interface healing after rotator cuff repair in a rat model

The rate of retear after surgical repair remains high.Mesenchymal stem cells(MSCs)have been extensively employed in regenerative medicine for several decades.However,safety and ethical concerns constrain their clinical application.Tendon Stem/Progenitor Cells(TSPCs)-derived exosomes have emerged as promising cellfree therapeutic agents.Therefore,urgent studies are needed to investigate whether TSPC-Exos could enhance tendon-bone healing and elucidate the underlying mechanisms.In this study,TSPC-Exos were found to promote the proliferation,migration,and expression of fibrogenesis markers in BMSCs.Furthermore,TSPC-Exos demonstrated an ability to suppress the polarization of M1 macrophages while promoting M2 macrophage polarization.In a rat model of rotator cuff repair,TSPC-Exos modulated inflammation and improved the histological structure of the tendon-bone interface,the biomechanical properties of the repaired tendon,and the function of the joint.Mechanistically,TSPC-Exos exhibited high expression of miR-21a-5p,which regulated the expression of PDCD4.The PDCD4/AKT/mTOR axis was implicated in the therapeutic effects of TSPC-Exos on proliferation,migration,and fibrogenesis in BMSCs.This study introduces a novel approach utilizing TSPC-Exos therapy as a promising strategy for cell-free therapies,potentially benefiting patients with rotator cuff tear in the future.

Ethanol changes Nestin-promoter induced neural stem cells to disturb newborn dendritic spine remodeling in the hippocampus of mice

Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.

Bioengineering breakthroughs:The impact of stem cell models on advanced therapy medicinal product development

The burgeoning field of bioengineering has witnessed significant strides due to the advent of stem cell models,particularly in their application in advanced therapy medicinal products(ATMPs).In this review,we examine the multifaceted impact of these developments,emphasizing the potential of stem cell models to enhance the sophistication of ATMPs and to offer alternatives to animal testing.Stem cell-derived tissues are particularly promising because they can reshape the preclinical landscape by providing more physiologically relevant and ethically sound platforms for drug screening and disease modelling.We also discuss the critical challenges of reproducibility and accuracy in measurements to ensure the integrity and utility of stem cell models in research and application.Moreover,this review highlights the imperative of stem cell models to align with regulatory standards,ensuring using stem cells in ATMPs translates into safe and effective clinical therapies.With regulatory approval serving as a gateway to clinical adoption,the collaborative efforts between scientists and regulators are vital for the progression of stem cell applications from bench to bedside.We advocate for a balanced approach that nurtures innovation within the framework of rigorous validation and regulatory compliance,ensuring that stem cell-base solutions are maximized to promote public trust and patient health in ATMPs.

Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury

Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.

Modeling the performance of perovskite solar cells with inserting porous insulating alumina nanoplates

Peng et al.[Science 379683(2023)]reported an effective method to improve the performance of perovskite solar cells by using thicker porous insulator contact(PIC)-alumina nanoplates.This method overcomes the trade-off between the open-circuit voltage and the fill factor through two mechanisms:reduced surface recombination velocity and increased bulk recombination lifetime due to better perovskite crystallinity.From arguments of drift-diffusion simulations,we find that an increase in mobility and carrier recombination lifetime in bulk are the key factors for minimizing the resistance-effect from thicker PICs and achieving a maximum power conversion efficiency(PCE)at approximately 25%reduced contact area.Furthermore,the partially replacement of perovskite films with thicker PICs would result in a reduction in short-current density,but the relative low refractive index of the PICs imbedded into the high refractive index perovskite creates light trapping structures that compensate for this loss.

Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke

It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke.Indeed,previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue.Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke,but its specific role and mechanism are currently unclear.To simulate stroke in vivo,a middle cerebral artery occlusion rat model was established,with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke.We found that in the early stage(within 24 hours)of ischemic stroke,neutrophils produced a large amount of hypochlorous acid,while in the recovery phase(10 days after stroke),microglia were activated and produced a small amount of hypochlorous acid.Further,in acute stroke in rats,hypochlorous acid production was prevented using a hypochlorous acid scavenger,taurine,or myeloperoxidase inhibitor,4-aminobenzoic acid hydrazide.Our results showed that high levels of hypochlorous acid(200μM)induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation.However,in the recovery phase of the middle cerebral artery occlusion model,a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes.This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury.Lower levels of hypochlorous acid(5 and 100μM)promoted nuclear translocation ofβ-catenin.By transfection of single-site mutation plasmids,we found that hypochlorous acid induced chlorination of theβ-catenin tyrosine 30 residue,which promoted nuclear translocation.Altogether,our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Modeling and Simulation of an Organic Photovoltaic Cell: ITO/MoO3/CARAPA/PCBM/Alq3/Al with SCAPS

