The major challenges in drug therapy for prostate cancer are the ineffectiveness and resistance to androgen deprivation therapy, the low response to immunotherapy and the poor efficacy of small molecule targeted drugs. As a brand-new drug design concept, proteolysis targeting chimera (PROTAC) reveals its strength in the field of cancer treatment by connecting the target protein to the ubiquitin-proteasome system and triggering the degradation of the target protein. In recent years, basic medical research on targeting androgen receptors, cell proliferation, and transcriptional regulation proteins for the treatment of prostate cancer has achieved significant progress. Meanwhile, clinical trials related to PROTAC for the treatment of prostate cancer are gradually being carried out. In an era of big data and precision medicine, PROTAC is a breakthrough in the field of prostate cancer drug therapy. This article summarizes the fundamental principles of PROTACs and the basic and clinical research advances in the field of prostate cancer treatment.

Purpose: Cavernous nerve injury induced erectile dysfunction (ED) is a refractory complication with high incidence in person under radical prostatectomy. Studies have shown that relaxin-2 (RLX-2) plays a vital role of endothelial protection, vasodilation, anti-fibrosis and neuroprotection in a variety of diseases. However, whether penile cavernous erection can benefit from RLX-2 remains unknown. The purpose of the experiment was to explore the effects of RLX-2 on ED in the rat suffering with bilateral cavernous nerve injury (BCNI). Materials and Methods: The rats were divided into three groups: Sham group was underwent sham operation, BCNI+RLX group or BCNI group was underwent bilateral cavernous nerve crush and then randomly treated with RLX-2 (0.4 mg/kg/d) or saline by continuous administration using a subcutaneously implanted micro pump for 4 weeks respectively. Then, erectile function was evaluated by electrical stimulation of cavernous nerves. Cavernous nerves and penile tissues and were collected for histological evaluation. Results: Erectile function of rats with BCNI was partially improved after RLX-2 treatment. The BCNI group had lower expression of relaxin family peptide receptor (RXFP) 1, p-AKT/AKT, p-eNOS/eNOS ratios than sham operation rats, but RLX-2 could partially reversed these changes. Histologically, the BCNI+RLX group had a significant effect on preservation of neurofilament, neuronal glial antigen 2 of penile tissue and nNOS of cavernous nerves when compared with BCNI group. RLX-2 could inhibited the lever of BCNI induced corporal fibrosis and apoptosis via regulating TGFβ1-Smad2/3-CTGF pathway and the expression of Bax/Bcl-2 ratio, caspase3. Conclusions RLX-2 could improve erectile function of BCNI rats by protecting cavernous nerve and endothelial function and suppressing corporal fibrosis and apoptosis via RXFP1 and AKT/eNOS pathway. Our findings may provide a promising treatment for refractory BCNI induced ED.

Objective:To identify preoperative clinical predictors of positive lymph nodes in patients with renal cell carcinoma (RCC)and provide a preoperative predictive model.Methods:The data of 173 RCC patients who underwent either retroperitoneal lymph node dissection or biopsy at a single institution from January 2016 to December 2020 were retrospectively analyzed. There were 109 males and 64 females, with an average age of (53.29±13.58) years, median tumor diameter of 70 (23-150) mm, 68 patients with local symptoms, 24 patients with systemic symptoms, and 56 patients with ECOG score ≥1. There were 96 patients with tumor pseudocapsule, 23 patients with renal vein or inferior vena cava tumor thrombus, 114 patients in stage T 1-2, 59 patients in stage T 3-4, 22 patients with distant metastasis and 88 patients with lymph node metastasis by preoperative imaging examination. Univariate analysis was performed by Mann-Whitney U test or Chi-square test, and multivariate logistic regression analysis was used to determine preoperative predictors of pathologic lymph node positivity. The significant variables were then included in a novel Nomogram to predict the probability of lymph node invasion.C-index and Bootstrap self-sampling methods were used to evaluate the discrimination and consistency of the model. Results:Of the 173 patients, 49(28.32%)and 124(71.68%)had pN 1 and pN 0 disease, respectively. Among 88 patients with suspected lymph node involvement (cN 1) assessed by preoperative imaging, only 47.73%(42/88) were confirmed to be pathologically positive. However, 8.24% (7/85) of the 85 patients with negative lymph nodes (cN 0) assessed by preoperative imaging were pathologically positive. Age, ECOG score, symptoms at presentation, tumor pseudocapsule, metastasis at diagnosis, clinical tumor stage, clinical nodal status, clinical nodal size, D-dimer, lactate dehydrogenase, microscopic hematuria were significant in the univariate analysis ( P<0.05). On multivariable analyses, the most informative independent predictors were age, clinical tumor stage, clinical nodal status, clinical nodal size and microscopic hematuria ( P<0.05). A Nomogram with good performance was developed to predict the probability of lymph node metastasis. The C-index of the model was 0.954, the calibration curve of forecasting curve with the ideal curve fit was good, indicating that the model has a good consistency. Conclusions:Younger age, microscopic hematuria, suspected lymph node involvement in imaging, larger lymph node diameter and higher T stage were independent risk factors for renal cell carcinoma with lymph node metastasis. The Nomogram based on the above factors has good identification and calibration ability, which can help predict the probability of lymph node metastasis of renal cell carcinoma before surgery.

