ObjectiveTo analyse the efficacy and mechanism of Guizhi Fulingwan in regulating sex hormone disorders in rats with benign prostatic hyperplasia （BPH）. MethodsThirty male SD rats were randomly divided into a sham group， a model group， a finasteride group （0.45 mg·kg^-1·d^-1）， and low-dose and high-dose groups of Guizhi Fulingwan （0.135， 0.337 5 g∙kg^-1∙d^-1）， with six in each group. The BPH model was prepared by subcutaneous injection of 3.5 mg∙kg^-1∙d^-1 testosterone propionate after debridement surgery in all groups except the sham group. The rats in the sham group and the model group were administered with an equal volume of saline by gavage， and the rest of the groups were administered with the corresponding medicinal solution by gavage for 35 days. Histopathology in rats was evaluated by prostate wet weight， volume， index， and hematoxylin-eosin （HE） staining. The serum sex hormone levels of testosterone （T）， dihydrotestosterone （DHT）， and estradiol （E₂） were determined by enzyme-linked immunosorbent assay. The protein expression of the androgen receptor （AR） was detected by immunohistochemistry. The serum metabolism profiles of rats in the sham group， the model group， and the high-dose group of Guizhi Fulingwan were compared by ultra-high performance liquid chromatography tandem Fourier transform mass spectrometry （UHPLCQ Exactive） to screen for metabolic markers and to obtain relevant metabolic pathways. ResultsCompared with those in the sham group， the wet weight， volume， index， serum sex hormone level， and AR protein expression of the prostate in the model group were all elevated （P<0.05， P<0.01）， and the histomorphology showed pathological changes. Compared with those in the model group， the wet weight， volume， index， serum sex hormone level， and AR protein expression of the prostate in the intervention groups showed a decreasing trend （P<0.05， P<0.01）， and histopathology was improved. Serum metabolomics analysis obtained a total of 40 metabolic markers related to the intervention effect of Guizhi Fulingwan， such as dehydrosafynol， hyoscyamine， and lumichrome， which were involved in the pathways of autophagy， riboflavin metabolism， and retrograde endocannabinoid signaling. ConclusionGuizhi Fulingwan can effectively regulate sex hormone disorders in BPH rats， and its mechanism may be related to autophagy， riboflavin metabolism， and retrograde endocannabinoid signaling.

Objective To explore the diagnosis,treatment and prognostic factors of urachal carcinoma(UrC),aiming to provide reference for the standardized diagnosis and treatment of this disease.Methods A retrospective analysis was conducted on the clinical data of 75 UrC patients confirmed with postoperative pathology treated in our hospital during Mar.2010 and Mar.2023.All patients underwent surgical treatment,and 35 received postoperative chemotherapy.Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors.Kaplan-Meier curves were adopted to calculate the cumulative survival rates and overall survival(OS).Results Among the 75 patients,the male to female ratio was 2.8∶1 and the mean age was(58.4±2.2)years.Median follow-up was 60 months and median OS was 48 months.The 3-year survival rate was 67.3％and the 5-year survival rate was 38.8％.There were 19 cases(25.3％)of CK7 positive,60 cases(80.0％)of Sheldon stage Ⅲ and above,and 26 cases(34.7％)of postoperative recurrence.CK7 positive(P=0.001),Sheldon staging Ⅲ+Ⅳ(P=0.005)and postoperative recurrence(P=0.003)were independent prognostic factors.Conclusion Urachal carcinoma is a rare malignant tumor in males with occult onset.CK7 positive,Sheldon staging and postoperative recurrence were independent prognostic factors of this disease.

Objective To explore the diagnosis,treatment and prognostic factors of urachal carcinoma(UrC),aiming to provide reference for the standardized diagnosis and treatment of this disease.Methods A retrospective analysis was conducted on the clinical data of 75 UrC patients confirmed with postoperative pathology treated in our hospital during Mar.2010 and Mar.2023.All patients underwent surgical treatment,and 35 received postoperative chemotherapy.Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors.Kaplan-Meier curves were adopted to calculate the cumulative survival rates and overall survival(OS).Results Among the 75 patients,the male to female ratio was 2.8∶1 and the mean age was(58.4±2.2)years.Median follow-up was 60 months and median OS was 48 months.The 3-year survival rate was 67.3％and the 5-year survival rate was 38.8％.There were 19 cases(25.3％)of CK7 positive,60 cases(80.0％)of Sheldon stage Ⅲ and above,and 26 cases(34.7％)of postoperative recurrence.CK7 positive(P=0.001),Sheldon staging Ⅲ+Ⅳ(P=0.005)and postoperative recurrence(P=0.003)were independent prognostic factors.Conclusion Urachal carcinoma is a rare malignant tumor in males with occult onset.CK7 positive,Sheldon staging and postoperative recurrence were independent prognostic factors of this disease.

