Objective To explore the clinical efficacy of the"S.L.O.T.S."(Separate,Loop,Observe,Tension,Sign)three-layer five-step method for preserving testicular artery in microsurgical subinguinal varicocelectomy.Methods Clinical data of 190 patients with varicocele in our hospital from March 2020 to September 2022 were retrospectively analyzed.A total of 97 cases underwent"S.L.O.T.S."three-layer five-step method with preservation of testicular artery in microsurgical subinguinal varicocelectomy(microscopic group),and 93 cases underwent laparoscopic spermatic vein bundle ligation(laparoscopic group).The semen quality and postoperative complications of the two groups were compared before and after surgery.Results The laparoscopic group had significantly shorter operation time[(32.2±7.3)min vs.(65.1±8.3)min,t=28.959,P=0.000]compared to the microscopic group.The proportion of postoperative secondary hydrocele[1.0％(1/97)vs.8.6％(8/93),x2=4.470,P=0.034].epididymitis[2.1％(2/97)vs.9.7％(9/93),x2=5.049,P=0.025].and total complications[3.1％(3/97)vs.21.5％(20/93),x2=15.128,P=0.000]in the microscopic group were significantly lower than those in the laparoscopic group.The indicators of semen quality such as total number of sperm[(53.3±5.8)× 106 vs.(50.4±4.9)× 106,t=3.676,P=0.000].sperm concentration[(19.6±2.2)× 106/ml vs.(18.1±2.4)×106/ml,t=4.418,P=0.000].rate of sperm anterior motility[(46.1±5.6)％vs.(41.5±4.1)％,t=6.476,P=0.000].total sperm motility[(55.7±4.9)％vs.(51.2±3.8)％,t=7.115,P=0.000].and percentage of normal sperm[(9.0±1.7)％vs.(7.6±1.6)％,t=5.550,P=0.000]were significantly better in the microscopic group than those in the laparoscopic group.Conclusion "S.L.O.T.S."three-layer five-step method has advantages of programmed surgical steps,and effective identification and preservation of testicular arteries and lymphatic vessels,which is beneficial for improving semen quality and reducing postoperative complications such as secondary hydrocele and epididymitis.

Objective:To evaluate the short-term efficacy of endoscopic-laparoscopic regional gastric resection combined with sentinel lymph node basin dissection in patients with early-stage gastric cancer.Methods:This is a retrospective case series study. Data of 17 consecutive early gastric cancer patients from a prospective cohort at Beijing Friendship Hospital,Capital Medical University were analyzed between August 2023 and August 2024. Sixteen cases were from the department of general surgery and 1 from the department of gastroenterology. The cohort included 9 males and 8 females,with a mean age of 61.4 years (range: 46 to 79 years). Clinical data,including demographics,pathological features,surgical procedures,and follow-up outcomes,were collected through medical records and databases. All patients were followed for over 3 months,with follow-up ending on December 5,2024.Results:A total of 17 patients were involved. Among them, 5 patients underwent endoscopic submucosal dissection (ESD) combined with laparoscopic sentinel lymph node dissection (LSBD),and another 3 patients who underwent complete ESD resection received LSBD due to pathological stage meeting the expanded indications. 6 patients who underwent non-curative ESD resection received laparoscopic gastric regional resection (LRG) combined with LSBD,and another 3 patients directly received LRG combined with LSBD. The average number of sentinel lymph nodes dissected before surgery ( M(IQR)) was 8.9 (4.5) (range: 4 to 21),and the detection rate and accuracy rate were both 100%. Postoperative pathology confirmed that there was no metastasis in the sentinel lymph nodes of 5 patients who underwent ESD combined with LSBD and 3 patients who underwent LSBD after complete ESD resection. The vertical and horizontal margins of ESD were all negative. One patient was an absolute indication for ESD. For the 6 patients who underwent non-curative ESD resection combined with LRG and LSBD,the horizontal margins were all negative. Two patients showed 1 metastasis in each of the 21 and 9 sentinel lymph nodes during the operation,and additional distal gastrectomy was performed during the operation. Postoperatively,73 and 39 lymph nodes were retrieved respectively. The former had 1 additional metastasis,while the latter had no metastasis. Among the 3 patients who underwent direct LRG combined with LSBD,the horizontal margins were negative. One patient was confirmed as an absolute indication for ESD by postoperative pathology,and one patient had 1 metastasis in 8 sentinel lymph nodes during the operation,and additional distal gastrectomy was performed. Postoperatively,there was no metastasis in 54 lymph nodes. All patients had no complications such as infection,bleeding,perforation,or death after surgery. Among the 14 patients who did not receive additional radical surgery,they were able to pass gas and defecate within 3 days after surgery,with an average hospital stay of 6 days. The nutritional indicators and gastric radionuclide emptying imaging half-emptying time were similar to those before surgery at 3 months after surgery. Conclusions:Laparoscopic and endoscopic cooperative regional gastrectomy with sentinel lymph node basin dissection has the advantages of minimal invasiveness,preservation of gastric function,and precise treatment. It maybe suitable for patients with early-stage gastric cancer at high risk of lymph node metastasis and has good short-term efficacy.

