Nature killer(NK)cells are lymphocytes of the innate immune that play a significant role in aging through direct cell killing and secretion of cytokines.NK cells can delay the occurrence of age-related diseases and prolong lifespan by eliminating senescencent cells.Significant progress has been achieved in the research utilizing NK cells to improve aging.This review aims to summarize that the recent research on the mechanism of NK cells in the context of senescence, as well as the progress made in anti-senescence interventions through animal and clinical studies.Nevertheless, substantial challenges remain for the clinical application of NK cell-based anti-senescence therapies.

Objective:To investigate the effect of oral administration of vitamin D3 on intestinal barrier function in patients after gastric cancer surgery,and to provide a reference for perioperative nutritional therapy in patients with gastric cancer.Methods:The conve-nience sampling method was used to select 80 patients with gastric cancer who were admitted to Department of Gastrointestinal Surgery in a grade A tertiary hospital in Xiamen,China,from June 2021 to May 2023,and the patients were divided into intervention group and control group using a random number table.The patients in the intervention group were given oral administration of vitamin D3 800 IU/d for 14 consecutive days before surgery.ELISA was used to measure the serum levels of 25-hydroxyvitamin D3[25(OH)D3],intestinal barrier indicators(D-lactate,Zonulin),and inflammatory indicators(C-reactive protein,interleukin-6)within 24 hours after admis-sion and on days 1,4,and 7 after surgery,and the changes in these indicators were compared between the two groups.Results:A total of 71 patients were enrolled finally,with 34 in the intervention group and 37 in the control group.On days 1,4,and 7 after surgery,the intervention group had a significantly lower level of D-lactate than the control group(F=3.978,P=0.026;F=9.649,P=0.005;F=4.389,P=0.021).On day 4 after surgery,the intervention group had a significantly lower level of Zonulin than the control group(F=3.198,P=0.035).Conclusion:Oral administration of vitamin D3 before surgery may accelerate the recovery of intestinal barrier function in pa-tients with gastric cancer.

Objective To investigate correlations of peripheral blood inflammatory and immune-related indices with clinicopathological features and prognosis in breast cancer patients.Methods A total of 144 breast cancer patients admitted to the Breast Surgery Department of Maternity and Child Healthcare Hospital of Tongzhou District of Beijing were included in cancer group,44 patients with a-typical breast hyperplasia were included in precancerous lesion group,and 131 patients with breast hyperplasia were included in breast hyperplasia group.The neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),and lymphocyte-to-monocyte ratio(LMR)were compared among the three groups.A three-year follow-up was conducted for prognosis assessment.Based on different NLR,PLR,and LMR levels,the cancer group was divided into low NLR group(＜2.12,67 pa-tients),high NLR group(≥2.12,77 patients),low PLR group(＜133.21,65 patients),high PLR group(≥ 133.21,79 patients),low LMR group(＜5.05,80 patients),and high LMR group(≥5.05,64 patients).The correlations of NLR,PLR,and LMR with clinicopathological features and prognosis in breast cancer patients were analyzed.Results NLR in the cancer group was higher than that in the precancerous lesion group and breast hyperplasia group,the PLR was higher than that in the breast hyperplasia group,and the LMR was lower than that in the breast hyperplasia group(P＜0.05).NLR and PLR in the precancerous lesion group were higher and LMR was lower than those in the breast hyperplasia group(P＜0.05).PLR between patients with different menopa-usal statuses and Ki-67 levels showed statistically significant differences(P＜0.05).LMR between patients with different menopausal status also showed a statistically significant difference(P＜0.05).After a three-year follow-up,5 patients in the cancer group had a poor prognosis and 139 had a good prognosis.Poor prognosis rates between the low NLR and high NLR groups,low PLR and high PLR groups,and low LMR and high LMR groups showed statistically significant differences(P＜0.05).Logistic regression analysis results indicated that increased NLR and PLR were risk factors for poor prognosis in cancer patients,while increased LMR was a protective factor.Conclu-sion Peripheral blood inflammatory and immune-related indicators in breast cancer patients exhibit abnormal changes.Increased NLR and PLR are risk factors for poor prognosis,while increased LMR is a protective factor.