【Objective】 To explore the clinical features, treatment and prognosis of paraganglioma of the urinary bladder (PUB). 【Methods】 The clinical data of 41 PUB patients treated at our hospital during Sep.2012 and Sep.2022 were collected. The clinical features, surgical records, pathological reports and follow-up records were retrospectively analyzed. Patients’ survival was estimated with Kaplan-Meier estimator. The differences among groups were compared with Log-rank test. 【Results】 Among the 41 patients, 20 were male and 21 were female, with a median age of 52 years. All patients were treated with surgery, including transurethral resection of bladder tumor (TURBT) in 16 cases, partial cystectomy (PC) in 23 cases, and radical cystectomy (RC) in 2 cases. All patients were followed up for 4.0 to 125.0 months, with a median of 59.0 months. Local recurrence occurred in 5 patients, and distant metastasis occurred in 5 patients. Survival analysis showed that the 5-year overall survival (OS) rate and 5-year relapse-free survival (RFS) rate were 95.7% and 84.8%, respectively. Further analysis showed statistically significant differences in OS and RFS among groups with different maximum tumor diameters, growth patterns, and Ki-67 expressions (P<0.05). For patients with a maximum tumor diameter ≤2.8 cm, there was no significant difference in OS and RFS among different surgical groups. 【Conclusion】 PUB is rare, and a definitive diagnosis is based on pathology. In addition, the main treatment is surgery and the prognosis is good.

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

The clinical data of a 64-year-old patient with adrenocortical adenoma complicated with inferior vena cava tumor thrombus(IVCTT) were retrospectively analyzed. The patient was admitted becourse of intermittent dizziness for 4 months. CT examination revealed right adrenal tumor, and IVCTT was found in operation. Adrenal cortical adenoma needs to be distinguished from adrenal cortical carcinoma pathologically. Preoperative color Doppler ultrasonography, CT angiography or inferior vena cava angiography can confirm the diagnosis of IVCTT and tumor thrombus grade, and different surgical methods should be selected according to tumor thrombus grade.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective:To investigate the expressions of eukaryotic initiation factor-4B (eIF4B) and eukaryotic initiation factor-5A (eIF5A) in papillary thyroid carcinoma tissues, and to analyze their regulatory effects on cell proliferation in vitro.Methods:The clinical data of 61 patients diagnosed with papillary thyroid carcinoma who received surgical resection at Yuncheng Central Hospital from January 2020 to October 2021 were retrospectively analyzed. The postoperative tumor tissues and paracancerous normal thyroid tissues (>1 cm from the margin of the mass) were retained. Immunohistochemistry was used to detect the expressions of eIF4B, eIF5A and proliferating cell nuclear antigen (PCNA) in different tissues. The correlation of eIF4B, eIF5A expressions with the clinicopathological characteristics of patients, and the relationship between eIF4B, eIF5A and PCNA were analyzed. The thyroid cancer cell line SW1736 and normal thyroid cell line HT-ori3 were selected. The expressions of eIF4B mRNA and eIF5A mRNA were detected by using real-ime quantitative polymerase chain reaction (qRT-PCR). After the small interfering RNA (siRNA) of siRNA-eIF4B and siRNA-eIF5A were synthesized, the interfering plasmids were constructed, and SW1736 cells were transfected, siRNA-eIF4B group and siRNA-eIF5A group were obtained; the empty plasmid transfection group and the blank control group without transfection intervention were established. The cell proliferation activity was detected by using CCK-8 assay, and the expression of PCNA mRNA was detected by using qRT-PCR.Results:The positive rates of eIF4B and eIF5A in papillary thyroid cancer tissues were higher than those in paracancerous normal thyroid tissues [65.57% (40/61) vs. 29.51% (18/61), 57.38% (35/61) vs. 9.84% (6/61), P < 0.001]. The positive rates of eIF4B and eIF5A were statistically different in patients with different tumor diameter [>3 cm vs. ≤3 cm: 88.89% (16/18) vs. 55.81% (24/43),77.78% (14/18) vs. 48.84% (21/43), all P < 0.05], lymph node metastasis [with vs. without: 85.00% (17/20) vs. 56.10% (23/41), 80.00% (16/20) vs. 46.34% (19/41), all P < 0.05] and the number of different nodes [multiple vs. single: 86.67% (13/15) vs. 58.70% (27/46), 86.67% (13/15) vs. 47.83% (22/46), all P < 0.05]; there were no statistically significant differences in the positive rates of eIF4B and eIF5A among patients with different age and gender (all P > 0.05). Positive correlation was found between eIF4B score and the positive cell proportion of PCNA ( r = 0.66, P = 0.0324), eIF5A score and the positive cell proportion of PCNA ( r = 0.62, P = 0.024), eIF4B score and eIF5A score ( r = 0.63, P = 0.021). The expression levels of eIF4B mRNA and eIF5A mRNA in thyroid cancer cell line SW1736 cell was higher than that of HT-ori3 cell in normal thyroid (all P < 0.05). The cell proliferation activity of SW1736 and PCNA mRNA expression level in siRNA-eIF4B group and siRNA-eIF5A group were lower than those in the empty vector transfected group and the blank control group (all P < 0.05). Conclusions:eIF4B and eIF5A are expressed elevated in papillary thyroid carcinoma, and both are involved in tumor development and progression. The role of eIF4B and eIF5A may be related to promoting the proliferation of tumor cells.