Malignant tumors represent a major global public health challenge,necessitating urgent innovation in diagnostic and therapeutic strategies.Lactate,a key metabolic product of tumor cell glycolysis,functions not merely as an energy metabolite but also as a signaling molecule to regulate malignant progression.Lactate mediates intercellular metabolite distribution through monocarboxylate transporter(MCT)-driven lactate shuttling and regulates epigenetics via histone lactylation.This integration establishes interconnected networks of energy,amino acid,and lipid metabolism that enhance tumor metabolic plasticity.In immune regulation,lactate induces a shift of T cells toward immunosuppressive phenotypes,impedes CD8+T cell memory differentiation,and attenuates cytotoxicity.Simultaneously,lactate not only reduces the immune efficacy of natural killer(NK)cells but also triggers apoptosis by inducing mitochondrial dysfunction,creating an immune-privileged niche for metastatic sites.Furthermore,elevated lactate levels activate multiple signaling pathways to recruit macrophages and drive their polarization toward the M2 phenotype,fostering an immunosuppressive microenvironment.Current therapeutic strategies target key aspects of lactate metabolism.Inhibiting lactate synthesis reduces lactate accumulation in tumor microenvironment(TME),countering the tumor's metabolic advantage and diminishing its role in driving metabolic reprogramming.Additionally,promoting the decomposition of lactate represents a promising new direction.Novel agents employing bioenzymes or biomimetic catalytic systems enhance local lactate clearance,alleviating the immunosuppressive effects of the acidic TME.This review comprehensively outlined the lactate-mediated regulatory network,aiming to provide systematic research directions and translational insights for developing more effective anti-tumor therapies.

Objective To investigate the mechanism by which Yangmai Tongluo formula improves microcirculation disorders induced by high homocysteine(Hcy)levels via regulation of the acid sphingomyelinase(ASM)and endoplasmic reticulum(ER)stress pathways.Methods Fifty male C57BL/6J mice were divided randomly into a control group,Hcy model group,Yangmai Tongluo formula low-/high dose groups(5.3,10.4 g/kg,respectively),and a folic acid group(0.08 g/kg).Except for the control group,microcirculation disorders were induced in all mice using drinking water containing 1.8 g/L Hcy for 6 weeks.After modeling for 2 weeks,mice were administered the corresponding treatments by gavage for 4 weeks.Serum Hey concentrations and the blood perfusion volume of the lower extremity microvessels were measured.Protein expression levels of zonula occludens ZO-1,ZO-2,intercellular adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),ASM,glucose-regulated protein 78(GRP78),and C/EBP homologous protein(CHOP)in the cardiac microvascular endothelium were analyzed using immunofluorescence.Results Serum Hcy levels were significantly increased in the Hcy model group compared with the control group(P＜0.05).Yangmai Tongluo formula did not significantly reduce Hey levels compared with the Hey model group,but blood perfusion in the lower extremities was significantly increased(P＜0.01)and expression levels of ZO-1 and ZO-2 in the cardiac microvascular endothelium were restored(P＜0.001)in the Yangmai Tongluo formula high dose group.It also inhibited the expression of ICAM-1,VCAM-1,ASM,GRP78,and CHOP(P＜0.05),with comparable effects to folic acid.Conclusions Yangmai Tongluo formula improves Hcy-induced microcirculation disorders and endothelial dysfunction by inhibiting ASM activity and alleviating ER stress,via a mechanism closely related to the regulation of endothelial inflammation and barrier stability.These result provide experimental evidence to support the use of traditional Chinese medicine to treat microvascular diseases.