Objectives:This study aims to investigate the incidence,characteristics and clinical outcomes of vagal response(VR)during pulmonary vein isolation(PVI).Methods:A total of 702 patients with nonvalvular atrial fibrillation(AF)who received the first PVI radiofrequency ablation in Central China Fuwai Hospital from January 2022 to December 2023 were consecutively enrolled.PVI was initiated from right superior pulmonary vein(RSPV),followed by other pulmonary veins(PVs).The VR was defined as atrioventricular block(AVB),asystole or a 50%increase in the RR interval.Results:Among 702 patients with AF,380 patients(54.1%)were paroxysmal AF and 322 patients(45.9%)were persistent AF.77 patients(11.0%)developed 81 VR episodes,which were more common in paroxysmal group than in persistent AF group(19.5%vs.0.9%,P<0.001).VR manifestations included 51 sinus arrest(63.0%),26 sinus bradycardia(32.1%),and 4 atrioventricular block(AVB,4.9%).Most VR episodes were observed in the left superior ganglionated plexi(67[82.7%]).Paroxysmal AF(OR=18.667,95%CI:6.638-52.491,P<0.001),body mass index(BMI)≥28.0 kg/m2(OR=2.361,95%CI:1.376-4.051,P=0.002)and left ventricular ejection fraction(LVEF)≥62.0%(OR=1.964,95%CI:1.119-3.447,P=0.019)were independent risk factors of VR.During a mean of(13.0±7.1)months follow up,among paroxysmal AF patients,6 patients(8.1%)with VR and 33 patients(10.8%)without VR experienced AF recurrence(P=0.496).Kaplan-Meier curves estimated that the AF-free survival rate was similar between VR group and non-VR group among paroxysmal AF patients(log-rank P=0.735).Conclusions:The most common sites of VR when initiating PVI from right RSPV occur in left superior ganglionated plexi.Paroxysmal AF,BMI≥28.0 kg/m2 and LVEF≥62.0%are independent risk factors of VR.VR does not affect AF-free survival.

OBJECTIVE To establish a population pharmacokinetic(PopPK)model to predict the PK characteristics of GLS-010 in humans.METHODS Fifty-eight cynomolgus monkeys were used,18 of which were randomly divided into three groups and received a single intravenous infusion of GLS-010 at doses of 2,6,and 18 mg·kg-1,respectively.The rest were randomly assigned to four groups and received multiple intravenous infusions of GLS-010 at doses of 0,5,25,and 100 mg·kg-1,respectively,once a week(quaque week,qw)for five consecutive weeks.Blood samples were collected before and after administration.The concentrations of GLS-010 in the monkey serum were measured using a validated enzyme-linked immunosorbent assay,while those of anti-drug antibodies(ADA)in the cynomolgus monkey serum were determined by ultra-sensitive electrochemiluminescence immunoassay.The PK data on GLS-010 in cynomolgus monkeys was obtained,and the drug-time curves were plotted.A PopPK model was constructed using non-compartmental analysis and evaluated by goodness-of-fit plots and visual predictive checks.The constructed PopPK model was used to predict the PK characteristics in humans,which were finally compared with actual Phase Ⅰ clinical study results for validation.RESULTS The predictive results of the PopPK model were highly consistent with the actual Phase Ⅰ clinical study results.The model was able to predict the human PK characteristics under various dosing regimens,including 1 mg·kg-1 quaque 2 weeks(q2w),4 mg·kg-1(q2w),240 mg(q2w),240 mg(q3w),and 10 mg·kg-1(q2w).The predicted maximum plasma concentrations(Cmax)were 24.8,99.1,85.0,85.0,and 247.8 mg·L-1,respectively,and the AUC0-336h was 4 902.0,20 060.0,17 147.7,22 145.7(AUC0-504h),and 50 817.6 mg·h·L-1,respectively.The safety risks for the corresponding dosing regimens were 47.3,11.6,13.5,10.5,and 4.6,respectively.The predicted receptor occupancy at steady state(ROss)at Cmax,average plasma concentration(Cavg),and minimum plasma concentration(Cmin)were 38.8％,72.7％,69.4％,64.1％and 87.2％,29.1％,63.8％,60.0％,49.8％and 82.1％,21.9％,55.5％,51.3％,36.3％and 76.7％,respectively.CONCLUSION The PopPK model can effectively predict the human PK characteristics under different dosing regimens with high consistency with actual Phase Ⅰ clinical study results,which can serve as an important reference for selection of safe and effective doses for first-in-human research.

