Role of exosomal circular RNAs as microRNA sponges and potential targeting for suppressing hepatocellular carcinoma growth and progression

In this editorial,we comment on the article by Lyu et al published in the recent issue of the World Journal of Gastroenterology(2023;2219-2840).Hepatocellular carcinoma(HCC)is a frequently encountered and highly aggressive primary liver cancer,which remains the third-commonest cause of cancer-related death despite the current therapeutic modalities.There is urgency in developing novel thera-peutic approaches,such as by manipulating extracellular vesicles,which con-stitute a highly heterogeneous nanoparticle population that contains various cargoes.These cargoes have a pivotal role in cell-to-cell communication and can modify the functional level of the recipient cells via their uptake by other recipient cells.Exosomal non-coding RNAs have particular evolving significance in HCC,such as circular RNAs,which have been found differentially expressed in normal hepatic and HCC tissues.The aberrations in their expression levels have a key role in the HCC development and progression and the overall prognosis.In this editorial,we will shed light on the emerging role of exosomal circular RNAs in HCC development and progression,focusing on the oncogenic or potentially tumor suppressive effect of mesenchymal stem cells-derived exosomal non-coding RNAs.

Overview of the immunological mechanisms in hepatitis B virus reactivation:Implications for disease progression and management strategies

Hepatitis B virus(HBV)reactivation is a clinically significant challenge in disease management.This review explores the immunological mechanisms underlying HBV reactivation,emphasizing disease progression and management.It delves into host immune responses and reactivation’s delicate balance,spanning innate and adaptive immunity.Viral factors’disruption of this balance,as are interac-tions between viral antigens,immune cells,cytokine networks,and immune checkpoint pathways,are examined.Notably,the roles of T cells,natural killer cells,and antigen-presenting cells are discussed,highlighting their influence on disease progression.HBV reactivation’s impact on disease severity,hepatic flares,liver fibrosis progression,and hepatocellular carcinoma is detailed.Management strategies,including anti-viral and immunomodulatory approaches,are critically analyzed.The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation.In conclusion,this compre-hensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation.With a dedicated focus on understanding its implic-ations for disease progression and the prospects of efficient management stra-tegies,this article contributes significantly to the knowledge base.The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches,ultimately enhancing disease management and elevating patient outcomes.The dynamic landscape of management strategies is critically scrutinized,spanning anti-viral and immunomodulatory approaches.The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Imbalance of Circulating Follicular Regulatory and Follicular Helper T Cell Subpopulations Is Associated with Disease Progression and Serum CYFRA 21-1 Levels in Patients with Non-small Cell Lung Cancer

Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.

A multi-platform analysis of human gingival crevicular fluid reveals ferroptosis as a relevant regulated cell death mechanism during the clinical progression of periodontitis

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases,yet its association with progressive periodontitis remains unexplored.To investigate the involvement and significance of ferroptosis in periodontitis progression,we assessed sixteen periodontitis-diagnosed patients.Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid(GCF)collection was performed for further analyses.Clinical metrics,proteomic data,in silico methods,and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis.Subsequent western blot analyses validated key findings.Finally,a single-cell RNA sequencing(scRNA-seq)dataset(GSE164241)for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression.Periodontitis progression was identified as occurring at a faster rate than traditionally thought.GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles.In addition,specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins,including SNCA,CA1,HBB,SLC4A1,and ANK1 was strongly associated with the clinical progression status of periodontitis.Moreover,we found specific proteins-drivers or suppressors-associated with ferroptosis(SNCA,FTH1,HSPB1,CD44,and GCLC),revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis.Additionally,the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis.Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients,which offer new insights into the molecular mechanisms of progressive periodontal disease.These findings may lead to novel diagnostic and therapeutic strategies.