Objective To construct a uricase-deficient mouse model with stable inheritance using the CRISPR/Cas9 system,and evaluate its ability to simulate the disease characteristics of patients with hyperuricemia.Methods Double single guide RNAs(sgRNAs)were designed on both sides of exon 2～4 of the Uox gene.sgRNA and Cas9 mRNA for gene knockout were microinjected into the fertilized eggs of mice.After culture for 2～4 h,the embryos were transferred to surrogate mother mice to produce an F0 generation.Uox-knockout mice were identified by polymerase chain reaction and sequencing analysis.Positive mice were then mated with wild-type(WT)mice to produce an F1 generation,and heterozygous female and male F1 mice were then selected to obtain homozygous F2 mice.Serum and urine levels of uric acid,creatinine,and urea,and serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected and compared between homozygous and wild-type mice.Pathological changes in kidney and liver tissues were observed by hematoxylin and eosin and Masson staining.Results Urine levels of serum uric acid(male:(4116.8±1928.1)μmol/L,P＜0.001;female:(2998.0±547.7)μmol/L,P＜0.01)and serum levels of uric acid(male:(478.4±114.6)μmol/L,P＜0.001;female:(507.7±129.6)μmol/L,P＜0.001),creatinine((91.8±55.6)μmol/L,P＜0.001),urea((28.6±13.9)mmol/L,P＜0.05),ALT((53.3±23.3)U/L,P＜0.01),and AST((203.3±70.3)U/L,P＜0.001)were significantly increased in Uox-/-mice compared with WT mice.Histopathological examination showed moderate hepatocyte degeneration in the liver,moderate-to-severe tubular cystic dilation,degeneration,and fibrosis in the kidney,glomerular hypertrophy and hyperplasia,small-vessel dilation and congestion,and infiltration of stromal monocytes and lymphocytes in Uox-/-mice.Conclusions We successfully established a homozygous uricase-deficient mouse strain using CRISPR/Cas9 technology,as a suitable animal model for research in the field of hyperuricemia.

Objective To construct a uricase-deficient mouse model with stable inheritance using the CRISPR/Cas9 system,and evaluate its ability to simulate the disease characteristics of patients with hyperuricemia.Methods Double single guide RNAs(sgRNAs)were designed on both sides of exon 2～4 of the Uox gene.sgRNA and Cas9 mRNA for gene knockout were microinjected into the fertilized eggs of mice.After culture for 2～4 h,the embryos were transferred to surrogate mother mice to produce an F0 generation.Uox-knockout mice were identified by polymerase chain reaction and sequencing analysis.Positive mice were then mated with wild-type(WT)mice to produce an F1 generation,and heterozygous female and male F1 mice were then selected to obtain homozygous F2 mice.Serum and urine levels of uric acid,creatinine,and urea,and serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected and compared between homozygous and wild-type mice.Pathological changes in kidney and liver tissues were observed by hematoxylin and eosin and Masson staining.Results Urine levels of serum uric acid(male:(4116.8±1928.1)μmol/L,P＜0.001;female:(2998.0±547.7)μmol/L,P＜0.01)and serum levels of uric acid(male:(478.4±114.6)μmol/L,P＜0.001;female:(507.7±129.6)μmol/L,P＜0.001),creatinine((91.8±55.6)μmol/L,P＜0.001),urea((28.6±13.9)mmol/L,P＜0.05),ALT((53.3±23.3)U/L,P＜0.01),and AST((203.3±70.3)U/L,P＜0.001)were significantly increased in Uox-/-mice compared with WT mice.Histopathological examination showed moderate hepatocyte degeneration in the liver,moderate-to-severe tubular cystic dilation,degeneration,and fibrosis in the kidney,glomerular hypertrophy and hyperplasia,small-vessel dilation and congestion,and infiltration of stromal monocytes and lymphocytes in Uox-/-mice.Conclusions We successfully established a homozygous uricase-deficient mouse strain using CRISPR/Cas9 technology,as a suitable animal model for research in the field of hyperuricemia.

