As a ligand-dependent transcription factor,retinoid-associated orphan receptor γt(RORyt)that controls T helper(Th)17 cell differentiation and interleukin(IL)-17 expression plays a critical role in the pro-gression of several inflammatory and autoimmune conditions.An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORyt to decrease Th17 cell development and IL-17 production.Several RORyt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORyt by binding to orthosteric-or allosteric-binding sites in the ligand-binding domain.Some of small-molecule inhibitors have entered clinical evaluations.Therefore,in current review,the role of RORyt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted.Notably,the recently developed RORyt inhibitors were summarized,with an emphasis on their optimization from lead compounds,ef-ficacy,toxicity,mechanisms of action,and clinical trials.The limitations of current development in this area were also discussed to facilitate future research.

Objective: To compare the prognosis and perioperative situation of patients with stage Ⅱ endometrial cancer (EC) between radical hysterectomy/modified radical hysterectomy (RH/mRH) and simple hysterectomy (SH). Methods: A total of 47 patients diagnosed EC with stage Ⅱ [International Federation of Gynecology and Obstetrics (FIGO) 2009] by postoperative pathology, from January 2006 to January 2021 in Peking University People's Hospital, were analyzed retrospectively. The patients were (54.4±10.7) years old, and the median follow-up time was 65 months (ranged 9-138 months). They were divided into RH/mRH group (n=14) and SH group (n=33) according to the scope of operation. Then the prognosis of patients between the groups were compared, and the independent prognostic factors of stage Ⅱ EC were explored. Results: (1) The proportions of patients with hypertension in RH/mRH group and SH group were 2/14 and 45% (15/33), the amounts of intraoperative blood loss were (702±392) and (438±298) ml, and the incidence of postoperative complications were 7/14 and 15% (5/33), respectively. There were significant differences (all P<0.05). (2) The median follow-up time of RH/mRH group and SH group were 72 vs 62 months, respectively (P=0.515). According to Kaplan-Meier analysis and log-rank method, the results showed that there were no significant difference in 5-year progression-free survival (PFS) rate (94.3% vs 84.0%; P=0.501), and 5-year overall survival rate (92.3% vs 92.9%; P=0.957) between the two groups. Cox survival analysis indicated that age, pathological type, serum cancer antigen 125 (CA₁₂₅), and estrogen receptor (ER) status were associated with 5-year PFS rate (all P<0.05). But the scope of hysterectomy (RH/mRH and SH) did not affect the 5-year PFS rate of stage Ⅱ EC patients (P=0.508). And level of serum CA₁₂₅ and ER status were independent prognostic factors for 5-year PFS rate (all P<0.05). Conclusions: This study could not find any survival benefit from RH/mRH for stage Ⅱ EC, but increases the incidence of postoperative complications. Therefore, the necessity of extending the scope of hysterectomy is questionable.
Female ; Humans ; Adult ; Middle Aged ; Aged ; Disease-Free Survival ; Retrospective Studies ; Neoplasm Staging ; Prognosis ; Endometrial Neoplasms/pathology* ; Hysterectomy/methods* ; Postoperative Complications/epidemiology* ; Uterine Cervical Neoplasms/pathology*

