Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

Objective:To study the influence of surgical margins on the prognosis of anatomical hepatectomy in patients with hepatocellular carcinoma (HCC) based on a propensity score-matched (PSM) analysis.Methods:Clinical data of 200 patients with HCC undergoing anatomical hepatectomy at the Affiliated Cancer Hospital of Guangxi Medical University from December 2019 to December 2023 were retrospectively analyzed, including 169 males and 31 females, aged 53.4±12.0 years. Patients were divided into the narrow margin group (surgical margin ≤10 mm, n=133) and wide margin group (>10 mm, n=67) according to the width of the surgical margin. PSM was used to compare preoperative indicators such as the maximum diameter of the tumor, the integrity of the tumor capsule, sublesions, and the clinical stage of Barcelona liver cancer (BCLC), perioperative indicators such as intraoperative blood loss, and 24-hour postoperative laboratory indicators such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase between the two groups of patients. The prognosis was analyzed by the Kaplan-Meier method, and the postoperative recurrence-free survival rate of the two groups was compared by the log-rank test. Yates corrected chi-square test was used to analyze the postoperative liver function of the two groups of patients. Results:Before PSM, 133 cases were included in the narrow margin group and 67 cases in the wide margin group. There were statistically significant differences in the clinical stage of BCLC, intraoperative blood loss, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase between the two groups (all P<0.05). After PSM, 55 cases were included in both the narrow margin group and the wide margin group. There were no statistically significant differences in the clinical stage, intraoperative blood loss, alanine aminotransferase and other indicators of BCLC between the two groups (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates of the wide margin group were 94.2%, 80.1%, and 75.1% respectively, which were higher than those of the narrow margin group (71.8%, 52.9%, and 44.1%), the difference was statistically significant ( χ2=6.25, P=0.012). After PSM, a total of 12 patients (10.9%, 12/110) in the two groups developed liver dysfunction after the operation, among which 10 cases (18.2%, 10/55) were in the wide margin group and 2 cases (3.6%, 2/55). The incidence of postoperative liver dysfunction in the wide margin group was higher than that in the narrow margin group, the difference was statistically significant difference ( χ2=4.58, P=0.032). Conclusion:A surgical margin >10 mm can improve the relapse free survival rate, but it will increase the incidence of postoperative liver dysfunction.

With the extended survival period of breast cancer patients and the increasing health demands, the concomitant diseases of breast cancer have gradually attracted the attention of both doctors and patients, and it is imperative to conduct comprehensive management of these diseases, in which the general practitioners, as the more comprehensive and complex medical talents, have not yet played their due roles. In this article, we report two cases of comprehensive management of concomitant diseases of breast cancer through collaboration of general practitioners and specialists (integrated general and specialist care). The role and function of general practitioners in this process were deeply analyzed, and the establishment of a consultation-liaison general practice model to further promote the role of integrated general and specialist care in integrated oncology care was advocated.

Objective:To study the influence of surgical margins on the prognosis of anatomical hepatectomy in patients with hepatocellular carcinoma (HCC) based on a propensity score-matched (PSM) analysis.Methods:Clinical data of 200 patients with HCC undergoing anatomical hepatectomy at the Affiliated Cancer Hospital of Guangxi Medical University from December 2019 to December 2023 were retrospectively analyzed, including 169 males and 31 females, aged 53.4±12.0 years. Patients were divided into the narrow margin group (surgical margin ≤10 mm, n=133) and wide margin group (>10 mm, n=67) according to the width of the surgical margin. PSM was used to compare preoperative indicators such as the maximum diameter of the tumor, the integrity of the tumor capsule, sublesions, and the clinical stage of Barcelona liver cancer (BCLC), perioperative indicators such as intraoperative blood loss, and 24-hour postoperative laboratory indicators such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase between the two groups of patients. The prognosis was analyzed by the Kaplan-Meier method, and the postoperative recurrence-free survival rate of the two groups was compared by the log-rank test. Yates corrected chi-square test was used to analyze the postoperative liver function of the two groups of patients. Results:Before PSM, 133 cases were included in the narrow margin group and 67 cases in the wide margin group. There were statistically significant differences in the clinical stage of BCLC, intraoperative blood loss, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase between the two groups (all P<0.05). After PSM, 55 cases were included in both the narrow margin group and the wide margin group. There were no statistically significant differences in the clinical stage, intraoperative blood loss, alanine aminotransferase and other indicators of BCLC between the two groups (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates of the wide margin group were 94.2%, 80.1%, and 75.1% respectively, which were higher than those of the narrow margin group (71.8%, 52.9%, and 44.1%), the difference was statistically significant ( χ2=6.25, P=0.012). After PSM, a total of 12 patients (10.9%, 12/110) in the two groups developed liver dysfunction after the operation, among which 10 cases (18.2%, 10/55) were in the wide margin group and 2 cases (3.6%, 2/55). The incidence of postoperative liver dysfunction in the wide margin group was higher than that in the narrow margin group, the difference was statistically significant difference ( χ2=4.58, P=0.032). Conclusion:A surgical margin >10 mm can improve the relapse free survival rate, but it will increase the incidence of postoperative liver dysfunction.

