Dysregulation of p53 and phosphoinositide (PIPn) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the nucleus to form a PIPn-p53 signalosome that modulates nuclear AKT activation and downstream signaling, thereby influencing cancer cell survival and motility. This review examines recent insights into nuclear PIPn signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIPns interact with p53 to form signalosomes that affect cell motility. We emphasize the critical role of PIPns in stabilizing p53 and activating de novo nuclear AKT signaling, which subsequently modulates key motility-related pathways. Understanding the unique operation and function of the PIPn-p53 signalosome in nuclear phosphatidylinositol 3-kinase (PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.
Humans ; Tumor Suppressor Protein p53/metabolism* ; Signal Transduction ; Cell Movement ; Cell Nucleus/metabolism* ; Phosphatidylinositols/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Animals ; Neoplasms/pathology* ; Phosphatidylinositol 3-Kinases/metabolism*

Objective:To investigate the prevalence and potential classification of symptoms after total knee arthroplasty (TKA) in patients with knee osteoarthritis (KOA), and to analyze the differences in demographic characteristics and surgical data, compare the different potential subgroups, in order to provide a basis for clinical symptom management plans.Methods:This study was a multicenter cross-sectional survey. Through convenience sampling, patients with KOA undergoing TKA in the orthopaedic wards of four tertiary hospitals in Urumqi were selected as the study from November 2023 to February 2024. The study subjects were surveyed using a general information questionnaire, the Visual Analogue Scale (VAS) for pain, the Hospital Anxiety and Depression Scale (HADS), and the Pitts Burgh Sleep Quality Index (PSQI), and the degree of postoperative joint swelling and size of ecchymosis were measured. Latent class analysis was performed using Mplus 8.3 software, and Logistic regression analysis was conducted using SPSS 26.0 software to explore the influencing factors of the latent classes.Results:Totally 337 effective questionnaires were collected, and the recovery rate was 94.7% (337/356), and the age distribution ranged from 47 to 85 (65.19 ± 6.99) years old, with 90 (26.7%) males and 247 (73.3%) females. There were 92.3% (311/337) of TKA patients with postoperative symptom cluster. The symptom cluster of patients with TKA were identified as 3 classes. They were named as "high level pain-psychological disorder group"(12.5%, 39/311), "high bruises-moderate psychological disorders group"(25.4%, 79/311) and "low symptom burden group" (62.1%, 193/311). The results of the unordered multi-class logistic regression analysis showed that age 45-59 years ( OR = 2.367), body mass index 24.0-27.9 kg/m 2 ( OR = 0.207), living with children/parents ( OR = 6.473), and this being the second joint surgery ( OR = 0.040) were the factors influencing the "high level pain-psychological disorders group" (all P<0.05). The factors influencing the "high bruises-moderate psychological disorders group" were living with children/parents ( OR = 4.023), comorbid chronic diseases ( OR = 1.979, 3.842), and intraoperative blood loss ≤100 ml ( OR = 2.342) (all P<0.05). Conclusions:The postoperative symptom cluster of TKA patients have a relatively high incidence, and there is heterogeneity within the symptom cluster, so nurses need to identify at-risk patients early according to the characteristics of different categories and give interventions.

Laryngopharyngeal reflux is an independent disease that affects the quality of life in children,but its pathogenesis is not clear and its diagnostic criteria is not unified.With the reports of laryngopharyngeal reflux continuing to emerge in recent years,this study aims to review the progress in pathogenesis,diagnosis and treatment of laryngopharyngeal reflux in children.

Objective To evaluate the correlation between the types of vertebral artery occlusion and their compensatory hemodynamic changes and posterior circulation ischemia using color Doppler flow imaging combined with transcranial color-coded sonography.Methods From June 2015 to June 2016,A total of 108 patients with vertebral artery occlusion confirmed by vascular sonography,digital subtraction angiography (DSA) or CT angiography (CTA) were enrolled retrospectively.According to the magnetic resonance imaging (MRI)-diffusion weighted imaging (DWI) findings,they were divided into posterior circulation infarction (n=78 in infarction group) and non-posterior circulation infarction (n=30 in TIA group).Color Doppler flow imaging and transcranial color Doppler ultrasonography were used to examine the contralateral vertebral artery extracranial diameter, peak systolic velocity(PSV) and end diastolic velocity(EDV) of bilateral extracranial and intracranial vertebral arteries.The differences of the vertebral artery occlusion types,establishment of collateral circulation and hemodynamic changes of the contralateral vertebral artery were compared between the two groups.Results The patients with single vertebral artery occlusion in the infarction group and TIA group were 69 (88.5%) and 26 (86.7%) respectively;those with bilateral vertebral artery occlusion were 9 (11.5%) and 4 (13.3%) respectively.There was no significant difference in the number of vertebral artery occlusion between the two groups (χ2=0.000,P=1.000).The proportion of patients with vertebral artery occlusion in intracranial segment in the infarction group was higher than that in the TIA group (70.5% [55/78] vs.36.7% (11/30);χ2=10.444,P=0.001).The proportion of patients with the establishment of collateral circulation in the infarction group was lower than that in the TIA group (14.1% [11/78] vs.43.3% (13/30);χ2=10.711,P=0.001).The peak systolic velocity (PSV) and the end diastolic velocity (EDV) of contralateral extracranial vertebral artery in patients with single vertebral artery occlusion in the TIA group were higher than those in the infarction group (65±21 cm/s vs.57±15 cm/s,25±8 cm/s vs.20±7 cm/s,t=2.043 and 2.606 respectively,all P<0.05).Conclusion The establishment of collateral circulation and hemodynamic compensation of the contralateral vertebral artery after vertebral artery occlusion were closely associated with the occurrence of posterior circulation ischemia.