Knee Osteoarthritis Progression after Distal Femur Closing Wedge Osteotomy

Background: Despite the conservative treatment of tibio-femoral osteoarthritis through realignment osteotomies, the rate of total knee replacements following an osteotomy is increasing. The aim of this study was to identify the factors associated with the progression of knee osteoarthritis after a medial closing-wedge distal femoral osteotomy. Methods: Hospital-based observational study on 20 patients who underwent a medial closing-wedge distal femoral osteotomy evaluating the progression of osteoarthritis using the Kellgren and Laurence classification. The Wilcoxon test was used to compare the variation in the progressive stage of the Kellgren and Laurence classification of knee osteoarthritis preoperatively and at the final follow up. Univariate analysis made it possible to determine the factors associated with progression. The final significance threshold for statistical tests was set at 5% (p Results: Overall, the mean follow-up of 46 months ± 6.6 months, with a mean age of 43 years (range: 27 - 69 years) and a female predominance (M: F = 3/7). The progression of tibiofemoral osteoarthritis following a medial closing-wedge distal femoral osteotomy is associated with valgus or varum malalignment been a moderate valgus (OR 6.2 [1.5 - 42.7] at 95% CI;p-value = 0.02), a correction of the mechanical deviation angle with a valgus alignment (OR 2.7 [0.9 - 8.3] at 95% CI), and loss of correction (OR 3.8 [1.3 - 11.6] at 95% CI;p -value) for the lateral compartment while varus alignment (OR 1.7 [0.9 - 8.3] 95% CI, p-value = 0.05) and with rupture of the lateral cortex (OR 2.8 [1.7 - 11.5] 95% CI, p-value = 0.02) were those of the medial compartment. Conclusion: Distal femur closing wedge osteotomy does not definitively interrupt the progression of valgus knee osteoarthritis. The factors associated with the progression of this pathology are modifiable. Taking them into account when performing this surgical technique could improve the osteotomy survival curve.

The current role of dendritic cells in the progression and treatment of colorectal cancer

Colorectal cancer(CRC)is the third most common cancer and the second leading cause of cancer-related deaths worldwide.Dendritic cells(DCs)constitute a heterogeneous group of antigen-presenting cells that are important for initiating and regulating both innate and adaptive immune responses.As a crucial component of the immune system,DCs have a pivotal role in the pathogenesis and clinical treatment of CRC.DCs cross-present tumor-related antigens to activate T cells and trigger an antitumor immune response.However,the antitumor immune function of DCs is impaired and immune tolerance is promoted due to the presence of the tumor microenvironment.This review systematically elucidates the specific characteristics and functions of different DC subsets,as well as the role that DCs play in the immune response and tolerance within the CRC microenvironment.Moreover,how DCs contribute to the progression of CRC and potential therapies to enhance antitumor immunity on the basis of existing data are also discussed,which will provide new perspectives and approaches for immunotherapy in patients with CRC.

PRSS50-mediated inhibition of MKP3/ERK signaling is crucial for meiotic progression and sperm quality

Serine protease 50(PRSS50/TSP50)is highly expressed in spermatocytes.Our study investigated its role in testicular development and spermatogenesis.Initially,PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes.To further explore this,we generated PRSS50 knockout(Prss50^(−/−))mice(Mus musculus),which exhibited abnormal spermatid nuclear compression and reduced male fertility.Furthermore,dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50^(−/−)mice,accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells.Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2(ERK1/2)and elevated levels of MAP kinase phosphatase 3(MKP3),a specific ERK antagonist,potentially accounting for testicular dysplasia in adolescent Prss50−/−mice.Taken together,these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis,with the MKP3/ERK signaling pathway playing a significant role in this process.

Psychological stress impact neurotrophic factor levels in patients with androgenetic alopecia and correlated with disease progression

BACKGROUND Androgenetic alopecia(AGA)is a common form of hair loss that can be influenced by psychological factors.AIM To investigate the impact of mental stress on neurotrophic factors in patients with AGA and correlate the findings with the progression of AGA.METHODS A total of 120 patients with AGA were analyzed in this study,which were divided into a non-stress group(n=30)and a stress group(n=90)on the basis of the presence or absence of psychological stress confirmed by Depression Anxiety Stress Scale-21 scale.The baseline demographic characteristics,serum cortisol levels,hair growth parameters,neurotrophic factors,and AGA progression scores between the non-stress and stress groups were compared.Correlation analyses were conducted to assess the relationships among stress,neurotrophic factors,hair loss progression,and AGA progression.RESULTS This study revealed significantly higher cortisol levels throughout the day in the stress group than in the non-stress group.The stress group exhibited lower levels of nerve growth factor,brain-derived neurotrophic factor,and glial cell linederived neurotrophic factor and higher expression levels of neurotrophin(NT)-3 and NT-4 than the non-stress group.Hair parameters indicated lower hair diameter,decreased hair density,and more severe AGA grading in the stress group,whereas follicle count and terminal/vellus hair ratio showed no significant differences between the two groups.After 1 year of treatment with 5%minoxidil,efficacy was observed to be lower but AGA progression was notably more pronounced in the stress group than in the non-stress group.Disease progression was positively correlated with high stress and NT-4 levels.CONCLUSION This study provides compelling evidence of the influence of mental stress on neurotrophic factors and its correlation with the progression of AGA.The findings underscore the need for a comprehensive approach to the management of AGA that considers the physiological and psychosocial aspects.Further research is warranted to validate the findings and explore targeted therapeutic interventions for individuals with stress-related AGA.