Neuronal intranuclear inclusion disease（NIID）is a rare hereditary neurodegenerative disorder that can affect multiple systems. However，it is uncommon for urinary dysfunction to be the initial symptom. This article reports five cases. The five patients began to experience voiding dysfunction such as frequent urination，weak urination，and incomplete urination at the mean ages of 55.4（47 - 65）years old. Four months to twelve years after urinary onset，neurological symptoms such as headache，memory decline，transient loss of consciousness，and unsteady gait began to appear. Four of the five cases had a family history. Brain MRI revealed the “ribbon sign” or “crest sign” in all cases. Skin biopsy revealed eosinophilic inclusions in the cell nuclei，and NOTCH2NLC gene testing identified abnormal GGC mutations. Three of the five patients underwent cystostomy due to secondary hydronephrosis，while the other two received no special treatment. After a follow-up of 18 to 35 months since diagnosis，the patients who underwent cystostomy had normal renal function. Neurological symptoms in all five patients worsened to varying degrees.

Objectives:This study aims to investigate the incidence,characteristics and clinical outcomes of vagal response(VR)during pulmonary vein isolation(PVI).Methods:A total of 702 patients with nonvalvular atrial fibrillation(AF)who received the first PVI radiofrequency ablation in Central China Fuwai Hospital from January 2022 to December 2023 were consecutively enrolled.PVI was initiated from right superior pulmonary vein(RSPV),followed by other pulmonary veins(PVs).The VR was defined as atrioventricular block(AVB),asystole or a 50%increase in the RR interval.Results:Among 702 patients with AF,380 patients(54.1%)were paroxysmal AF and 322 patients(45.9%)were persistent AF.77 patients(11.0%)developed 81 VR episodes,which were more common in paroxysmal group than in persistent AF group(19.5%vs.0.9%,P<0.001).VR manifestations included 51 sinus arrest(63.0%),26 sinus bradycardia(32.1%),and 4 atrioventricular block(AVB,4.9%).Most VR episodes were observed in the left superior ganglionated plexi(67[82.7%]).Paroxysmal AF(OR=18.667,95%CI:6.638-52.491,P<0.001),body mass index(BMI)≥28.0 kg/m2(OR=2.361,95%CI:1.376-4.051,P=0.002)and left ventricular ejection fraction(LVEF)≥62.0%(OR=1.964,95%CI:1.119-3.447,P=0.019)were independent risk factors of VR.During a mean of(13.0±7.1)months follow up,among paroxysmal AF patients,6 patients(8.1%)with VR and 33 patients(10.8%)without VR experienced AF recurrence(P=0.496).Kaplan-Meier curves estimated that the AF-free survival rate was similar between VR group and non-VR group among paroxysmal AF patients(log-rank P=0.735).Conclusions:The most common sites of VR when initiating PVI from right RSPV occur in left superior ganglionated plexi.Paroxysmal AF,BMI≥28.0 kg/m2 and LVEF≥62.0%are independent risk factors of VR.VR does not affect AF-free survival.

