Objective:To study the effects of cathepsin K(CTSK)on the healing process of tooth extraction socket and type H blood vessel angiogenesis in mice.Methods:Ctsk knockout(Ctsk-/-)mice were generated by CRISPR/Cas9 technology,and genotype sequen-cing,general observation,Micro-CT and immunohistochemistry were performed to confirm successful knockout of Ctsk.Then 8 week-old WT and Ctsk-/-mice were used to establish the tooth extraction modle by extracting the left maxillary first molars,and the mice were sac-rificed at the day 7,10,14,21,28 and 35 respectively(n=3)after tooth extraction.Then samples were subjected to stereo microscope and Micro-CT examination.Immunofluorescence staining was used to study the effect of Ctsk knockout on type H blood vessel angiogene-sis.Results:Ctsk knockout did not affect the soft tissue healing of tooth extraction socket,but significantly promoted the bone healing process,and Ctsk deficency significantly enhanced type H blood vessel angiogenesis in the tooth extraction socket.Conclusion:Ctsk knockout can enhance type H vessel angiogenesis,and promote bone healing process of tooth extraction socket in mice.

Objective To analyze the research trends and frontier of TCM regulation of NF-κB;To provide reference for related research.Methods Relevant literature about TCM regulation of NF-κB was retrieved from CNKI,VIP,Wanfang Data,CBM and Web of Science from January 1,2013 to December 31,2022.VOSviewer 1.6.19 and CiteSpace 6.2.R4 software were used for visualization analysis on authors,institutions and keywords.Results Totally 3 728 articles in Chinese and 995 in English were included,and the number of articles was on the rise.The Chinese and English articles involved 487 and 237 core authors,respectively,forming research teams represented by Yan Guanghai,Liu Jian,Wang Li,and Li Wei,Zhang Li,Zhang Yu,etc.There were 7 and 8 effective clusters in Chinese and English articles respectively.Keyword analysis showed that this research field mainly focused on diseases(inflammatory diseases,tumors,cardiovascular and cerebrovascular diseases,etc.),research methods(in vivo experiment,in vitro experiment)and intervention methods(acupuncture,TCM monomer,TCM compound,etc.).Conclusion TCM regulation of NF-κB mainly focuses on related diseases and intervention methods,and it is a research trend to find drug action targets and conduct experimental verification through network pharmacology and molecular docking technology.

Objective:To retrospectively analyze and summarize the clinical experience and therapeutic effect of anterograde Needle-perc combined with RIRS, namely N+ R (Needle perc + RIRS) technique in the treatment of complex calyceal diverticular stone.Methods:Retrospective analysis of 23 cases of complex renal caliceal diverticulum stones admitted to our hospital from January 2020 to December 2022. The complex factors mainly include the invisible cervical orifice of diverticulum, large stone volume, and special anatomical location, which makes single RIRS or PCNL treatment difficult or unsuccessful. There were 14 males and 9 females with an average age of (42.3±6.1) years. Three cases were upper calyceal diverticular stone, average size was (0.9±0.2)cm. Nine patients had diverticular stone in the middle posterior calyx, and the average size was (1.2±0.3)cm. The average size of four diverticular stone was (1.8±0.2)cm in the anterior middle calyx. Seven patients had diverticular stone with an average size of (1.3±0.1)cm in lower calyx. Among them, 12 patients underwent RIRS which were difficult or stone undiscovered, and 3 patients underwent PCNL and the operation was terminated due to failure of channel establishment. In our center, oblique supine lithotomy position (male) or prone split-leg position (female) was adopted, and the combined treatment of Needle-perc and RIRS was performed. Needle-perc puncture was completed under the guidance of full ultrasound. During the operation, methylene blue reagent or mutual guidance of two endoscopes was used to find the diverticulum neck and expand the outlet with holmium laser incision. Depending on the size and location of the stones, a single Needle-perc laser lithotripsy combined with stone removal in flexible ureteroscope was used, or dual lasers were be used simultaneously for stone removal under double endoscopes. The first stage stone free rate, operation time, hemoglobin decrease, complications, postoperative hospital stay and other conditions were analyzed.Results:All the 23 operations were completed successfully. The stone free rate within 48 hours and one month after surgery was 78.2% and 100.0% respectively. The average operation time was (61.5±12.2)min. The mean postoperative hospital stay was (2.8±0.6) days. The mean decrease of hemoglobin was (3.6±0.4)g/L. Three patients had fever and one patient had renal subcapsular effusion. After anti-inflammatory and symptomatic treatment, the patient was discharged. There was no incidence of Clavien-Dindo≥Ⅱcomplications such as blood transfusion, abdominal organ injury or urosepsis.Conclusions:Treatment of complex renal caliceal diverticulum stones using N+ R technique of anterograde needle-perc combined with RIRS can effectively improve the success rate of first-stage surgery. Overall, it is safe, efficient and feasible with the advantages of high stone free rate, lower damage, and few postoperative complications.