Objective:To evaluate the efficacy and side effects of PD-1 monoclonal antibody in the treatment of advanced metastatic renal cell carcinoma in China.Methods:The clinical data of 117 patients with advanced metastatic renal cell carcinoma (mRCC) treated with PD-1 monoclonal antibody from October 2016 to February 2022 were retrospectively analyzed. There were 87 males (74.4%) and 30 females (25.6%), with an average age of (57.9±10.9) years old, BMI of (23.6±3.4) kg/m 2and smoking history of 79 (67.5%). There were 44 cases (37.6%) with hypertension, 19 (16.2%) cases of diabetes. The ECOG score of 59.8% (70/117) patients was 0, 33.3% (39/117) was 1, 4.3% (5/117) was 2, and 2.5% (3/117) was 3. The pathological type of 104 cases were renal clear cell carcinoma (ccRCC), 8 cases of papillary renal cell carcinoma, 2 cases of chromophobe cell carcinoma, 2 cases of collecting duct carcinoma and 1 case of eosinophilic cell carcinoma. The general condition of the overall population and the overall survival (OS) of relevant subgroups were analyzed. Secondary goals included progression free survival (PFS), objective response rate (ORR), adverse reactions, overall survival (OS), and progression free survival (PFS). Results:65.8% (77 / 117) of the patients chose targeted combined with PD-1 monoclonal antibody in the first-line treatment. The main targeted drugs were acitinib (81.8%, 63 / 77), tirelizumab (37.6%, 29 / 77) and cindilimab (25.9%, 20 / 77). After first-line treatment, 19.6.1% (23 / 117) patients needed to be converted to second-line treatment, and 15 patients changed the type of PD-1 antibody during treatment. In addition, the targeted drug of combined therapy was replaced by acitinib in 8 patients. The main causes of drug withdrawal were disease progression (70.7%, 29 / 41) and death (29.2%, 12 / 41). The median OS of the overall population was 35.6 (19-60) months and PFS was 12.1 (1-60) months. The ORR of the overall population was 47.8% (56 / 117). 4.2% (5/117) patients had complete remission, another 17.0% (20/117) patients were in stable condition, and 43.5% (51 / 117) patients were in partial remission. In the first-line treatment, the median PFS time of targeted combined with PD-1 monoclonal antibody was 12.6 (1-30) months, the median PFS time of PD-1 single drug immunotherapy was 10.5 (1-60) months. In the second-line treatment, the PFS of patients treated with PD-1 monoclonal antibody was 10.1 (4-19) months, and that of patients treated with PD-1 monoclonal antibody combined with targeted therapy was 11.7 (1-25) months. The most common adverse reactions were elevated blood pressure (18.5%, 23 / 124), followed by hypothyroidism (15.3%%, 19/124), rash (14.5%, 18 / 124), elevated transaminase (10.5%, 13 / 124) and bone marrow suppression (9.7%, 12/124). 9.4% (11 / 117) patients needed to reduce the related adverse reactions by interrupting the treatment control of PD-1 monoclonal antibody.Conclusions:The safety and efficacy of PD-1 monoclonal antibody in domestic patients are better, and the side effects are less. The efficacy and safety of PD-1 monoclonal antibody combined with targeted therapy in the real world population are consistent with many key clinical trials abroad. PD-1 monoclonal antibody combined with targeted drugs can be popularized in the domestic MRCC population.

OBJECTIVE: To carry out genetic testing for a pedigree affected with carotid body tumor (CBT). METHODS: Members of the pedigree were enrolled and underwent physical examination, ultrasonography and CT scan. Genomic DNA of the proband was extracted from peripheral blood sample and subjected to exome sequencing. Candidate variants were predicted using bioinformatic tools and verified among members from his pedigree. RESULTS: A c.170-1G>T splicing variant of the SDHD gene was detected in 15 individuals from the pedigree. Physical examination and imaging confirmed that 9 of them had CBT and hypertension, while the remaining 6 died of cardiovascular and cerebrovascular diseases. CONCLUSION The c.170-1G>T variant of the SDHD gene probably underlies the CBT in this pedigree. Genetic testing should be considered for CBT patients with CBT in addition to conventional clinical examination.

