Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Functions of nuclear factor Y in nervous system development,function and health

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

Risk factors for congenital nasolacrimal duct obstruction in children under two years of age

·AIM:To identify various risk factors that may play a significant role in the development of congenital nasolacrimal duct obstruction(CNLDO).·METHODS:This observational case-control study included a case group of 122 children less than two years of age with CNLDO who underwent probing and irrigation treatment at the ophthalmology department of Imam Khomeini Hospital in Ahvaz,Iran,from June 2022 to June2024.A control group of 122 age-matched children without CNLDO was also included for comparison.Data was collected from the children's medical records.·RESULTS:The study found a significant correlation between the occurrence of CNLDO and several maternal factors,such as preeclampsia,the use of levothyroxine,hypothyroidism,having more than three pregnancies(gravidity>3),natural pregnancy,and gestational diabetes mellitus.Additionally,in children,factors,such as oxygen therapy,anemia,reflux,jaundice,and a family history of CNLDO in first-degree relatives were associated with CNLDO,and maternal preeclampsia and hypothyroidism were found to significantly increase the risk of developing CNLDO in children.·CONCLUSION:Given that CNLDO affects both premature and full-term children,the present findings may potentially facilitate the early identification of children and infants at risk of nasolacrimal duct obstruction,thereby preventing the onset of chronic dacryocystitis.

The effects of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents:a meta-analysis

Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Heat shock transcription factors regulate thermotolerance gene networks in tomato(Solanum lycopersicum)flower buds

Tomato(Solanum lycopersicum)is an important fruit and vegetable crop in worldwide.The fertility of tomato reproductive organs can be dramatically decreased when ambient temperatures rise above 35°C,reducing tomato fruit yield.It is necessary to identify transcription factors(TFs)and target genes involved in heat stress response(HSR)signaling cascades in tomato flower buds to improve tomato plant thermotolerance.In this study,we profiled genes expressed in three developmental stages of tomato flower buds.Red and turquoise modules for heat stress(HS)were identified through gene co-expression network analysis,and the genes within these modules were enriched in HS-related pathways.By focusing on the TFs in the two modules,we identified several novel HSR-related TFs,including SlWRKY75,SlMYB117,and SlNAM.Furthermore,homology analysis illustrated a conserved signaling cascade in tomato.Lastly,we identified and experimentally validated four HSF-regulated genes,namely SlGrpE,SlERDJ3A,SlTIL,and SlPOM1,that likely modulate thermotolerance in plants.These results provide a high-resolution atlas of gene expression during tomato flower bud development under HS conditions,which is a valuable resource for uncovering potential regulatory networks associated with the HSR in tomato.

Evaluation of the prevalence and risk factors of burnout syndrome among healthcare workers:A cross-sectional study

BACKGROUND Burnout syndrome is a significant issue among healthcare professionals worldwide,marked by depersonalization,emotional exhaustion,and a reduced sense of personal achievement.This psychological and physical burden profoundly affects healthcare professionals'quality of care and overall well-being.In Somalia,where the healthcare system faces numerous challenges,the escalating demand for medical services and inadequate resources,coupled with overwhelming workloads,long hours,and high-stress levels,make healthcare providers particularly vulnerable to burnout syndrome.This,in turn,affects both the mental health of healthcare personnel and the quality of care they provide.AIM To examine the prevalence and determinants of burnout syndrome among healthcare practitioners in Mogadishu,Somalia.METHODS This cross-sectional prospective study was performed among 246 healthcare providers employed at a tertiary care hospital in Mogadishu,Somalia,who were recruited via random sampling.Data were collected using questionnaires that covered sociodemographic,psychological,work-related characteristics,and burnout syndrome.Bivariate and multivariate logistic regression analyses were performed to identify the variables that correlated with burnout syndrome.The results were presented using adjusted odds ratios(AORs),95%CIs,and P values,with a cutoff of 0.05 for identifying significant associations.RESULTS Among the participants,24%(95%CI:18.8%–29.8%)exhibited symptoms of burnout syndrome.Factors associated with burnout included female gender(AOR=6.60;95%CI:2.29-19.04),being married(AOR=3.07;95%CI:1.14-8.28),being divorced or widowed(AOR=5.84;95%CI:1.35-25.35),working more than 7 night shifts(AOR=3.19;95%CI:1.30–7.82),having less than 5 years of job experience(AOR=5.28;95%CI:1.29-21.65),experiencing poor sleep quality(AOR=5.29;95%CI:1.88-14.89),and exhibiting depressive(AOR=4.46;95%CI:1.59-12.53)and anxiety symptoms(AOR=7.34;95%CI:2.49-21.60).CONCLUSION This study found that nearly one in four healthcare professionals suffers from burnout syndrome.Improving sleep quality,monitoring,and providing mental health support could enhance their well-being and patient care.