Renewable energies are of major interest due to their inexhaustible and clean nature, with minimal impact on the environment. Numerous technological pathways exist in this field, each distinguished by the materials used and their implementation principles. However, the cost-efficiency ratio remains a significant challenge for researchers. Currently, organic materials are gaining popularity due to their relatively low cost. However, their performance, particularly in terms of conversion efficiency, still requires improvements. This study focuses on optimizing the organic photovoltaic cell ITO/MoO3/CARAPA/PCBM/Alq3/Al using SCAPS. Several parameters were considered, such as layer thickness, recombination center density, and doping, to improve the cell’s performance. The optimal parameters obtained include an efficiency of 3%, a fill factor of 81.67%, an open-circuit voltage of 1610 mV, and a short-circuit current of 2.28 mA/cm2. The study also revealed that doping the phenyl-C61-butyric acid methyl ester (PCBM) layer has a significant impact on efficiency and short-circuit current, improving these parameters up to a certain point before causing degradation due to increased recombination. Furthermore, high doping of the tri (8-hydroxyquinoline) aluminum (Alq3) layer improves performance up to a critical threshold, after which degradation is also observed. In contrast, doping the molybdenum trioxide (MoO3) layer does not have a notable impact on cell performance. Regarding the thickness of the active Carapaprocera (CARAPA) and PCBM layers, non-optimal values lead to a decrease in performance. Similarly, an optimal thickness of the Alq3 layer significantly improves efficiency. These results highlight the importance of parameter optimization to maximize the efficiency of organic solar cells.

Development of a cell adhesion-based prognostic model for multiple myeloma:Insights into chemotherapy response and potential reversal of adhesion effects

Multiple myeloma(MM)is a hematologic malignancy notorious for its high relapse rate and development of drug resistance,in which cell adhesion-mediated drug resistance plays a critical role.This study integrated four RNA sequencing datasets(CoMMpass,GSE136337,GSE9782,and GSE2658)and focused on analyzing 1706 adhesionrelated genes.Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes,including KIF14,TROAP,FLNA,MSN,LGALS1,PECAM1,and ALCAM,which demonstrated the strongest associations with poor overall survival(OS)in MM patients.To comprehensively evaluate the impact of cell adhesion on MM prognosis,an adhesion-related risk score(ARRS)model was constructed using Lasso Cox regression analysis.The ARRS model emerged as an independent prognostic factor for predicting OS.Furthermore,our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs,protein kinase inhibitors,and drugs targeting the PI3K/Akt/mTOR signaling pathway.Nevertheless,we identified promising drug candidates,such as tirofiban,pirenzepine,erlotinib,and bosutinib,which exhibit potential in reversing this resistance.In vitro,experiments employing NCIH929,RPMI8226,and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs.By employing siRNA-mediated knockdown of the key ARRS model gene KIF14,we observed suppressed proliferation of NCIH929 cells,along with decreased adhesion to BMSCs and fibronectin.This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM.Additionally,potential molecular mechanisms underlying adhesion-related resistance are proposed,along with viable strategies to overcome such resistance.These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

Two-dimensional particle-in-cell modeling of blow-off impulse by X-ray irradiation

Space objects such as spacecraft or missiles may be exposed to intense X-rays in outer space,leading to severe damage.The reinforcement of these objects to reduce the damage caused by X-ray irradiation is a significant concern.The blow-off impulse(BOI)is a crucial physical quantity for investigating material damage induced by X-ray irradiation.However,the accurate calculation of BOI is challenging,particularly for large deformations of materials with complex configurations.In this study,we develop a novel two-dimensional particle-in-cell code,Xablation2D,to calculate BOIs under far-field X-ray irradiation.This significantly reduces the dependence of the numerical simulation on the grid shape.The reliability of this code is verified by simulation results from open-source codes,and the calculated BOIs are consistent with the experimental and analytical results.

Predicting the Prognosis and Immunotherapeutic Response of Triple-Negative Breast Cancer by Constructing a Prognostic Model Based on CD8+T Cell-Related Immune Genes

Objective Triple-negative breast cancer(TNBC)poses a significant challenge for treatment efficacy.CD8+T cells,which are pivotal immune cells,can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology.By leveraging these genes,our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy.Methods Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases.In the initial stage,we identified 67 differentially expressed genes associated with immune response in CD8+T cells.Subsequently,we narrowed our focus to three key genes,namely CXCL13,GBP2,and GZMB,which were used to construct a prognostic model.The accuracy of the model was assessed using the validation set data and receiver operating characteristic(ROC)curves.Furthermore,we employed various methods,including Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway,immune infiltration,and correlation analyses with CD274(PD-L1)to explore the model's predictive efficacy in immunotherapeutic responses.Additionally,we investigated the potential underlying biological pathways that contribute to divergent treatment responses.Results We successfully developed a model capable of predicting the prognosis of patients with TNBC.The areas under the curve(AUC)values for the 1-,3-,and 5-year survival predictions were 0.618,0.652,and 0.826,respectively.Employing this risk model,we stratified the samples into high-and low-risk groups.Through KEGG enrichment analysis,we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism,whereas the low-risk group demonstrated significant enrichment in cytokine pathways.Furthermore,immune landscape analysis revealed noteworthy variations between(PD-L1)expression and risk scores,indicating that our model effectively predicted the response of patients to immune-based treatments.Conclusion Our study demonstrates the potential of CXCL13,GBP2,and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC.These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.

Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and microenvironment.Breast cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and differentiation.Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer.The tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ability.Hence,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis.In this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory mechanisms.Furthermore,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis.Overall,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

Additional comments on extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis

Recently,we read an article published by the Yang et al.The results of this study indicated that engineered exosomes loaded with microRNA-29a(miR-29a)alleviate knee inflammation and maintain extracellular matrix stability in Sprague Dawley rats.The study’s results provide useful information for treating knee osteoarthritis(KOA).This letter,shares our perspectives on treating KOA using engineered exosomes for miR-29a.

Establishing prognostic models for intrahepatic cholangiocarcinoma based on immune cells

BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is a malignant liver tumor that is challenging to treat and manage and current prognostic models for the disease are inefficient or ineffective.Tumor-associated immune cells are critical for tumor development and progression.The main goal of this study was to establish models based on tumor-associated immune cells for predicting the overall survival of patients undergoing surgery for ICC.AIM To establish 1-year and 3-year prognostic models for ICC after surgical resection.METHODS Immunohistochemical staining was performed for CD4,CD8,CD20,pan-cytokeratin(CK),and CD68 in tumors and paired adjacent tissues from 141 patients with ICC who underwent curative surgery.Selection of variables was based on regression diagnostic procedures and goodness-of-fit tests(PH assumption).Clinical parameters and pathological diagnoses,combined with the distribution of immune cells in tumors and paired adjacent tissues,were utilized to establish 1-and 3-year prognostic models.RESULTS This is an important application of immune cells in the tumor microenvironment.CD4,CD8,CD20,and CK were included in the establishment of our prognostic model by stepwise selection,whereas CD68 was not significantly associated with the prognosis of ICC.By integrating clinical data associated with ICC,distinct prognostic models were derived for 1-and 3-year survival outcomes using variable selection.The 1-year prediction model yielded a C-index of 0.7695%confidence interval(95%CI):0.65-0.87 and the 3-year prediction model produced a C-index of 0.69(95%CI:0.65-0.73).Internal validation yielded a C-index of 0.761(95%CI:0.669-0.853)for the 1-year model and 0.693(95%CI:0.642-0.744)for the 3-year model.CONCLUSION We developed Cox regression models for 1-year and 3-year survival predictions of patients with ICC who underwent resection,which has positive implications for establishing a more comprehensive prognostic model for ICC based on tumor immune microenvironment and immune cell changes in the future.

Differential expression of miRNA in THP-1-derived foam cell model induced by drug-containing serum of Yimaijiangzhi decoction

Objective: To investigate the differential expression of miRNA and related biological functions and signaling pathways after the intervention of the THP-1-derived foam cell model with the drug-containing serum of Yimaijiangzhi Decoction. Methods: The experiment was divided into macrophage group, foam cell model group and Yimaijiangzhi drug-containing serum group. THP-1 cells were induced into macrophages by Fopol ester, and induced differentiated macrophages were given ox-LDL to establish foam cell model, and Yimaijiangzhi decoction rat serum was used to intervene the foam cells. Total RNA was extracted from cells in each group for miRNA sequencing, differential expression of miRNA was screened, and relevant target genes were predicted for GO analysis and KEGG analysis, protein interaction network and miRNA-target gene interaction network were established, and RT-qPCR was used to verify the possible signaling pathways for improving atherosclerosis. Result: The difference miRNA between blank group and model group was hsa-miR-302c-3p, hsa-miR-302d-3p, hsa- mir-30d-3p, hsa-mir-3189-3p, hsa-mir-374b-5p, hsa-mir-423-5p, hsa-mir-423-5p, and hsa- mir-4781-3p, hsa-mir-663a;The miRNAs of model group and Yimaijiangzhi drug-containing serum group were hsa-mir-3150a-3p, hsa-mir-7704, hsa-mir-887-3p, hsa-mir-150-5p, hsa- mir-423-5p, hsa-mir-374c-3p, hsa-mir-374c-3p, hsa-mir-374b-5p;The difference of miRNAs prediction target genes between model group and Yimaijiangzhi drug-containing serum group showed that the miRNA prediction target genes were mainly enriched in MAPK signaling pathway, ErbB signaling pathway, Hippo signaling pathway, Wnt signaling pathway and other signaling pathways. SCN1A, PRKACA, MECP2, EIF4E, SRSF1, MBNL1, PRKCA, PPARGC1A may be the potential key targets for the effect of the drug-containing serum of Yimaijiangzhi Decoction on THP-1-derived foam cells. Conclusion: hsa-mir-374c-3p, hsa- mir-423-5p, and hsa-mir-374b-5p are important miRNAs that the drug-containing serum of Yimaijiangzhi Decoction acts on foam cells. The significantly differentially expressed mirnas and significantly enriched related signaling pathways may provide new ideas for the diagnosis and treatment of atherosclerosis.