Objective To explore the relationship between congenital vesical ureteral reflux(VUR) and bladder dysfunction in children through videourodynamic examination.Methods Sixty-seven children with congenital VUR in the First Affiliated Hospital of Zhengzhou University from Apr.2011 to Jul.2013 were included,and their clinical information of urnary tract infection,detrusor activity,dysfunctional voiding and grade of VUR were recorded.All the children were categorized as normal,isolated detrusor overactivity (DO)and dysfunctional voiding (DV) (with or without DO) according to the manifestation of urodynamic patterns,who were also divided into groups of low grade (Ⅰ-Ⅱ) VUR or high grade (Ⅲ-Ⅴ) VUR.Data of video-urodynamic examination,urinalysis,and voiding cystourethrogram were collected to investigate the relationship between bladder dysfunction,sides and grade of VUR and urinary tract infection.Results Totally 73.1％ (49/67 cases) of children with VUR were found having bladder dysfunction,which consisted of 49.3％ (33/49 cases) of DO,23.8％ (16/49 cases) of DV.Children with isolated DO tended to manifest unilateral,low grade reflux (grade Ⅰ-Ⅱ) with less urinary infection.However,children with DV,isolated or combined with DO manifest bilateral,high grade reflux(grade Ⅲ-Ⅳ),and often with urinary infection.Conclusions Video urodynamic study is useful for evaluation of bladder function in children with VUR,which is important in management of VUR.

Objective To compare the application of ambulatory urodynamic(AUM)and conventional urodynamic(CUD)in detecting stress urinary incontinence(SUI)and detrusor overactivity(DO)in females.Methods Incontinence questionnaire short form(ICI-Q-SF),CUD and AUM were administrated on 30 female patients with the mean age of 49.4(32-63)years.The duration of symptom was 4.7 (1-9)years.The patients were divided into 3 groups of mild(n =9),moderate(n =15)and severe (n =6)according to ICI-Q-SF.Three micturition cycles were recorded during AUM.Results SUI and DO detected by AUM were 90％ and 37％,significantly more than those by CUD of 70％ and 10％(P ＜0.05).Twenty-one moderate and severe SUI patients diagnosed by ICI-Q-SF,detected by AUM and CUD simultaneously showed that abdominal leak point pressure(ALPP)and voided volume were lower,and detrusor pressure was higher recorded by AUM than those by CUD significantly(P ＜ 0.05).Conclusions SUI and DO are easier detected by AUM than by CUD.AUM is a useful additional tool in clinical practice for those patients CUD failed to explain their symptoms.