Objective: To explore the effects of preoperative hysteroscopic guided biopsy and segmental diagnosis and curettage on the risk of abdominal dissemination and prognosis of non-endometrioid carcinoma. Methods: The clinical and pathological data of 97 patients who underwent surgical treatment and were pathologically confirmed as non-endometrioid carcinoma (including serous carcinoma, clear cell carcinoma, mixed adenocarcinoma, and undifferentiated carcinoma, etc.) from October 2008 to December 2021 in Peking University People's Hospital, were collected for retrospective analysis. According to preoperative diagnostic methods, they were divided into hysteroscopic group (n=44) and non-hysteroscopic group (n=53). The impact of hysteroscopy examination on peritoneal cytology and prognosis was analyzed. Results: (1) There were no statistical differences in age, body mass index, tumor size, pathological characteristics, and treatment methods between the hysteroscopic group and the non-hysteroscopic group (all P>0.05), but the proportion of stage Ⅰ-Ⅱ patients in the hysteroscopic group was significantly higher than that in the non-hysteroscopic group [68% (30/44) vs 47% (25/53); χ²=4.32, P=0.038]. (2) Among 97 patients, 25 (26%, 25/97) of them were cytologically positive for ascites. The hysteroscopic group had a lower positive rate of peritoneal cytology than that in the non-hysteroscopy group, which was significantly different [11% (5/44) vs 38% (20/53); χ²=8.74, P=0.003]. Stratification according to surgical and pathological stages showed that the positive rate of peritoneal cytology in the hysteroscopic group (3%, 1/30) was lower than that in the non-hysteroscopic group (12%, 3/25) in the 55 patients with stage Ⅰ-Ⅱ, and that in the hysteroscopic group (4/14) was also lower than that in the non-hysteroscopic group (61%, 17/28) in the 42 patients with stage Ⅲ-Ⅳ. There were no significant differences (all P>0.05). (3) The 5-year disease-free survival (DFS) rate of the hysteroscopic group and the non-hysteroscopic group were respectively 72.7% and 60.4%, and there was no significant difference between the two groups (P=0.186). After stratification according to staging, the 5-year DFS rate were respectively 90.0% and 72.0% (P=0.051) between the hysteroscopic and non-hysteroscopic groups of patients in stage Ⅰ-Ⅱ, and 35.7% and 50.0% (P=0.218) between the hysteroscopic and non-hysteroscopic groups of patients in stage Ⅲ-Ⅳ, in which there were not statistically significant differences. The 5-year overall survival (OS) rate were respectively 86.4% and 81.1% between the hysteroscopic group and the non-hysteroscopic group, with no significant difference between the two groups (P=0.388). The 5-year OS rate were respectively 93.3% and 96.0% in the hysteroscopic group and non-hysteroscopic group for patients with stage Ⅰ-Ⅱ(P=0.872), and 71.4% and 67.9% in the hysteroscopic group and non-hysteroscopic group in patients with stage Ⅲ-Ⅳ (P=0.999), with no statistical significance. Conclusions: Diagnostic hysteroscopy do not increase the rate of positive peritoneal cytology result at the time of surgery in this cohort, and no significant correlation between preoperative hysteroscopy examination and poor prognosis of non-endometrioid carcinoma is observed. Therefore, preoperative hysteroscopic guided biopsy and segmental diagnosis and curettage in non-endometrioid carcinoma maybe safe.
Female ; Pregnancy ; Humans ; Endometrial Neoplasms/pathology* ; Retrospective Studies ; Hysteroscopy/methods* ; Cytology ; Prognosis ; Carcinoma ; Neoplasm Staging

Aim To explore the apoptosis of small eell lung eancer ( SCLC ) eells HI688 and H446 induced by nitidine chloride and its possible mechanism.Methods The effect of nitidine chloride or cisplatin ( DDP ) on the activity of SCLC cells was detected by j J MTT method; the morphological changes of cells trea¬ted with nitidine chloride or DDP were observed by in- verted fluorescence microscope and HE staining; the effect of nitidine chloride or DDP on apoptosis was de¬tected by flow cytometry; the effect of apoptosis inhibi¬tor Z-VAD-FMK on apoptosis induced by nitidine chlo¬ride or DDP was detected by MTT method.The expres¬sions of Bax , Bcl-2, caspase-3 , PARP, p-PI3K and p- Akt in the cells treated with nitidine chloride or DDP were detected by Western blot.Results MTT results showed that the viability of SCLC cells was significantly reduced after 48 hours of treatment with nitidine chlo¬ ride; compared with DDP, nitidine chloride could in¬hibit SCLC cells with less IC50; inverted fluorescence microscope and HE staining showed that nitidine chlo¬ride could induce apoptosis in SCLC cells, similar to DDP; flow cytometry showed that nitidine chloride J J could induce apoptosis in SCLC cells.The results of MTT assay showed that the inhibitory effect of nitidine chloride on apoptosis of SCLC cells could be partially antagonized by apoptosis inhibitor Z-VAD-FMK.West¬ern blot results showed that, similar to DDP, nitidine chloride could inhibit the expression of PI3K and Akt, increase Bax, inhibit Be 1-2, and promote the cleavage of caspase-3 and PAH P.Conclusion Nitidine chlo¬ride can induce apoptosis of SCLC cells by inhibiting the activation of P13K and Akt.