Objective To evaluate the pathological stage,the presence of detrusor muscle and the clinical significance for standardized examination of specimens for en bloc transurethral resection technique with Hybrid Knife to treat NMIBC (ERBT) compared with conventional TURBT.Methods This was prospective randomized controlled study.This study was approved by the Ethics Committee of Tongji Hospital,Tongji Medical College of Huazhong University of Science and Technology (TJ-IRB20180604),and patients all signed informed consent.The clinical study registration number of this study:NCT03221062.The margin of the tumor was recognized and marked by with Hybrid Knife (0.5 cm away from the normal mucosa).Then water was injected into the submucosa and form a water pad,with a circular cutting layer by layer (0.5 cm away from the marked position),reaching the detrusor muscle in depth.After complete resection,the tumor was removed by specimen bag.Specimens for ERBT cohort were given standard handling.Resected specimen of ERBT stretched with pins on foam and its margin was stained.The basement of specimen was also stained.Total specimen sectioned into appropriate pieces for histological assessment in the department of pathology.TURBT cohort performed traditional surgical methods and pathological examination.All patients received postoperative intravesical instillation according to their pathology.Imaging and cystoscopy were performed every 3 months.The primary study end-point was the quality of resection,including the pathological stage and the presence of DM.Secondary outcomes were:short-term tumour recurrence rate (18 month),feasibility,and safety.Results From January 2017 to October 2017,109 patients were enrolled.51 patients underwent ERBT,and 58 patients underwent TURBT.The clinical characteristics of the patients in each cohort,such as average age,gender,average BMI,smoking history,the mean number of lesions and tumour size had no significant differences (P ＞ 0.05).The operation of 109 cases was completed successfully.There was no statistical difference between the operative time and the postoperative bladder irrigation time.Major intraoperative or postoperative complications (Clavien ≥ Ⅱ) did not occur in all of the patients.The percentage of T1 staging was higher in the ERBT cohort vs.TURBT cohort [21/51 (41.2％) vs.13/58 (22.4％),P =0.035],of which ERBT cohort accurately detected 9 cases (42.8％) of T1b patients,significantly higher than TURBT cohort (2 cases,15.4％) (P =0.096).All the ERBT samples showed the presence of DM (100.0％),while there was only 77.4％ in TURBT cohort (P ＜ 0.05).Mean follow-up (20.3 ± 3.1) months (ranged from 18 to 24 months).Recurrence rate were 8.9％ (4/45) in ERBT cohort vs.22.2％ (12/54) in TURBT cohort (P=0.059).Conclusions ERBT with Hybrid Knife for treatment NMIBC is a safe,effective,and provides high-quality specimens compared to TURBT.More high-risk NMIBC patients,especially T1 b patients,can be detected obviously by pathologist with the standardized treatment of specimens.

OBJECTIVE To screen for mutations in a Chinese pedigree affected with hypokalemic periodic paralysis. METHODS The proband and nine family members were enrolled for the analysis of CACNA1S and SCN4A gene mutations. Genomic DNA was extracted from peripheral blood samples. The coding regions of the two genes were amplified with PCR and subjected to Sanger sequencing. Potential impact of suspected mutations was predicted with Bioinformatics software. The mutations were also verified among 100 healthy controls. RESULTS The proband and 5 family members (including 5 males and 1 female) had presented with episodes of flaccid paralysis accompanied by low serum potassium. Genetic testing has identified a c.664C>T (p.Arg222Trp) mutation in the proband, which has been reported previously. The same mutation was identified in other 5 affected members from the family. No mutation of the CACNA1S gene was detected. CONCLUSION The c.664C>T mutation of the SCN4A gene probably underlies the hypokalemic periodic paralysis in this family. All patients from the family have shown a complete penetrance of the disease.