ObjectiveTo investigate the mechanism of Xumingtang in Gu Jin Lu Yan （《古今录验》） in regulating cell pyroptosis through the hypoxia-inducible factor-1α （HIF-1α）/NOD-like receptor pyrin domain-containing protein 3 （NLRP3） pathway in ischemic stroke （IS）. MethodSD rats were randomly divided into a sham operation group， a model group， low- and high-dose Xumingtang groups， and a metformin group， with 20 rats in each group. Oral administration was performed for 3 days， and tissue samples were collected. Differential messenger RNA （mRNA） was screened using high-throughput sequencing， and Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analyses were performed on key differentially expressed genes. The modified neurological severity score （mNSS） and 2，3，5-triphenyltetrazolium chloride （TTC） staining were used to evaluate the effect of brain infarction. Hematoxylin-eosin （HE） staining was used for pathological morphological observation of brain tissue. Enzyme-linked immunosorbent assay （ELISA） was used to compare the levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） in the ischemic cortical region. Double staining immunohistochemistry was used to detect the co-localization of HIF-1α and NLRP3. Real-time quantitative polymerase chain reaction （PCR） was performed to detect the mRNA expression of NLRP3， HIF-1α， Caspase-1 （CASP-1）， and gasdermin D （GSDMD）. Western blot was used to detect the protein expression of HIF-1α， NLRP3， CASP-1， and GSDMD. ResultA total of 5 705 differentially expressed genes （2 733 downregulated and 2 972 upregulated） were obtained by mRNA sequencing. After conversion to homologous genes and intersection with the pyroptosis gene set， 95 key differentially expressed pyroptosis genes were obtained. Compared with the sham operation group， the model group showed significantly increased mNSS scores， larger brain infarction areas （P<0.01）， diverse neuronal morphology， disordered arrangement， widened cell gaps， significantly increased levels of IL-1β and IL-18 in the ischemic cortical region （P<0.01）， enhanced co-localization fluorescence intensity， and significantly increased mRNA and protein expression levels of HIF-1α， NLRP3， CASP-1， and GSDMD （P<0.01）. Compared with the model group， the high-dose Xumingtang group showed the most significant improvement in neurological function scores and brain infarction areas （P<0.01）. The neuronal integrity and arrangement were more complete， and the cell gaps were narrower in all groups with drug treatment， with significantly reduced co-localization fluorescence intensity. Xumingtang could reduce the levels of IL-1β， IL-18， and the mRNA and protein expression of HIF-1α， NLRP3， CASP-1， and GSDMD （P<0.05， P<0.01）， with the high-dose Xumingtang group showing the most significant effect （P<0.01）. ConclusionXumingtang in Gu Jin Lu Yan can inhibit cell pyroptosis and promote neurological function recovery after IS， which may be related to the inhibition of the HIF-1α/NLRP3 pathway.