Objective:To construct and validate a clinical model combining CYP11B2 gene polymorphisms with clinical parameters to predict complete postoperative hypertension remission in primary aldosteronism patients.Methods:The clinical data of a total of 116 patients with primary aldosteronism who underwent unilateral adrenalectomy from April 2018 to August 2024 were retrospectively included. There were 63 males and 53 females，with a body mass index（BMI）of（25.50 ± 2.03）kg/m 2. Genomic DNA was extracted from venous blood leukocytes before surgery，and polymerase chain reaction-restriction fragment length polymorphisms（PCR-RFLP）were used to detect CYP11B2（rs1799998）promoter region 344（C > T）base substitution. The follow-up duration was more than 6 months，with the following parameters recorded at the last follow-up：plasma aldosterone，renin，serum potassium，and sodium levels. Blood pressure progression and antihypertensive medication usage were also assessed. The postoperative outcome was determined according to the Primary Aldosteronism Surgical Outcome score（PASO）for primary aldosteronism，and the specific criteria were as follows. ① Clinical complete remission：the patient's blood pressure returned to normal（< 140/90 mmHg，1 mmHg = 0.133 kPa）and all antihypertensive drugs were discontinued；②Partial clinical remission：blood pressure returns to normal，and the number or dose of antihypertensive drugs is reduced compared with before；③Clinical non-remission：blood pressure does not drop and antihypertensive drugs do not change or increase compared with before surgery. Patients were divided into complete and incomplete remission groups. The chi-square test was used for univariate analysis，followed by binary logistic forward conditional regression for multivariate analysis，and a variety of machine learning algorithms such as random forest，logistic regression，support vector machine and gradient lifter were integrated，and the results of multivariate analysis were included to construct a postoperative blood pressure outcome model，and the predictive performance of the model was evaluated by using receiver operating characteristic（ROC）curve，calibration curve and clinical decision curve. Results:The PCR-RFLP detection results of 116 cases showed the genotype distribution of CYP11B2（344C > T）（rs1799998）as follows：CC type in 50 cases（43.1%），CT type in 46 cases（39.7%），and TT type in 20 cases（17.3%）. There were 74 cases in the complete remission group and 42 cases in the incomplete remission group，and the rate of complete remission with hypertension at the end of the operation was 63.8%. Univariate analysis showed that the the differences between complete remission group and incomplete remission group in body mass index［（24.27 ± 2.90）kg/m 2 vs.（26.98 ± 3.17）kg/m 2， P<0.001］，preoperative hypertension grade（grade 1/2/3：29/29/16 cases vs. 9/13/20 cases， P = 0.012），preoperative antihypertensive drugs（0/1/≥ 2：25/32/17 cases vs. 7/15/20 cases， P = 0.016），and CYP11B2（344C > T）（CC/TT + CT：39/35 cases vs. 11/31 cases， P = 0.006）were statistically significant. Multivariate analysis showed that the type of preoperative antihypertensive drugs［≥ 2： OR = 5.26（95% CI 1.12?24.61， P = 0.016；1： OR = 4.55（95% CI 1.23?22.47）， P = 0.025］was the strongest independent predictor，followed by CYP11B2（344C > T）［ OR = 4.02（95% CI 1.16?13.82）， P = 0.028］and BMI［ OR = 3.96（95% CI 2.26?6.92）， P < 0.001］. Comparing the receiver operating feature（ROC）curves of the four types of machine learning models，the best model was the support vector machine model with an area under the curve（AUC）of 0.88（95% CI 0.82?0.95），followed by the gradient elevator model of 0.83（95% CI 0.76?0.91），the logistic regression model of 0.78（95% CI 0.68?0.88），and the random forest model of 0.77（95% CI 0.68?0.86）. The optimal threshold of the Yoden index of the support vector machine model was 0.588，with a sensitivity of 78.5% and a specificity of 86.5%. The clinical decision curve and calibration curve show that the support vector machine model has a higher net benefit and acceptable stability and reliability. Conclusions:The support vector machine model incorporating CYP11B2 gene polymorphisms，BMI，and types of preoperative antihypertensive medications could effectively predict postoperative hypertension remission in primary aldosteronism patients，providing new evidence for personalized treatment strategies

