Hereditary gingival fibromatosis (HGF) is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity. Five distinct loci related to non-syndromic HGF have been identified; however, only two disease-causing genes, SOS1 and REST, inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. Here, based on a family pedigree with 26 members, including nine patients with HGF, we identified double heterozygous pathogenic mutations in the ZNF513 (c.C748T, p.R250W) and KIF3C (c.G1229A, p.R410H) genes within the GINGF3 locus related to HGF. Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo. ZNF513, a transcription factor, binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts. Furthermore, a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513 (p.R250W) or Kif3c (p.R412H) alone do not led to clear phenotypes with gingival fibromatosis, whereas the double mutations led to gingival hyperplasia phenotypes. In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels. ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. In summary, these results demonstrate ZNF513 + KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.
Animals ; Humans ; Mice ; Fibromatosis, Gingival/pathology* ; Gingiva ; Kinesins/genetics* ; Mutation/genetics* ; Phosphatidylinositol 3-Kinases/genetics*

Objective: To establish and validate a nomogram-based predictive model for idiopathic hyperaldosteronism (IHA). Methods: This cross-sectional study was conducted with the collected clinical and biochemical data of patients with primary aldosteronism (PA) including 249 patients with unilateral primary aldosteronism (UPA) and 107 patients with IHA, who were treated at the Department of Endocrinology of the First Affiliated Hospital of Chongqing Medical University from November 2013 to November 2022. Plasma aldosterone concentration (PAC) and plasma renin concentration (PRC) were measured by chemiluminescence. Stepwise regression analysis was applied to select the key predictors of IHA, and a nomogram-based scoring model was developed. The model was validated in another external independent cohort of patients with PA including 62 patients with UPA and 43 patients with IHA, who were diagnosed at the Department of Endocrinology, First Affiliated Hospital of Zhengzhou University. An independent-sample t test, Mann-Whitney U test, and χ² test were used for statistical analysis. Results: In the training cohort, in comparison with the UPA group, the IHA group showed a higher serum potassium level [M(Q₁, Q₃), 3.4 (3.1, 3.8) mmol/L vs. 2.7 (2.1, 3.1) mmol/L] and higher PRC [4.0 (2.1, 8.2) mU/L vs. 1.5 (0.6, 3.4) mU/L] and a lower PAC post-saline infusion test (SIT) [305 (222, 416) pmol/L vs. 720 (443, 1 136) pmol/L] and a lower rate of unilateral adrenal nodules [33.6% (36/107) vs. 81.1% (202/249)]; the intergroup differences in these measurements were statistically significant (all P<0.001). Serum potassium level, PRC, PAC post-SIT, and the rate of unilateral adrenal nodules showed similar performance in the IHA group in the validation cohort. After stepwise regression analysis for all significant variables in the training cohort, a scoring model based on a nomogram was constructed, and the predictive parameters included the rate of unilateral adrenal nodules, serum potassium concentration, PAC post-SIT, and PRC in the standing position. When the total score was ≥14, the model showed a sensitivity of 0.65 and specificity of 0.90 in the training cohort and a sensitivity of 0.56 and specificity of 1.00 in the validation cohort. Conclusion: The nomogram was used to successfully develop a model for prediction of IHA that could facilitate selection of patients with IHA who required medication directly.
Humans ; Hyperaldosteronism/diagnosis* ; Nomograms ; Hypertension ; Cross-Sectional Studies ; Aldosterone ; Saline Solution ; Renin ; Potassium