Objective:To observe the effects of Traditional Chinese Medicine (TCM)ultrasound drug permeation electrotherapy device on the inflammatory response of rats with cerebral ischemia, and to provide an experimental basis for the clinical application of TCM ultrasound drug permeation electrotherapy device in the treatment of cerebral ischemia.Methods:A total of 72 SD rats were randomly divided into sham-operation group (12 rats) and modeling group (60 rats). The middle cerebral artery occlusion (MCAO) model was prepared by thread embolism in the model group. The rats were divided into model group, Chinese medicine tablet group, blank tablet + TCM ultrasound drug permeation electrotherapy group (hereinafter referred to as "blank tablet + electrotherapy group"), Chinese medicine tablet + TCM ultrasound drug permeation electrotherapy group (hereinafter referred to as "Chinese medicine tablet + electrotherapy group") and butylphthalide group according to the random number table method, with 12 rats in each group. The corresponding treatment was given continuously for 7 days. The neurological function was scored using Longa method evaluation criteria; TTC staining was used to observe the infarct volume and calculate the percentage of infarct volume; HE staining was used to observe the cell morphology of cortical area in each group of rats; ELISA was used to detect the serum TNF-α and IL-1β levels in each group of rats; TLR4, MyD88 and NF-κBp65 protein expressions in hippocampal tissue of each group of rats on the infarct side were detected by Western blot method.Results:Compared with the model group, the neurological function scores of rats in the blank tablet + electrotherapy group, the herbal tablet + electrotherapy group, and the butylphthalein group significantly decreased ( P<0.05), the percentage of cerebral infarct volume significantly decreased ( P<0.05), the contents of serum TNF-α and IL-1β significantly decreased ( P<0.05), and the expressions of TLR4 (0.42±0.07, 0.31±0.07, 0.19±0.04 vs. 0.68±0.14), MyD88 (0.39±0.12, 0.30±0.07, 0.23±0.11 vs. 0.67±0.10), NF-κBp65 (0.32±0.03, 0.27±0.02, 0.17±0.03 vs. 0.57±0.12) protein in hippocampal tissue significantly decreased ( P<0.05). Conclusion:The TCM ultrasound drug permeation electrotherapy device can inhibit TLR4, MyD88, NF-κBp65 protein expressions and reduce the release of serum inflammatory factors TNF-α and IL-1β, thus exerting cerebral ischemic protective effects.

Objective:To summarize the preliminary clinical experience of endoscopic treatment of upper urinary tract urothelial carcinoma, and to analyze its indications and efficacy.Methods:The clinical data of 14 patients underwent endoscopic treatment for upper urinary tract urothelial carcinoma in our hospital from December 2014 to December 2019 were retrospectively analyzed. Among them, there were 5 males and 9 females, with a median age of 75.5(44-84) years. There were 11 patients with hematuria, 2 patients with flank pain and one asymptomatic patient. Five patients had a history of bladder cancer and one had a history of contralateral UTUC. There were 4 patients with solitary kidney, 3 patients with renal insufficiency, 1 patient with bilateral renal pelvis carcinoma, 4 patients prohibitory to nephroureterectomy because of poor general condition (American Society of Anesthesiologists score ≥3), and 2 patients were pathologically diagnosed as low-grade non-invasive urothelial carcinoma and requested renal preservation therapy. A total of 15 renal units included. The main tumor sites were renal pelvis in 6 renal units, upper calyx in 4 renal units, middle calyx in 3 renal units, and lower calyx in 2 renal units. The median tumor diameter was 2.0 (0.8-4.0) cm. All patients were diagnosed with urothelial carcinoma by preoperative computed tomography (CT/CTU), magnetic resonance imaging (MRI), and cytological or pathological biopsy. In 13 patients, ultrasond-guided percutaneous renal access and tract dilation were performed to establish a F24 standard tract. The tumor tissues were vaporized by 1470 semiconductor laser (60-80 W) or thulium laser (15-20 W) under nephroscopy, and electrocoagulation was used to coagulate the bleeding when necessary. Two patients were treated with felxible ureteroscope, under which tumor ablation was performed with 200 μm holmium laser fiber, and neodymium laser was used for hemostasis. The range of tumor vaporization ablation included 0.5-1.0 cm normal renal pelvis mucosa around the tumor, deep to the fatty layer of renal sinus. Biopsy was taken again at the base of the wound after vaporization ablation when necessary.Results:In this study, six sites were pathological high grade, 9 sites were pathological low grade tumors. Eight were in pathological T a stage, 5 in T 1 stage, and 2 in T 2 stage. The median blood loss was 20.0 (2-50) ml. There were 5 postoperative complications, including one patient with fever (body temperature >38.5℃) and 4 patients with hemorrhage requiring blood transfusion (postoperative hemoglobin <70 g/L) with 2-4 U suspended red blood cells.No patient underwent embolization. The median follow-up time were 31(11-70)months. Ten patients experienced recurrence, and the median time to recurrence was 11.3 (4-41) months. Four of them received conservative treatment after recurrence, including immunotherapy and radiotherapy in 1 patient, systemic chemotherapy in 1 patient, and watchful waiting in 2 patients. Three of them received repeated endoscopic treatment after recurrence, including 2 patients with percutaneous nephroscopic laser ablation and 1 patient with transurethral resection of bladder tumor, all of them survived during the follow-up period. Three patients underwent full-length nephroureterectomy after recurrence, 2 died and 1 survived during the follow-up period. Six patients eventually died, and the median time of death after surgery was 21(9-33) months. Five of them died from tumor-specific death and one died from gastric perforation. The median tumor-free survival interval were11 (4-41) months during the follow-up period. The 2-year tumor-specific survival rate was 78.6%, 50% for high-grade patients and 100% for low-grade patients. Conclusions:In patients who were in early stage (≤T 2) and intolerant to the nephroureterectomy, or with solitary kidney, renal insufficiency, or bilateral tumors, endoscopic treatment could be used as an alternative treatment approach for upper urinary tract epithelial carcinoma, especially for low-grade non-invasive patients.