Deep learning model based on PET/CT and combination with Cox proportional hazard model for predicting progression of lung invasive adenocarcinoma after surgery

Objective To observe the efficacy of deep learning(DL)model based on PET/CT and its combination with Cox proportional hazard model for predicting progressive disease(PD)of lung invasive adenocarcinoma within 5 years after surgery.Methods The clinical,PET/CT and 5-year follow-up data of 250 patients with lung invasive adenocarcinoma were retrospectively analyzed.According to PD or not,the patients were divided into the PD group(n=71)and non-PD group(n=179).The basic data and PET/CT findings were compared between groups,among which the quantitative variables being significant different between groups were transformed to categorical variables using receiver operating characteristic(ROC)curve and corresponding cut-off value.Multivariant Cox proportional hazard model was used to select independent predicting factors of PD of lung invasive adenocarcinoma within 5 years after surgery.The patients were divided into training,validation and test sets at the ratio of 6∶2∶2,and PET/CT data in training set and validation set were used to train model and tuning parameters to build the PET/CT DL model,and the combination model was built in serial connection of DL model and the predictive factors.In test set,the efficacy of each model for predicting PD of lung invasive adenocarcinoma within 5 years after surgery was assessed and compared using the area under the curve(AUC).Results Patients'gender and smoking status,as well as the long diameter,SUV max and SUV mean of lesions measured on PET images,the long diameter,short diameter and type of lesions showed on CT were statistically different between groups(all P<0.05).Smoking(HR=1.787[1.053,3.031],P=0.031)and lesion SUV max>4.15(HR=5.249[1.062,25.945],P=0.042)were both predictors of PD of lung invasive adenocarcinoma within 5 years after surgery.In test set,the AUC of PET/CT DL model for predicting PD was 0.847,of the combination model was 0.890,of the latter was higher than of the former(P=0.036).Conclusion DL model based on PET/CT had high efficacy for predicting PD of lung invasive adenocarcinoma within 5 years after surgery.Combining with Cox proportional hazard model could further improve its predicting efficacy.

Resilience provides mediating effect of resilience between fear of progression and sleep quality in patients with hematological malignancies

BACKGROUND Hematological tumors are common malignant tumors,with high morbidity and mortality rates.Most patients with hematological malignancies develop sleep disorders that seriously affect their life and health because of acute onset of disease,rapid progression,high recurrence rates,complex treatment methods,and treatment costs.AIM To explore the mediating effect of resilience on fear of disease progression and sleep quality in patients with hematological malignancies.METHODS A cross-sectional analysis of 100 patients with hematological malignancies,treated in the First Affiliated Hospital of Jinzhou Medical University between August 2022 and August 2023,was conducted.Patients were assessed using a general data survey,a simplified scale for the fear of progression(FoP)of disease,a resilience scale,and the Pittsburgh Sleep Quality Index.Statistical analysis was conducted to determine the relationship between various patient characteristics and FoP,resilience,and sleep quality.Spearman’s correlation analysis was used to examine the correlations between mental resilience,FoP,and sleep quality.RESULTS The total FoP score mean value in patients with hematological malignancies was 38.09±5.16;the total resilience score mean value was 40.73±7.04;and the Pittsburgh Sleep Quality Index score mean value was 10.72±1.90.FoP,resilience,and sleep quality of the patients were associated with family per capita monthly income and patient education level(P<0.05).Spearman correlation analysis revealed that FoP was negatively correlated with resilience and sleep quality scores(r=-0.560,-0.537,P<0.01),respectively,and resilience was significantly associated with sleep quality scores(r=0.688,P<0.01).Mediation analysis showed that the mediating effect of resilience between FoP and sleep quality in patients with hematological malignancies was-0.100 and accounted for 50.51%of the total effect.This indicated that FoP directly and indirectly affected sleep quality through the mesomeric effect of resilience.CONCLUSION Resilience is an intermediary variable between FoP and sleep quality in patients with hematological malignancies.Medical staff should evaluate and follow-up FoP and resilience to implement measures to improve sleep quality.