Objective To investigate the diagnostic value of PSV/PSVpop,a new parameter detected by color Doppler ultrasonography,for patients with severe s tenosis (70 ％-99 ％)in superficial femoral artery (SFA).Methods One hundred and eighty-five cases (234 limbs) with SFA stenosis detected by CDU and confirmed by DSA were included in this study.Peak systolic velocity of intra stenotic(PSV),proximal stenotic (PSVpro),and popliteal artery (PSVpop) were measured and recorded respectively.The ratio of PSV/PSVpro,PSV/PSVpop were calculated.Using DSA as the gold standard,the cut off values for the diagnosis of severe stenosis were determined with receiver operating characteristics (ROC) analysis.The efficacy of the above parameters were compared.Results The new parameter PSV/PSVpop≥4 had 96.3％ of sensitivity,91.6％ of specificity,94.4％ of accuracy,95.7％ of positive predictive value,and 91.4％ of negative predictive value and 0.978 of area under the ROC curve(AUC) could define 70％-99％ stenosis of SFA.The AUC of PSV/PSVpop was higher than those of the traditional parameters PSV(0.922) and PSV/ PSVpro(0.920),the difference was statistically significant (P ＜0.01).The AUC of combined parameter PSV/PSVpop + PSV surpassed conventional combined parameter PSV/PSVpro + PSV (0.978 ∶ 0.940,P ＜ 0.05),but had no statistically significant difference with single parameter of PSV/PSVpop (0.978 ∶ 0.978,P ＞ 0.05).Conclusions The diagnostic efficacy of PSV/PSVpop is superior to traditional hemodynamic parameters in the diagnosis of SFA severe stenosis.

AIM:ToinvestigatetheexpressionofFoxp3+regulatoryTcells(Foxp3+Tregs)andprogrammed death receptor 1 (PD1) in gastric cancer tissues and their association with clinicopathological factors and prognosis of the patients.The correlation between the 2 molecules was also analyzed at the same time.METHODS: The tumor sections from 111 gastric cancer patients were stained for Foxp3 and PD1 by the method of immunohistochemistry.The associations of the expression levels of these 2 molecules with clinicopathological factors involved in the disease progression and progno-sis were statistically analyzed .The relationship of their expression was detected.RESULTS:Foxp3 +Tregs and PD1 were expressed in the gastric cancer tissues, and PD1 was expressed in the tumor infiltrating lymphocytes ( TILs) .The expres-sion of Foxp3 and PD1 was correlated with lymph node metastasis, clinicopathological stage and prognosis of gastric cancer patients.The expression of these 2 determinants in the patients with lymph node metastasis and an advanced clinicopatho-logical stage was distinctly higher ( P<0.05 ) .The patients with positive expression of the 2 indexes presented a lower overall survival rate and worse prognosis (P<0.05).A significantly positive correlation between the infiltration of Foxp3 +Tregs and the expression of PD1+TILs was also observed (P<0.01).CONCLUSION:Foxp3 +Tregs and PD1 +TILs co-infiltrate in the gastric cancer tissues, which can be used as biological markers to predict the disease progression and prog-nosis.