Risk factors,monitoring,and treatment strategies for early recurrence after rectal cancer surgery

Early recurrence(ER)following surgery for rectal cancer is a significant factor impacting patient survival rates.Tsai et al identified age,preoperative neoadjuvant therapy,length of hospital stay,tumour location,and pathological stage as factors influencing the risk of ER.Postoperative monitoring for ER should encompass a thorough medical history review,physical examination,tumour marker testing,and imaging studies.Additionally,noninvasive circulating tumour cell DNA testing can be utilized to predict ER.Treatment strategies may involve radical surgery,radiation therapy,chemotherapy,and immunotherapy.Through a comprehensive analysis of risk factors,the optimization of monitoring methods,and the development of personalized treatment strategies,it is anticipated that both the efficacy of treatment and the quality of life for rectal cancer patients with postoperative recurrence can be significantly improved.

Prognosis in stage II colon cancer:Expanding the horizons of risk factors

we critically review the authors’perspective and analyze the relevance of the results obtained in the original article of clinical research by Liu et al.We consider that additional factors associated with colon cancer progression have recently been described in extensive clinical research,and should be included in this analysis to achieve a more accurate prognosis.These factors include inflammation,gut microbiota composition,immune status and nutritional balance,as they influence the post-surgical survival profile of patients with stage II colorectal cancer.We also address the clinical implementation and limitations of these analyses.Evaluation of the patient´s entire context is essential for selection of the most appropriate therapy.

Parameter changes and influencing factors in sixty patients with interventional surgery for liver cancer diagnoses

BACKGROUND The development of hepatocellular carcinoma(HCC)is influenced by multiple factors.Interventional therapy offers an effective treatment option for patients with unresectable intermediate-to-advanced HCC.Interventional therapy can induce electrocardiographic(ECG)abnormalities that may be associated with liver dysfunction,electrolyte disorders,and cardiac injury.AIM To explore the ECG alterations and determinants following interventional therapy in patients with HCC.METHODS Sixty patients undergoing interventional treatment for liver cancer were selected as study participants.According to the results of the dynamic ECG examination 1 day after surgery,the patients were divided into an abnormal group(n=21)and a nonabnormal group(n=39).With the help of dynamic ECG examination,the ECG parameters were compared and the baseline data of patients was recorded in the two groups.RESULTS The 24 hours QT interval variability,24 hours normal atrial polarization to ventricular polarization(R-R)interval(standard deviation),24 hours consecutive 5 minutes normal R-R interval,and 24 hours continuous 5 minutes normal R-R interval(standard deviation mean)were lower than patients in the nonabnormal group(P<0.05).The logistic analysis showed that age>60 years,liver function grade B,and postoperative body temperature 38°C were risk factors for abnormal dynamic electrocardiogram in patients with liver cancer intervention(P<0.05).CONCLUSION Interventional therapy for HCC can lead to ECG abnormalities,underscoring the clinical need for enhanced cardiac monitoring to mitigate myocardial complications.

Classification and identification of risk factors for type 2 diabetes

The risk factors for type 2 diabetes mellitus(T2DM)have been increasingly researched,but the lack of systematic identification and categorization makes it difficult for clinicians to quickly and accurately access and understand all the risk factors,which are categorized in this paper into five categories:Social determinants,lifestyle,checkable/testable risk factors,history of illness and medication,and other factors,which are discussed in a narrative review.Meanwhile,this paper points out the problems of the current research,helps to improve the systematic categorisation and practicality of T2DM risk factors,and provides a professional research basis for clinical practice and industry decision-making.