Neuronal intranuclear inclusion disease（NIID）is a rare hereditary neurodegenerative disorder that can affect multiple systems. However，it is uncommon for urinary dysfunction to be the initial symptom. This article reports five cases. The five patients began to experience voiding dysfunction such as frequent urination，weak urination，and incomplete urination at the mean ages of 55.4（47 - 65）years old. Four months to twelve years after urinary onset，neurological symptoms such as headache，memory decline，transient loss of consciousness，and unsteady gait began to appear. Four of the five cases had a family history. Brain MRI revealed the “ribbon sign” or “crest sign” in all cases. Skin biopsy revealed eosinophilic inclusions in the cell nuclei，and NOTCH2NLC gene testing identified abnormal GGC mutations. Three of the five patients underwent cystostomy due to secondary hydronephrosis，while the other two received no special treatment. After a follow-up of 18 to 35 months since diagnosis，the patients who underwent cystostomy had normal renal function. Neurological symptoms in all five patients worsened to varying degrees.

OBJECTIVE To establish a population pharmacokinetic(PopPK)model to predict the PK characteristics of GLS-010 in humans.METHODS Fifty-eight cynomolgus monkeys were used,18 of which were randomly divided into three groups and received a single intravenous infusion of GLS-010 at doses of 2,6,and 18 mg·kg-1,respectively.The rest were randomly assigned to four groups and received multiple intravenous infusions of GLS-010 at doses of 0,5,25,and 100 mg·kg-1,respectively,once a week(quaque week,qw)for five consecutive weeks.Blood samples were collected before and after administration.The concentrations of GLS-010 in the monkey serum were measured using a validated enzyme-linked immunosorbent assay,while those of anti-drug antibodies(ADA)in the cynomolgus monkey serum were determined by ultra-sensitive electrochemiluminescence immunoassay.The PK data on GLS-010 in cynomolgus monkeys was obtained,and the drug-time curves were plotted.A PopPK model was constructed using non-compartmental analysis and evaluated by goodness-of-fit plots and visual predictive checks.The constructed PopPK model was used to predict the PK characteristics in humans,which were finally compared with actual Phase Ⅰ clinical study results for validation.RESULTS The predictive results of the PopPK model were highly consistent with the actual Phase Ⅰ clinical study results.The model was able to predict the human PK characteristics under various dosing regimens,including 1 mg·kg-1 quaque 2 weeks(q2w),4 mg·kg-1(q2w),240 mg(q2w),240 mg(q3w),and 10 mg·kg-1(q2w).The predicted maximum plasma concentrations(Cmax)were 24.8,99.1,85.0,85.0,and 247.8 mg·L-1,respectively,and the AUC0-336h was 4 902.0,20 060.0,17 147.7,22 145.7(AUC0-504h),and 50 817.6 mg·h·L-1,respectively.The safety risks for the corresponding dosing regimens were 47.3,11.6,13.5,10.5,and 4.6,respectively.The predicted receptor occupancy at steady state(ROss)at Cmax,average plasma concentration(Cavg),and minimum plasma concentration(Cmin)were 38.8％,72.7％,69.4％,64.1％and 87.2％,29.1％,63.8％,60.0％,49.8％and 82.1％,21.9％,55.5％,51.3％,36.3％and 76.7％,respectively.CONCLUSION The PopPK model can effectively predict the human PK characteristics under different dosing regimens with high consistency with actual Phase Ⅰ clinical study results,which can serve as an important reference for selection of safe and effective doses for first-in-human research.

Nature killer(NK)cells are lymphocytes of the innate immune that play a significant role in aging through direct cell killing and secretion of cytokines.NK cells can delay the occurrence of age-related diseases and prolong lifespan by eliminating senescencent cells.Significant progress has been achieved in the research utilizing NK cells to improve aging.This review aims to summarize that the recent research on the mechanism of NK cells in the context of senescence, as well as the progress made in anti-senescence interventions through animal and clinical studies.Nevertheless, substantial challenges remain for the clinical application of NK cell-based anti-senescence therapies.