The programmed cell death receptor 1 (PD-1) antibody has been used in the treatment of a variety of malignant tumors, in which colorectal cancer is considered immune " cold" tumor and is not sensitive to anti-PD-1 therapy. The molecular characteristics of mismatch repair deficient (dMMR)/high microsatellite instability (MSI-H) are important molecular markers for screening patients with immune checkpoint inhibitors therapy (ICIs). However, only some patients can benefit from ICIs treatment, and some patients even have disease progression. This article summarizes the research progress of anti-PD-1 immunotherapy of MSI-CRC in recent years, including the mechanisms of resistance, new efficacy biomarkers and treatment options, so as to provide ideas for expanding the application of immunotherapy in colorectal cancer.

Objective: To summarize our preliminary clinical experience of ultrasound-guided needle-perc combined with standard percutaneous nephrolithotomy (PCNL) in the treatment of staghorn stones, and to analyze its safety and efficacy. Methods: The clinical data of 65 patients with staghorn stones treated by ultrasound-guided needle-perc combined with standard PCNL under general anesthesia with the patient in prone position from December 2017 to June 2019 were retrospectively reviewed. A total of 41 males and 24 females were included. The mean age was (53.5+ 8.9) years. The mean body mass index (BMI) was (25.1±2.9) kg/m², and the mean stone diameter was (10.9±3.1) cm. Among them, there were 3 cases with bilateral staghorn stones, 38 cases with complete staghorn calculi, 36 cases with non- or mild preoperative hydronephrosis, 12 cases with previous ipsilateral renal surgery, and 9 cases with solitary kidneys. Ultrasound-guided renal access and tract dilation were used to establish F24 standard channel. Pneumatic combined with ultrasonic lithotripsy with suction system was used to treat staghorn stones under nephroscope. Needle-perc consists of F4.2 needle-like metal sheath connected with a three-way tube. A 0.6 mm diameter video fiber, 200 um holmium laser fiber and liquid perfusion device can be connected through the three-way tube respectively. The residual stone in the parallel calyx after standard PCNL were punctured by needle-perc under ultrasound guidance, and then the holmium laser fiber was used for lithotripsy. Results: In this study, a total of 68 renal units were included. The median operative time was 79.8 minutes, ranging 45-129 minutes. The median decrease of hemoglobin on postoperative day 1 was 10.6 g/L, ranging 0-25.9 g/L. The median length of postoperative hospital stay was 5.5 days, ranging 4-7 days and the median time of tract establishment was 4.8 minutes, ranging 2.5-9.6 minutes. The median number of standard tract established was 1.5, ranging 1-3 and the median number of needle-perc punctured was 1.0, ranging 1-3. The total complication rate was 10.3% (7 cases), including 5 cases of Clavien grade Ⅰ, 2 cases of postoperative fever, 3 cases of analgesic use. There were 2 cases of Clavien grade Ⅱ. All of them were blood transfusion. The initial stone free rate was 79.4%(54/68). Of the 14 patients with residual stones, 9 patients underwent second-stage operation, 7 patients were stone free, and the final stone free rate was 89.7%(61/68). Conclusions Ultrasound-guided needle-perc combined with standard PCNL is safe and effective in the treatment of staghorn stone.