Colony-stimulating factor 3 and its receptor promote leukocyte immunoglobulin-like receptor B2 expression and ligands in gastric

BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

Two APETALA2/ETHYLENE RESPONSE FACTORS coordinately with Ca MYC2 positively regulate capsaicinoid biosynthesis in pepper(Capsicum annuum)

The transcriptional cascade and regulatory loop play crucial roles in regulating plant-specialized metabolite biosynthesis.Capsaicinoids are unique to the genus Capsicum and confer a pungent flavor to its fruits.However,the transcriptional regulation of capsaicinoid biosynthesis remains largely unknown.In this study,two AP2/ERF transcription factors(TFs),CaERF102 and CaERF111,were characterized for their role in the capsaicinoid biosynthesis process.Expression analysis of two ERFs and capsaicinoid biosynthetic genes(CBGs)suggested that they were associated with capsaicinoid biosynthesis.Both ERFs encode nuclear-localized proteins and function as transcriptional activators through their C-terminal activation motifs.The two ERF TFs participated in capsaicinoid biosynthesis by directly activating the promoters of key CBGs,and this activation was significantly enhanced when CaMYC2 was co-expressed.Moreover,CaERF102 and CaERF111 were found to interact with CaMYC2.This study helps elucidate the AP2/ERF TF regulatory network that governs capsaicinoid biosynthesis in Capsicum species.

Evaluating risk factors for surgical site infections and the effectiveness of prophylactic antibiotics in patients undergoing laparoscopic cholecystectomy

BACKGROUND Surgical site infections(SSIs)are a significant complication in laparoscopic cholecystectomy(LC),affecting patient outcomes and healthcare costs.AIM To identify risk factors associated with SSIs and evaluate the effectiveness of prophylactic antibiotics in reducing these infections.METHODS A comprehensive retrospective evaluation was conducted on 400 patients who underwent LC from January 2022 to January 2024.Patients were divided into infected(n=36)and non-infected(n=364)groups based on the occurrence of SSIs.Data collected included age,diabetes mellitus status,use of prophylactic antibiotics,and specific surgical complications.Statistical analyses using SPSS(Version 27.0)involved univariate and multivariate logistic regression to determine factors influencing the risk of SSIs.RESULTS The use of prophylactic antibiotics significantly reduced the incidence of SSIs(χ²=68.34,P<0.01).Older age(≥60 years)and comorbidities such as diabetes mellitus were identified as significant risk factors.Surgical complications like insufficient cystic duct stump,gallbladder perforation,and empyema also increased SSI risk.Notably,factors such as intraoperative blood loss and operation time did not significantly impact SSI occurrence.CONCLUSION Prophylactic antibiotics are effective in reducing the risk of SSIs in patients undergoing LC.Age,diabetes mellitus,and certain surgical complications significantly contribute to the risk.Effective management of these risk factors is essential to improve surgical outcomes and reduce the incidence of SSIs.

Influence factors of clinical effects on patients with early gastric cancer:A retrospective study

BACKGROUND Identifying factors that influence non-curative resection(NCR)is critical to optimize treatment strategies and improve patient outcomes in patients with early gastric cancer(EGC).AIM To investigate the factors influencing the NCR of EGC and to evaluate the predictive value of these factors.METHODS The clinical data of 173 patients with EGC admitted between July 2020 and July 2023 were retrospectively collected.According to radical resection criteria,the patients were further divided into curative resection group(n=143)and NCR group(n=30).Clinical information was collected,including surgical method,tumor diameter,tumor site,ulcer formation,depth of invasion,pathological type,and lymph node metastasis.Logistic regression analysis was used to explore the factors affecting non-curable resection.RESULTS Multivariate logistic regression analysis showed that ulcer formation[odds ratio(OR)=3.53;95%confidence interval(CI):1.55-8.01,P=0.003],pathological type(OR=3.73;95%CI:1.60-8.74,P=0.002),tumor diameter(OR=3.15;95%CI:1.40-7.05,P=0.005),tumor location(OR=3.50;95%CI:1.16-10.58,P=0.027),lymph node metastasis(OR=4.40;95%CI:1.83-10.57,P=0.001),and depth of penetration(OR=3.75;95%CI:1.60-8.74,P=0.002)were all risk factors for NCR in EGC patients.Predictive analysis showed varying area under the curve values for factors such as tumor diameter(0.636),tumor location(0.608),ulcer formation(0.652),infiltration depth(0.658),pathological type(0.656),and lymph node metastasis(0.674).CONCLUSION The results suggest that factors such as tumor diameter,tumor location,ulcer formation,depth of invasion,pathological type,and lymph node metastasis increase the risk of NCR in EGC patients.

SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1

BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.

Role of octamer transcription factor 4 in proliferation,migration,drug sensitivity,and stemness maintenance of pancreatic cancer cells

BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.