Correlation among anxiety and depression,fear of disease progression,and social support in coronary heart disease

BACKGROUND The mental well-being of individuals with coronary heart disease(CHD)during the intensive care unit(ICU)transition period is a multifaceted and significant concern.In this phase,the individuals might encounter psychological challenges like anxiety and depression,which can impede their recuperation and potentially have lasting effects on their health.AIM To investigate the correlation among psychological factors in CHD patients in the ICU transition period.METHODS A questionnaire survey was conducted with 119 patients admitted to the ICU after coronary artery bypass grafting between March and December 2023.Variations in Hamilton Anxiety Scale(HAMA)and Hamilton Depression Scale(HAMD),Fear of Progression Questionnaire-Short Form(Fop-Q-SF),and Social Support Rating Scale(SSRS)were collected and analyzed among diverse populations.We used Pearson’s correlation analysis to examine the correlation.Multiple linear regression analysis was used to explore whether these indicators influenced depression and anxiety in the patients.RESULTS The total scores for anxiety,depression,fear of disease progression,and social support were(7.50±1.41)points,(8.38±1.62)points,(35.19±8.14)points,and(36.34±7.08)points,respectively(P<0.05).Multivariate regression analysis showed that both the level of disease progression and social support affected the level of postoperative depression and anxiety in patients.CONCLUSION The anxiety and depression levels were positively related to each dimension of phobia disease progression and negatively related to each dimension of social support among patients with CHD.

Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.

A Study on the Learning Progressions of Understanding the Core Concepts of Kinetic Energy in High School

Learning progressions divide the logical system of a subject into ordered and continuously developing levels that are suitable for the cognitive development level of students,which plays an important role in understanding students’learning process.This paper focuses on the theme of“kinetic energy”in high school physics as the research object.Firstly,the concept map was used to represent the relationship between knowledge,and then five core concepts were selected based on the opinions of high school teachers.Secondly,the test tools were compiled and tested based on the relevant test questions.Finally,the paper analyzed the results based on the Rasch model,clarified students’cognitive development level of“kinetic energy”and constructed the learning progressions of“kinetic energy”based on the logical order of subject knowledge.The research provides theoretical and methodological support for the study of other subjects and learning progressions,and provides a valuable reference for high school teachers to effectively carry out the instruction of“kinetic energy.”

Roles of Mutant TP53 Gene in Cancer Development and Progression

TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research.p53 plays a critical role in regulating the expression of target genes and is involved in key processes such as apoptosis,cell cycle regulation,and genomic stability,earning it the title“guardian of the genome.”Numerous studies have demonstrated p53’s influence on and regulation of autophagy,ferroptosis,the tumor microenvironment,and cell metabolism,all of which contribute to tumor suppression.Alterations in p53,specifically mutant p53(mutp53),not only impair its tumor-suppressing functions but also enhance oncogenic characteristics.Recent data indicate that mutp53 is strongly associated with poor prognosis and advanced cancers,making it an ideal target for the development of novel cancer therapies.This review summarizes the post-translational modifications of p53,the mechanisms of mutp53 accumulation,and its gain-of-function,based on previous findings.Additionally,this review discusses its impact on metabolic homeostasis,ferroptosis,genomic instability,the tumor microenvironment,and cancer stem cells,and highlights recent advancements in mutp53 research.

Mediating role of fear of progression between sensory processing sensitivity and stigma in lung cancer patients:a cross-sectional study

Objective:To explore the association of sensory processing sensitivity(SPS)and stigma as well as the mediating role of fear of progression(FoP)in lung cancer patients.Methods:Two hundred and forty-two lung cancer patients completed a self-reported questionnaire,which included the highly sensitive person scale(HSPS),fear of progression questionnaire-short form(FoP-Q-SF),and the Cataldo Lung Cancer Stigma Scale(CLCSS).Results:CLCSS was positively correlated with FoP(Pearson correlation=0.217,P<0.01)and HSPS(Pearson correlation=0.187,P<0.01),FoP was positively correlated with HSPS(Pearson correlation=0.199,P<0.01).FoP played a mediating role between SPS and stigma(a×b=0.025,95%confidence intervals[CI][0.004,0.054]),and the proportion of mediating effect(ab/c)was 21%(ab=0.025,c=0.120).Conclusions:Patients with higher SPS reported higher level of stigma,and FoP has a mediating role between SPS and stigma.Our discussion deemed that psychological intervention may help higher SPS patients reduce the harm of FoP and further reduce stigma.