Objective To investigate the feasibility of tract dilation monitored by ultrasound in percutaneous nephrolithotomy (PCNL),and the risk factors for its failure.Methods A retrospective study was conducted on patients underwent PCNL with only one access (F24) using balloon dilator and sequential dilators (Amplatz and telescopic metal dilators) from December 2014 to December 2018 in Beijing Tsinghua Changgung Hospital.A total of 231 patients (130 males and 101 females) underwent ultrasound-guided PCNL with a mean age of (52.3 ± 9.8) years were included in our study.Mean BMI was (25.8 ± 3.1) kg/m2.Mean size of stone was (3.9 ± 1.1)cm,51.1％ (118/231) of which were staghorn stones.Under ultrasound guidance,after puncture of the target calyx,the balloon dilator was advanced through the guide wire,and inflated to establish the F24 standard renal access.Patients' clinical parameters such as age,gender,BMI,stone diameter,history of open nephrolithotomy were collected.Risk factors for the failure of ultrasound guided balloon dilation were analyzed by logistic regression analysis.Results Tract dilation succeed in 89.2 ％ cases (206 succeed,25 failed) at first attempt.Median tract dilation time was 4.2 min (2.2-8.0 min).Mean operation time was 85.5 min(45.0-120.0 min).Median hemoglobin drop at the first postoperative day was 16.0 g/L (5.0-25.8 g/L).The total rate of complication was 9.1％ (21 cases),including 18 cases Clavien Ⅰ and 3 cases Clavien Ⅱ.The stone free rate was 89.6％ (207/231).Logistic regression analysis revealed that lower pole access (P =0.014) was a risk factor for the failure of access establishment,while the presence of hydronephrosis of target calyx (P ＜ 0.001) would significantly increase the success rate.Conclusions Tract dilation using balloon catheter can be safely monitored by ultrasound with high success rate and low complication rate.Lower pole puncture will make tract establishment difficulty.Patients with a hydronephrotic target calyx are more suitable for this procedure.

Objective To describe and introduce the initial clinical application of a novel instrument needle-perc for percutaneous nephrolithotomy (PCNL) in upper urinary tract stones.Methods 24 patients with upper urinary stone treated by PCNL were collected retrospectively between August 2017 and January 2018.Sixteen patients were male and 8 were female.Average age was 41.2 years,ranging 26-65 years.Eight cases had upper pole stones,6 cases had pelvic stones,8 cases had lower pole stones and 4 cases had the stone in UPJ.The mean calculus size was 1.2 cm,ranging 0.5-1.4 cm.All patients were punctured under total ultrasound with needle-perc.Six cases had upper calyceal puncture,10 cases had middle calyceal puncture and 8 cases had lower calyceal puncture.The needle-shaped nephroscope consists of a puncture sheath and a needle handle.The puncture sheath is a hollow metal sheath with an outer diameter of F4.2,an inner diameter of F3.6,and a length of 15 cm.The tip of the sheath is beveled to facilitate puncture.The outer end of sheath is connected to the needle handle through a screw interface.And the three interfaces of the three-way tube can be respectively connected with a liquid irrigation device,a video optical fiber and a 200 μm holmium laser fiber.The needle-perc integrated image system,the irrigation system,and the nephroscope channel are integrated.The tissue passing through the needle can be simultaneously observed through video optical fiber during puncturing.After the tip of the sheath is inserted into the target calyx,the holmium laser fiber is connected for fragmenting or dusting.Results Needle-perc was successful in 22 cases,2 patients were converted to larger tract(F16).The mean opeartive time was 49.2 min,ranging 22-75 min and the mean hemoglobin loss was 5.2 g/L,ranging 0-13.8 g/L.Mean postoperative hospital stay was 3 days,ranging 1 to 6 days.No Double-J stents or nephrostomy tube was placed in the 22 patients.Complications (Clavien Ⅱ) occurred in 4 cases,including fever in 2 cases and renal colic in 2 cases.Plain film of KUB or CT scan was done and stone free rate at 1 month was 90.9％ (20/22),2 patients needed ESWL to remove the residual stones.Conclusions Needle-perc is efficient and safe for small renal stones (size ＜ 1.5 cm) from our initial experience,with high stone-free rate and low complication rate in early follow-up.