Objective Using Wisconsin Stone Quality of Life questionnaire (WISQOL) to compare standard percutaneous nephrolithotomy(PCNL) and tubeless PCNL.Methods From January 2017 to June 2017,patients who met the criteria (no urinary tract infection,stones between 1-3 cm,hydronephrosis larger than 3cm,renal cortex thickness ＞ 2 cm and without serious heart,lung,liver and kidney dysfunction and coagulation dysfunction) and underwent PCNL were prospectively enrolled and randomized into 2 groups,standard PCNL group and tubeless PCNL group.Diclofenac sodium suppositories were used to relieve pain in all patients with obvious pain.The quality of life of these patients were estimated and compared by using WISQOL.Safety and efficacy were also estimated.Result At the end of the study,a total of 50 patients were included in the analysis.There were 24 patients in the standard PCNL group and 26 patients in the tubeless PCNL group.There were 9 male patients in the standard PCNL group and 17 male patients in the tubeless PCNL group.There was no significant difference in gender between the two groups.The differences between the standard PCNL group and tubeless PCNL group in mean age (yrs.) [(53.21 ±13.35) vs.(51.1 ± 11.5),P =0.55],stone diameter (mm) [(18.46 ± 5.58) vs.(18.75 ± 5.39),P =0.85],stone-free rate (23/24 vs.24/26,P =0.60),mean hemoglobin decline (g/L) [(11.87 ± 9.20)vs.(10.43 ± 8.49),P =0.56] were not significant.Mean dosage of acesodyne(pcs) in tubeless PCNL group (4.07 ± 1.49) was significantly less than that in standard PCNL group (7.54 ± 2.23).There were no patient need transfusion or postoperative fever management.The influence of perioperative quality of life of patients treated with tubeless PCNL is significantly better than those treated with standard PCNL in 16 items which includ energy,sleep,work and family,physical symptoms,concerns related to intimacy and travel,and general emotional well-being.Conclusion Tubeless PCNL can improve patients' quality of life compared with standard PCNL.

Objective: To evaluate the safety and effectiveness of ultrasound-guided percutaneous nephrolithotomy (PCNL) accessed by SVOF-principle and two-step puncture techniques. Methods: A total of 838 cases with upper urinary stones underwent percutaneous nephrolithotomy successfully accessed by ultrasound-guided between June 2007 and December 2015 at Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Of all cases were divided in two groups: hydronephrosis calyces puncture group include 425 cases and SVOF-principle puncture group include 413 cases. The access establishment time, operation time, stone free rate (SFR), postoperative complications, and postoperative hospitalization time between the two groups we compared by t test or χ² test. Results: Statistically significant differences were observed between hydronephrosis calyces puncture group and SVOF-principle puncturegroup in the first access establishment time ((16.5±8.4) minutes vs. (11.2±5.9) minutes, t=3.931, P=0.013), one-stage SFR (74.3% vs. 85.7%, χ²=16.868, P=0.000), postoperative hospitalization time ((6.4±2.1) days vs. (4.8±1.8)days, t=4.574, P=0.000), transfusion rate (7.1% vs. 2.9%, χ²=8.027, P=0.006), and embolization rate (3.3% vs. 1.0%, χ²=5.390, P=0.020). There were no statistically significant differences in operation time, total SFR, postoperative fever and sever infection between these two groups (all P>0.05). In both two groups, no serious complications such as peripheral organ injury and death occurred. Conclusions PCNL accessed guided by ultrasound with SVOF-principle and two-step puncture techniques has advantages of quick puncture location, high stone free rate, fewer complications and fast recovery. This technique is an effective and safe treatment option for upper urinary stones and deserved promotion and application in clinic.

OBJECTIVETo investigate the clinical features and mutations of RET proto-oncogene in a pedigree affected with multiple endocrine neoplasia type 2A (MEN2A).

METHODSClinical data of the family members was collected. Genomic DNA from peripheral blood leukocytes were extracted and subjected to PCR amplification. Exons 8, 10, 11, 13, 14, 15, 16 of the RET gene was sequenced.

RESULTSA missense mutation p.C634W was detected in 8 members from the family. Among them, 3 were diagnosed with pheochromocytoma, 1 with medullary thyroid carcinoma, 1 with medullary thyroid carcinoma and pheochromocytoma, 1 with medullary thyroid carcinoma and hyperparathyroidism. One member was found with thyroid enlargement but refused further examination, and another one was identified as carrier of the RET gene mutation.

CONCLUSIONA p.C634W mutation has been detected in a family affected with MEN2A, in which most carriers have developed clinical symptoms. RET mutation detection should be routinely performed for families affected with MEN2A.

Adult ; Aged ; Base Sequence ; Carcinoma, Medullary ; genetics ; Carcinoma, Neuroendocrine ; genetics ; Child ; Child, Preschool ; Exons ; genetics ; Family Health ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; Male ; Middle Aged ; Multiple Endocrine Neoplasia Type 2a ; genetics ; Mutation, Missense ; Pedigree ; Pheochromocytoma ; genetics ; Proto-Oncogene Proteins c-ret ; genetics ; Sequence Analysis, DNA ; methods ; Thyroid Neoplasms ; genetics