Objective: To methodically assess the clinical effectiveness and safety of robot-assisted total rectal mesenteric resection (RTME), laparoscopic-assisted total rectal mesenteric resection (laTME), and transanal total rectal mesenteric resection (taTME). Methods: A computer search was conducted on PubMed, Embase, Cochrane Library, and Ovid databases to identify English-language reports published between January 2017 and January 2022 that compared the clinical efficacy of the three surgical procedures of RTME, laTME, and taTME. The quality of the studies was evaluated using the NOS and JADAD scales for retrospective cohort studies and randomized controlled trials, respectively. Direct meta-analysis and reticulated meta-analysis were performed using Review Manager software and R software, respectively. Results: Twenty-nine publications comprising 8,339 patients with rectal cancer were ultimately included. The direct meta-analysis indicated that the length of hospital stay was longer after RTME than after taTME, whereas according to the reticulated meta-analysis the length of hospital stay was shorter after taTME than after laTME (MD=-0.86, 95%CI: -1.70 to -0.096, P=0.036). Moreover, the incidence of anastomotic leak was lower after taTME than after RTME (OR=0.60, 95%CI: 0.39 to 0.91, P=0.018). The incidence of intestinal obstruction was also lower after taTME than after RTME (OR=0.55, 95%CI: 0.31 to 0.94, P=0.037). All of these differences were statistically significant (all P<0.05). There were no statistically significant differences between the three surgical procedures regarding the number of lymph nodes cleared, length of the inferior rectal margin, or rate of positive circumferential margins (all P>0.05). An inconsistency test using nodal analysis revealed no statistically significant differences between the results of direct and indirect comparisons of the six outcome indicators (all P>0.05). Furthermore, we detected no significant overall inconsistency between direct and indirect evidence. Conclusion: taTME has advantages over RTME and laTME, in terms of radical and surgical short-term outcomes in patients with rectal cancer.
Humans ; Robotics ; Robotic Surgical Procedures/adverse effects* ; Network Meta-Analysis ; Retrospective Studies ; Postoperative Complications/etiology* ; Transanal Endoscopic Surgery/methods* ; Rectum/surgery* ; Rectal Neoplasms/pathology* ; Laparoscopy/methods* ; Treatment Outcome

Bone defects caused by different causes such as trauma, severe bone infection and other factors are common in clinic and difficult to treat. Usually, bone substitutes are required for repair. Current bone grafting materials used clinically include autologous bones, allogeneic bones, xenografts, and synthetic materials, etc. Other than autologous bones, the major hurdles of rest bone grafts have various degrees of poor biological activity and lack of active ingredients to provide osteogenic impetus. Bone marrow contains various components such as stem cells and bioactive factors, which are contributive to osteogenesis. In response, the technique of bone marrow enrichment, based on the efficient utilization of components within bone marrow, has been risen, aiming to extract osteogenic cells and factors from bone marrow of patients and incorporate them into 3D scaffolds for fabricating bone grafts with high osteoinductivity. However, the scientific guidance and application specification are lacked with regard to the clinical scope, approach, safety and effectiveness. In this context, under the organization of Chinese Orthopedic Association, the Expert consensus for the clinical application of autologous bone marrow enrichment technique for bone repair ( version 2023) is formulated based on the evidence-based medicine. The consensus covers the topics of the characteristics, range of application, safety and application notes of the technique of autologous bone marrow enrichment and proposes corresponding recommendations, hoping to provide better guidance for clinical practice of the technique.

The acute combination fractures of the atlas and axis in adults have a higher rate of neurological injury and early death compared with atlas or axial fractures alone. Currently, the diagnosis and treatment choices of acute combination fractures of the atlas and axis in adults are controversial because of the lack of standards for implementation. Non-operative treatments have a high incidence of bone nonunion and complications, while surgeries may easily lead to the injury of the vertebral artery, spinal cord and nerve root. At present, there are no evidence-based Chinese guidelines for the diagnosis and treatment of acute combination fractures of the atlas and axis in adults. To provide orthopedic surgeons with the most up-to-date and effective information in treating acute combination fractures of the atlas and axis in adults, the Spinal Trauma Group of Orthopedic Branch of Chinese Medical Doctor Association organized experts in the field of spinal trauma to develop the Evidence-based guideline for clinical diagnosis and treatment of acute combination fractures of the atlas and axis in adults ( version 2023) by referring to the "Management of acute combination fractures of the atlas and axis in adults" published by American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) in 2013 and the relevant Chinese and English literatures. Ten recommendations were made concerning the radiological diagnosis, stability judgment, treatment rules, treatment options and complications based on medical evidence, aiming to provide a reference for the diagnosis and treatment of acute combination fractures of the atlas and axis in adults.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

A new quercetin nanocrystals self-stabilized Pickering emulsion(QT-NSSPE) was prepared by high-pressure homogenization combined with probe ultrasonic method. The influences of oil fraction, quercetin(QT) concentration, and pH of water phase on the formation of QT-NSSPE were investigated. On this basis, the QT-NSSPE prepared under optimal conditions was evaluated in terms of microstructure, stability, and in vitro release and the droplet size and drug loading were 15.82 μm and 4.87 mg·mL~(-1), respectively. The shell structure formed by quercetin nanocrystals(QT-NC) on the emulsion droplet surface was observed under a scanning electron microscope(SEM). X-ray diffraction(XRD) showed that the crystallinity of adsorbed QT-NC decreased significantly as compared with the raw QT. There were not significant changes of QT-NSSPE properties after 30 days of storage at room temperature. The in vitro release experiment confirmed that QT-NSSPE has a higher accumulative release rate than the raw QT. All these results indicated that QT-NSSPE has a great stability and a satisfactory in vitro release behavior, which is a promising new oral delivery system for QT.
Emulsions/chemistry* ; Nanoparticles ; Particle Size ; Quercetin ; Water/chemistry*