Objective To investigate the effects of Xueshuantong injection on levels of inflammatory factors and homocysteine (Hcy) in patients with acute cerebral infarction.Methods 128 patients of acute cerebral infarction who received therapy in the hospital from January 2014 to May 2015 were collected as research objects to retrospectively analyze their clinical materials.According to therapeutic schemes, those patients were divided into control group (n=62) and observation group (n=66).The control group were given conventional treatments, such as anti-platelet aggregation, lipid regulation, maintaining balance of water-electrolyte and acid-base, controlling blood glucose, controlling blood pressure and so on.Besides that, the observation group were given Xueshuantong injection.After two weeks treatment, the curative efficacy, levels of inflammatory factors as high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor α(TNF-α), interleukin 8 (IL-8), Hcy and adverse reactions were compared.Results The total efficacy of observation group was 93.9%, which was statistically higher than that of 80.6%in control group (χ2 =5.166,P=0.023).After treatment, hs-CRP, TNF-α, IL-8 levels in observation group were significantly lower than those in control group (all P<0.05).After one and two weeks treatment, The Hcy level in observation group was statistically lower than that in control group ( all P<0.05 ).The adverse reactions in observation group was 8 cases ( 12.1%), 6 cases ( 9.7%) in control group, with no significant difference between two groups (χ2 =0.196, P =0.658 ). Conclusion Xueshuantong injection is effective in treatment of acute cerebral infarction, which could significantly increase curative efficacy, alleviate inflammatory reaction and reduce level of Hcy with less adverse reactions.

Background Dimethyl sulfoxide(DMSO) is a commonly used adjuvant to promote testing drug solubility to prepare multi-levels testing drug concentrations.DMSO is cell type-dependent cytotoxic and its toxicity can interfere the testing drug evaluation.Determining its safe concentration on commonly used cell types is important for ocular drug development.Objective This study was to determine the minimal toxic concentration of DMSO for in vitro ocular cell lines in a simulated drug screening setting.Methods Retinal pigment epithelial (RPE) cells were isolated from one pigmented rabbit and primarily cultured.Human RPE cell strain (ARPE19),scleral fibroblasts line (S75-Fron),human Müller cell line (MIO-M1),human lens epithelial cell line (HLEC),human choroidal melanoma cell line (OCM-1),human umbilical endothelial cell (HUVEC) and human HeLa cell line (HELA) were cultured.Different concentrations of DMSO (1.6％,1.0％,0.8％,0.4％,0.2％ and 0.1％) were prepared with 160 μl DMSO solution and 9.84 ml RPMI1640 (or DMEM/F12 or DMEM) containing 2％ fetal bovine serum.Different concentrations of DMSO were added in medium for 96 hours,and the and viability (absorbance) of the cells was detected using MTS to evaluate the cytotoxicity of DMSO.Results Rabbit primary RPE cells showed the yellow-green fluorescence for cytokeratin(CK) and HMB45 red fluorescence for S100.The viability of the cells was gradually declined as the increase of DMSO dose,showing significant differences in ARPE19,S75-Fron,HLEC,OCM-1,HUVEC and primary RPE cells (all at P＜0.05),and when DMSO concentrations were ≥ 0.8％,the cell viabilities were significantly lower.But no significant difference was found in MIO-M1 cells among different doses of DMSO (F=0.830,P=0.547).The minimal toxic concentration of DMSO for ARPE19,HUVEC,HELA,HLEC,MIO-M1,OCM-1,primary RPE cells and S75-Fron was 0.8％,0.1％,0.8％,＞1.6％,＞1.6％,0.2％,0.2％,0.2％,respectively,and HUVEC was more sensitive to the cytotoxicity of DMSO (P=0.02),and MIO-M1 was the least sensitive to DMSO (P =0.39).The viability of HUVEC and primary RPE cells went down with the increase of DMSO dose,and S75-Fron viability started to decline in 0.1％ DMSO and then stabilize with the higher concentrations until 1.6％ DMSO at which the viability showed further decline.Conclusions The tolerability of ocular cells in vitro to DMSO varies depending on the cell types.The minimal toxic concentration ranged from 0.1％ to 1.6％.The result suggests that a concurrent DMSO control should be set up along with the testing compound.

Objective:To investigate the effects of 17β-Estradiol (E2) on mesenchymal stem cells (MSC) and to evaluate the effects of MSC treated with E2 on the maturation and function of dendritic cells (DC).Methods: We first isolated and cultured MSC from the human fetal lung.The MSC were treated with E2 for 24 hours at various concentrations ( 10~(-9),10~(-8) and 10~(-7) mol/L).After cell counting,proliferation,adherent ability and immunophenotypes of MSC were detected by flowcytometry.The gene expressions of cytokine (IL-6,TGF-βand VEGF) were measured by RT-PCR.The effects of MSC treated with E2 on the maturation and function of DC were determined.Results:After treated with E2,the proliferation and adherent ability of MSC were increased,while the immunophenotypes of MSC were not affected.When MSCs co-cultured with DC,MSC could inhibit the immuophenotypes and function of DC.However,when DC co-cultured with E2-pretreated MSC,the immunophenotypes (MHC Ⅱ,CD80 and CD86) of DC had been reconstructed.After treated with the high concentration of E2 for 24 hours,MSC secreted lower level of TGF-β than that in the control group,while IL-6 and VEGF expressions were increased compared with those in the control group.Conclusion: Estrogen may alter the immuno-suppressive effects of MSC on DC via modulating the cytokine secretion of MSC.