Objective To investigate the effect of epifriedelanol(Epi)on gene expression of P-glycoprotein(P-gp)in human colorectal adenocarcinoma cell line LS174T and its mechanism.Methods LS174T cells were divided into control group and experimental-L,-M,-H groups.Experimental-L,-M,-H groups were treated with 5,10,20 μmol·L-1 Epi,respectively.Control group was treated with 0.1％dimethyl sulfoxide.Polymerase chain reaction was used to detect the mRNA expression level of P-gp.Theeffect of Epi on multidrug resistance protein 1(MDR1/P-gp)luciferase activity was investigated by pregnane X receptor(PXR)-MDR1/P-gp dual luciferase reporter gene assay.In addition,Western Blot was used to detect the protein expression level of P-gp and the nuclear factor-κB(NF-κB)pathway related proteins.Results The relative expression levels of P-gp mRNA in experimental-M,-H groups and control group were 52.24±5.19,23.00±3.52 and 100.00±9.00;the relative expression levels of P-gp protein were 86.37±9.96,74.85±15.92 and 100.00±12.91;the relative activities P-gp luciferase were 230.19±41.32,203.10±52.84 and 279.67±19.20;the relative expression levels of p65(RelA/p65)in nucleus were 132.36±23.93,145.96±25.15 and 100.00±10.88;the relative expression levels of phosphorylation NF-κB inhibits protein kinase α/β(p-IKKα/β)in cytoplasm were 184.00±54.82,290.10±49.59 and 100.00±15.34;the relative expression levels of phosphorylated NF-κB inhibitory protein α(p-IκBα)in cytoplasm were 125.73±18.77,133.69±20.25 and 100.00±8.12;the relative expression levels of IκBα in cytoplasm were 78.36±14.83,70.44±14.57 and 100.00±22.82,respectively.The above indexes of experimental-M and experimental-H groups were compared with control group,and the differences were statistically significant(P＜0.05,P＜0.01,P＜0.001).Conclusion Epi can down-regulate the gene expression of P-gp in human colorectal adenocarcinoma cell line LS174T,and the mechanism may be related to activation of NF-κB and suppression of PXR.

With the extended survival period of breast cancer patients and the increasing health demands, the concomitant diseases of breast cancer have gradually attracted the attention of both doctors and patients, and it is imperative to conduct comprehensive management of these diseases, in which the general practitioners, as the more comprehensive and complex medical talents, have not yet played their due roles. In this article, we report two cases of comprehensive management of concomitant diseases of breast cancer through collaboration of general practitioners and specialists (integrated general and specialist care). The role and function of general practitioners in this process were deeply analyzed, and the establishment of a consultation-liaison general practice model to further promote the role of integrated general and specialist care in integrated oncology care was advocated.

Objective To investigate the effect of epifriedelanol(Epi)on gene expression of P-glycoprotein(P-gp)in human colorectal adenocarcinoma cell line LS174T and its mechanism.Methods LS174T cells were divided into control group and experimental-L,-M,-H groups.Experimental-L,-M,-H groups were treated with 5,10,20 μmol·L-1 Epi,respectively.Control group was treated with 0.1％dimethyl sulfoxide.Polymerase chain reaction was used to detect the mRNA expression level of P-gp.Theeffect of Epi on multidrug resistance protein 1(MDR1/P-gp)luciferase activity was investigated by pregnane X receptor(PXR)-MDR1/P-gp dual luciferase reporter gene assay.In addition,Western Blot was used to detect the protein expression level of P-gp and the nuclear factor-κB(NF-κB)pathway related proteins.Results The relative expression levels of P-gp mRNA in experimental-M,-H groups and control group were 52.24±5.19,23.00±3.52 and 100.00±9.00;the relative expression levels of P-gp protein were 86.37±9.96,74.85±15.92 and 100.00±12.91;the relative activities P-gp luciferase were 230.19±41.32,203.10±52.84 and 279.67±19.20;the relative expression levels of p65(RelA/p65)in nucleus were 132.36±23.93,145.96±25.15 and 100.00±10.88;the relative expression levels of phosphorylation NF-κB inhibits protein kinase α/β(p-IKKα/β)in cytoplasm were 184.00±54.82,290.10±49.59 and 100.00±15.34;the relative expression levels of phosphorylated NF-κB inhibitory protein α(p-IκBα)in cytoplasm were 125.73±18.77,133.69±20.25 and 100.00±8.12;the relative expression levels of IκBα in cytoplasm were 78.36±14.83,70.44±14.57 and 100.00±22.82,respectively.The above indexes of experimental-M and experimental-H groups were compared with control group,and the differences were statistically significant(P＜0.05,P＜0.01,P＜0.001).Conclusion Epi can down-regulate the gene expression of P-gp in human colorectal adenocarcinoma cell line LS174T,and the mechanism may be related to activation of NF-κB and suppression of PXR.

Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

Objective To evaluate the efficacy of transurethral resection of bladder tumor(TURBT)in treating cystitis glandularis(CG),and to explore the influencing factors.Methods A retrospective analysis was conducted on 243 CG patients treated with TURBT during Jan.2013 and Dec.2020 in our hospitals.Postoperative efficacy was assessed using global response assessment(GRA).The correlation between GRA score and the demographic characteristics,comorbidities,initial complaints,and postoperative recurrence was determined with logistic regression analysis.Results Among the 243 patients,3.70％(9/243)had dysplasia,2.47％(6/243)had exuberant hyperplasia of Brinell's nest,and 2.06％(5/243)had intestinal metaplasia.The mean GRA score was(2.02±0.72)after a follow-up of(47.10±28.53)months.Re-operation was performed in 10.29％(25/243)of the patients due to recurrence,and the improvement of hydronephrosis and dysuria was 70.59％(12/17)and 50.00％(15/30),respectively.Pelvic fat increase developed in 1 patient(0.41％)after surgery.Logistic regression analysis showed that postoperative GRA score was not significantly correlated with demographic characteristics,body mass index,comorbidities,alcoholism and postoperative recurrence(P＞0.05).Conclusion TURBT is an effective method in the treatment of CG,which can significantly improve patients'hydronephrosis and dysuria.However,approximately 10％of the patients experience recurrence,necessitating further surgery,which suggests the need for vigilance regarding potential recurrence during treatment.