Malignant tumors represent a major global public health challenge,necessitating urgent innovation in diagnostic and therapeutic strategies.Lactate,a key metabolic product of tumor cell glycolysis,functions not merely as an energy metabolite but also as a signaling molecule to regulate malignant progression.Lactate mediates intercellular metabolite distribution through monocarboxylate transporter(MCT)-driven lactate shuttling and regulates epigenetics via histone lactylation.This integration establishes interconnected networks of energy,amino acid,and lipid metabolism that enhance tumor metabolic plasticity.In immune regulation,lactate induces a shift of T cells toward immunosuppressive phenotypes,impedes CD8+T cell memory differentiation,and attenuates cytotoxicity.Simultaneously,lactate not only reduces the immune efficacy of natural killer(NK)cells but also triggers apoptosis by inducing mitochondrial dysfunction,creating an immune-privileged niche for metastatic sites.Furthermore,elevated lactate levels activate multiple signaling pathways to recruit macrophages and drive their polarization toward the M2 phenotype,fostering an immunosuppressive microenvironment.Current therapeutic strategies target key aspects of lactate metabolism.Inhibiting lactate synthesis reduces lactate accumulation in tumor microenvironment(TME),countering the tumor's metabolic advantage and diminishing its role in driving metabolic reprogramming.Additionally,promoting the decomposition of lactate represents a promising new direction.Novel agents employing bioenzymes or biomimetic catalytic systems enhance local lactate clearance,alleviating the immunosuppressive effects of the acidic TME.This review comprehensively outlined the lactate-mediated regulatory network,aiming to provide systematic research directions and translational insights for developing more effective anti-tumor therapies.

Objective:To construct and validate a clinical model combining CYP11B2 gene polymorphisms with clinical parameters to predict complete postoperative hypertension remission in primary aldosteronism patients.Methods:The clinical data of a total of 116 patients with primary aldosteronism who underwent unilateral adrenalectomy from April 2018 to August 2024 were retrospectively included. There were 63 males and 53 females，with a body mass index（BMI）of（25.50 ± 2.03）kg/m 2. Genomic DNA was extracted from venous blood leukocytes before surgery，and polymerase chain reaction-restriction fragment length polymorphisms（PCR-RFLP）were used to detect CYP11B2（rs1799998）promoter region 344（C > T）base substitution. The follow-up duration was more than 6 months，with the following parameters recorded at the last follow-up：plasma aldosterone，renin，serum potassium，and sodium levels. Blood pressure progression and antihypertensive medication usage were also assessed. The postoperative outcome was determined according to the Primary Aldosteronism Surgical Outcome score（PASO）for primary aldosteronism，and the specific criteria were as follows. ① Clinical complete remission：the patient's blood pressure returned to normal（< 140/90 mmHg，1 mmHg = 0.133 kPa）and all antihypertensive drugs were discontinued；②Partial clinical remission：blood pressure returns to normal，and the number or dose of antihypertensive drugs is reduced compared with before；③Clinical non-remission：blood pressure does not drop and antihypertensive drugs do not change or increase compared with before surgery. Patients were divided into complete and incomplete remission groups. The chi-square test was used for univariate analysis，followed by binary logistic forward conditional regression for multivariate analysis，and a variety of machine learning algorithms such as random forest，logistic regression，support vector machine and gradient lifter were integrated，and the results of multivariate analysis were included to construct a postoperative blood pressure outcome model，and the predictive performance of the model was evaluated by using receiver operating characteristic（ROC）curve，calibration curve and clinical decision curve. Results:The PCR-RFLP detection results of 116 cases showed the genotype distribution of CYP11B2（344C > T）（rs1799998）as follows：CC type in 50 cases（43.1%），CT type in 46 cases（39.7%），and TT type in 20 cases（17.3%）. There were 74 cases in the complete remission group and 42 cases in the incomplete remission group，and the rate of complete remission with hypertension at the end of the operation was 63.8%. Univariate analysis showed that the the differences between complete remission group and incomplete remission group in body mass index［（24.27 ± 2.90）kg/m 2 vs.