Objective:To investigate the correlation between serum thyroglobulin antibody (TG-Ab) and thyroid peroxidase antibody (TPO-Ab) cconcentrations and arteriosclerosis development in middle-aged and older adult patients with depression.Methods:A total of 200 middle-aged and older adult patients with depression who received treatment in the Third People's Hospital of Huzhou from January 2018 to October 2019 were included in this study. They were divided into four groups ( n = 50/group) according to TG-Ab and TPO-Ab test results: TG-Ab-positive (group 1), TPO-Ab-positive (group 2), TG-Ab-positive and TPO-Ab-positive (group 3), TG-Ab-negative and TPO-Ab-negative (control group). Serum thyroid hormone level, ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity, and the incidences of intima-media thickening and plaque formation in the lower extremity arteries were compared between groups. Results:Total thyroxine concentration in the control group, groups 1, 2 and 3 was (89.96 ± 2.45) nmol/L, (101.29 ± 3.35) nmol/L, (90.09 ± 2.70) nmol/L, (97.55 ± 2.57) nmol/L, respectively. There was a significant difference in total thyroxine concentration between groups ( F = 3.85, P < 0.05). Brachial-ankle pulse wave velocity in the control group, groups 1, 2, and 3 was (1 327.55 ± 67.78) cm/s, (1 510.36 ± 83.05) cm/s, (1 422.71 ± 71.40) cm/s, (1 533.95 ± 87.01) cm/s, respectively. There was a significant difference in brachial-ankle pulse wave velocity between groups ( F = 65.12, P < 0.05). The incidence of intima-media thickening in the control group, groups 1, 2, and 3 was 18% (9/50), 50% (25/50), 32% (16/50), 60% (30/50), respectively. The incidence of plaque formation in the control group, groups 1, 2, and 3 was 22% (11/50), 56% (28/50), 40% (20/50), 70% (35/50), respectively. There were significant differences in intima-media thickening and plaque formation between groups ( χ2 = 21.83, 25.77, all P < 0.001). Logistic multivariate regression analysis showed that age ( OR = 0.953) and TG-Ab ( OR = 1.116) were independent risk factors for developing arteriosclerosis in middle-aged and older adult patients with depression ( P < 0.05). Conclusion:TG-Ab-positive results are an independent risk factor for developing arteriosclerosis in middle-aged and older adult patients with depression. TPO-Ab-positive results have a synergistic effect on the occurrence and development of arteriosclerosis in middle-aged and older adult patients with depression. Monitoring serum TG-Ab and TPO-Ab concentrations is of great clinical significance for the prevention and treatment of arteriosclerosis in middle-aged and older adult patients with depression.

In the past few years, continuous manufacturing(CM) has been put forward by the FDA. Pharmaceutical enterprises are encouraged to promote the implementation of CM, which has become a hot research direction of pharmaceutical technology. In February 2019, the FDA issued a draft guideline for the implementation of CM, which greatly promoted the development of CM and provided reference for continuous manufacturing of traditional Chinese medicine(TCM). The production process of TCM is a complex system. With the innovation of production equipment and the promotion of automation and informatization of TCM production, the exis-ting policies, regulations and traditional production control capacity are difficult to meet the market demand for high-quality TCM pro-ducts. In this paper, we reviewed the new technologies and methods of quality control in accordance with the characteristics of TCM production by referring to modern manufacturing technology, information technology and quality control technology. Based on the "QbD" theory and "PAT" technology, process knowledge system(PKS), an advanced control strategy, was proposed to provide a reference for the implementation of CM in TCM production.
Commerce ; Drugs, Chinese Herbal ; Medicine, Chinese Traditional ; Quality Control ; Technology, Pharmaceutical

Local focal adhesion kinase (FAK) is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation, development, metastasis and invasion, and is considered to be an important target for the development of antineoplastic drugs. It has both kinase-dependent and non-kinase-dependent scaffolding functions. However, traditional small molecular inhibitors can only inhibit its kinase-dependent activity, so it is difficult to target the kinase-independent scaffolding function. Therefore, there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors. Proteolysis targeting chimera (PROTAC) is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system. The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein, thus eliminating the scaffolding function of FAK. In this review, FAK protein, the signaling pathway, and small molecule inhibitors are briefly described, and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.