Variant rs8400 enhances ALKBH5 expression through disrupting miR-186 binding and promotes neuroblastoma progression

Objective:AlkB homolog 5(ALKBH5)has been proven to be closely related to tumors.However,the role and molecular mechanism of ALKBH5 in neuroblastomas have rarely been reported.Methods:The potential functional single-nucleotide polymorphisms(SNPs)in ALKBH5 were identified by National Center for Biotechnology Information(NCBI)dbSNP screening and SNPinfo software.TaqMan probes were used for genotyping.A multiple logistic regression model was used to evaluate the effects of different SNP loci on the risk of neuroblastoma.The expression of ALKBH5 in neuroblastoma was evaluated by Western blotting and immunohistochemistry(IHC).Cell counting kit-8(CCK-8),plate colony formation and 5-ethynyl-2'-deoxyuridine(EdU)incorporation assays were used to evaluate cell proliferation.Wound healing and Transwell assays were used to compare cell migration and invasion.Thermodynamic modelling was performed to predict the ability of miRNAs to bind to ALKBH5 with the rs8400 G/A polymorphism.RNA sequencing,N6-methyladenosine(mA)sequencing,mA methylated RNA immunoprecipitation(MeRIP)and a luciferase assay were used to identify the targeting effect of ALKBH5 on SPP1.Results:ALKBH5 was highly expressed in neuroblastoma.Knocking down ALKBH5 inhibited the proliferation,migration and invasion of cancer cells.miR-186-3p negatively regulates the expression of ALKBH5,and this ability is affected by the rs8400 polymorphism.When the G nucleotide was mutated to A,the ability of miR-186-3p to bind to the 3'-UTR of ALKBH5 decreased,resulting in upregulation of ALKBH5.SPPI is the downstream target gene of the ALKBH5 oncogene.Knocking down SPP1 partially restored the inhibitory effect of ALKBH5 downregulation on neuroblastoma.Downregulation of ALKBH5 can improve the therapeutic efficacy of carboplatin and etoposide in neuroblastoma.Conclusions:We first found that the rs8400 G>A polymorphism in the m6A demethylase-encoding gene ALKBH5 increases neuroblastoma susceptibility and determines the related mechanisms.The aberrant regulation of ALKBH5 by miR-186-3p caused by this genetic variation in ALKBH5 promotes the occurrence and development of neuroblastoma through the ALKBH5-SPP1 axis.

A Comparative Study on the Post-Buckling Behavior of Reinforced Thermoplastic Pipes(RTPs)Under External Pressure Considering Progressive Failure

The collapse pressure is a key parameter when RTPs are applied in harsh deep-water environments.To investigate the collapse of RTPs,numerical simulations and hydrostatic pressure tests are conducted.For the numerical simulations,the eigenvalue analysis and Riks analysis are combined,in which the Hashin failure criterion and fracture energy stiffness degradation model are used to simulate the progressive failure of composites,and the“infinite”boundary conditions are applied to eliminate the boundary effects.As for the hydrostatic pressure tests,RTP specimens were placed in a hydrostatic chamber after filled with water.It has been observed that the cross-section of the middle part collapses when it reaches the maximum pressure.The collapse pressure obtained from the numerical simulations agrees well with that in the experiment.Meanwhile,the applicability of NASA SP-8007 formula on the collapse pressure prediction was also discussed.It has a relatively greater difference because of the ignorance of the progressive failure of composites.For the parametric study,it is found that RTPs have much higher first-ply-failure pressure when the winding angles are between 50°and 70°.Besides,the effect of debonding and initial ovality,and the contribution of the liner and coating are also discussed.

Progress in the generation of spinal cord organoids over the past decade and future perspectives

Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.

Alternative polyadenylation events in epithelial cells sense endometritis progression in dairy cows

Endometritis(inflammation of the endometrial lining) is one of the most devastating reproductive diseases in dairy cattle, resulting in substantial production loss and causing more than $650 million in lost revenue annually in the USA.We hypothesize that alternative polyadenylation(APA) sites serve as decisive sensors for endometrium health and disease in dairy cows. Endometrial cells collected from 18 cows with purulent vaginal discharge scored 0 to 2 were used for APA profiling with our whole transcriptome termini site sequencing(WTTS-seq) method. Overall, pathogens trigger hosts to use more differentially expressed APA(DE-APA), more intronic DE-APA, more DE-APA sites per gene and more DE-genes associated with inflammation. Host CD59 molecule(CD59), Fc fragment of IgG receptor IIa(FCGR2A), lymphocyte antigen 75(LY75) and plasminogen(PLG) may serve as initial contacts or combats with pathogens on cell surface, followed by activation of nuclear receptor subfamily 1 group H member 4(NR1H4) to regulate AXL receptor tyrosine kinase(AXL), FGR proto-oncogene, Src family tyrosine kinase(FGR), HCK protooncogene, Src family tyrosine kinase(HCK) and integrin subunit beta 2(ITGB2) for anti-inflammation. This study is the first to show significance of cilium pathways in endometrium health and animal reproduction. MIR21 and MIR30A would be perfect antagonistic biomarkers for diagnosis of either inflammation or anti-inflammation. These novel findings will set precedent for future genomic studies to aid the dairy industry develop new strategies to reduce endometritis incidence and improve fertility.