（26.98 ± 3.17）kg/m 2， P<0.001］，preoperative hypertension grade（grade 1/2/3：29/29/16 cases vs. 9/13/20 cases， P = 0.012），preoperative antihypertensive drugs（0/1/≥ 2：25/32/17 cases vs. 7/15/20 cases， P = 0.016），and CYP11B2（344C > T）（CC/TT + CT：39/35 cases vs. 11/31 cases， P = 0.006）were statistically significant. Multivariate analysis showed that the type of preoperative antihypertensive drugs［≥ 2： OR = 5.26（95% CI 1.12?24.61， P = 0.016；1： OR = 4.55（95% CI 1.23?22.47）， P = 0.025］was the strongest independent predictor，followed by CYP11B2（344C > T）［ OR = 4.02（95% CI 1.16?13.82）， P = 0.028］and BMI［ OR = 3.96（95% CI 2.26?6.92）， P < 0.001］. Comparing the receiver operating feature（ROC）curves of the four types of machine learning models，the best model was the support vector machine model with an area under the curve（AUC）of 0.88（95% CI 0.82?0.95），followed by the gradient elevator model of 0.83（95% CI 0.76?0.91），the logistic regression model of 0.78（95% CI 0.68?0.88），and the random forest model of 0.77（95% CI 0.68?0.86）. The optimal threshold of the Yoden index of the support vector machine model was 0.588，with a sensitivity of 78.5% and a specificity of 86.5%. The clinical decision curve and calibration curve show that the support vector machine model has a higher net benefit and acceptable stability and reliability. Conclusions:The support vector machine model incorporating CYP11B2 gene polymorphisms，BMI，and types of preoperative antihypertensive medications could effectively predict postoperative hypertension remission in primary aldosteronism patients，providing new evidence for personalized treatment strategies

Objective To investigate the mechanism by which Yangmai Tongluo formula improves microcirculation disorders induced by high homocysteine(Hcy)levels via regulation of the acid sphingomyelinase(ASM)and endoplasmic reticulum(ER)stress pathways.Methods Fifty male C57BL/6J mice were divided randomly into a control group,Hcy model group,Yangmai Tongluo formula low-/high dose groups(5.3,10.4 g/kg,respectively),and a folic acid group(0.08 g/kg).Except for the control group,microcirculation disorders were induced in all mice using drinking water containing 1.8 g/L Hcy for 6 weeks.After modeling for 2 weeks,mice were administered the corresponding treatments by gavage for 4 weeks.Serum Hey concentrations and the blood perfusion volume of the lower extremity microvessels were measured.Protein expression levels of zonula occludens ZO-1,ZO-2,intercellular adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),ASM,glucose-regulated protein 78(GRP78),and C/EBP homologous protein(CHOP)in the cardiac microvascular endothelium were analyzed using immunofluorescence.Results Serum Hcy levels were significantly increased in the Hcy model group compared with the control group(P＜0.05).Yangmai Tongluo formula did not significantly reduce Hey levels compared with the Hey model group,but blood perfusion in the lower extremities was significantly increased(P＜0.01)and expression levels of ZO-1 and ZO-2 in the cardiac microvascular endothelium were restored(P＜0.001)in the Yangmai Tongluo formula high dose group.It also inhibited the expression of ICAM-1,VCAM-1,ASM,GRP78,and CHOP(P＜0.05),with comparable effects to folic acid.Conclusions Yangmai Tongluo formula improves Hcy-induced microcirculation disorders and endothelial dysfunction by inhibiting ASM activity and alleviating ER stress,via a mechanism closely related to the regulation of endothelial inflammation and barrier stability.These result provide experimental evidence to support the use of traditional Chinese medicine to treat microvascular diseases.