Objective: To analyze and evaluate the differences in sex hormones after laparoscopic Roux-en-Y Gastric Bypass Surgery (LRYGB) and laparoscopic sleeve gastrectomy (LSG) in male patients with obesity. Methods: This study was a retrospective cohort study. The inclusion criteria were (1) male patients with obesity who met the surgical indications of the "Chinese Guidelines for Surgical Treatment of Obesity and Type 2 Diabetes" (2019 Edition); (2) patients with a body mass index (BMI) of ≥27.5 kg/m2 and obesity-related metabolic diseases, or patients with severe obesity and a BMI of ≥35 kg/m2; and (3) sex hormone levels checked 1 year after surgery. The exclusion criteria included (1) patients with endocrine diseases (thyrotoxicosis, hyperprolactinemia) and hypothalamic-pituitary lesions and (2) those with severe major organ dysfunction who could not tolerate anesthesia or surgery. According to the above criteria, the clinical data of male patients with obesity admitted to the Gastrointestinal Surgery/Bariatric Center of the First Affiliated Hospital of Jinan University from October 2017 to January 2020 were included. A total of 52 male patients with obesity were included in this study. The mean age, body weight, BMI, and total testosterone level were (29.3±10.2) years, (123.6±35.4) kg, (40.1±11.1) kg/m², and 7.6 (5.5, 9.1) nmol/L, respectively. Forty-five patients (86.5%) exhibited testosterone deficiency. Among all the patients, 29 underwent LSG (LSG group) and 23 underwent LRYGB surgery (LRYGB group). The main outcome measure was the change in sex hormone levels before and after bariatric surgery in all the patients. The secondary outcome measures were the comparison of changes in sex hormone levels before and after LSG and LRYGB. Results: Pearson correlation analysis showed that preoperative estradiol was positively correlated with waist circumference (R=0.299, P<0.05), hip circumference (R=0.326, P<0.05), and chest circumference (R=0.388, P<0.05). Testosterone was negatively correlated with BMI (R=-0.563, P<0.01), waist circumference (R=-0.521, P<0.01), hip circumference (R=-0.456, P<0.01), chest circumference (R=-0.600, P<0.01), and neck circumference (R=-0.547, P<0.01). One year following bariatric surgery, the serum testosterone (7.6 [5.5, 9.1] nmol/L vs. 13.6 [10.5, 15.4] nmol/L, Z=-5.910, P<0.001), follicle-stimulating hormone (4.7 [2.7, 5.3] IU/L vs. 6.5 [3.6, 7.8] IU/L, Z=-4.658, P<0.001), and progesterone (1.2 [0.4, 1.5] nmol/L vs. 1.9 [0.8, 1.3] nmol/L, Z=-2.542, P=0.011) levels were significantly higher in all the patients. Both estradiol (172.8 [115.6, 217.5] pmol/L vs. 138.3 [88.4, 168.1] pmol/L, Z=-2.828, P=0.005) and prolactin (11.4 [6.4, 14.6] mIU/L vs. 8.6 [4.8, 7.3] mIU/L, Z=-2.887, P=0.004) levels were decreased. In addition to prolactin levels in the LRYGB group, there were statistically significant differences in the levels of estradiol (P=0.030), follicle-stimulating hormone (P < 0.001), luteinizing hormone (P=0.033), progesterone (P=0.034), and testosterone (P<0.001) compared with their preoperative levels. In the LSG group, there were statistically significant differences in the levels of follicle-stimulating hormone (P=0.011), prolactin (P=0.023), and testosterone (P<0.001) compared with their preoperative levels. Conclusion: The degree of obesity in men was negatively correlated with testosterone levels. Both LRYGB and LSG can significantly improve sex hormone levels in male patients with obesity, and testosterone levels show a significant increase after surgery.
Adult ; Bariatric Surgery ; Body Mass Index ; Diabetes Mellitus, Type 2/surgery* ; Estradiol ; Follicle Stimulating Hormone ; Humans ; Luteinizing Hormone ; Male ; Obesity/surgery* ; Progesterone ; Prolactin ; Retrospective Studies ; Testosterone ; Weight Loss ; Young Adult

Objective:To understand the current status of foreign dual-degree programs of Medical Doctor (MD) and Master of Public Health (MPH) and provide evidence-based decision-making reference for promoting the education of high-level applied public health talents in China.Methods:The list of involved institutions and information of foreign MD-MPH dual-degree programs was collected through literature retrieval, online information searching, and additional survey of key figures. We extracted the details of each project regarding professional fields, core competence, length of schooling, teaching and learning arrangement, internship eligibility, and graduation assessment. Python 3.8.0 was used for data cleaning, and the occurrence frequency of related items in each dimension was calculated.Results:A total of 99 MD-MPH programs from 104 foreign institutions were included, among which 97.1% of them were implemented in universities from the United States. The School of Public Health provided 42.4% (42/99) of the programs. Epidemiology was the major discipline set up among most programs, accounting for 12.0% (29/241) of all the specialties involved. Epidemiological research methods, health policy management and practice, and public health practice were the top 3 core competencies to be mastered. Of the 99 programs, 87 gave information on the length of the program, of which 74.7% (65/87) were five years, 6.9% (6/87) were four years, and 18.4% (16/87) included both 4-year and 5-year programs.Conclusions:The international MD-MPH programs were sophisticated and mainly organized by the School of Public Health alone or in conjunction with the School of Medicine. Epidemiology is the core course and competence objective, with a length of 4-5 years. Through learning experience from international MD-MPH programs and the Chinese unique medical development background, China should optimize its medical education system to develop a suitable talent training strategy for MD-MPH dual-degree programs in the new era.

De-etiolation consists of a series of developmental and physiological changes that a plant undergoes in response to light. During this process light, an important environmental signal, trig-gers the inhibition of mesocotyl elongation and the production of photosynthetically active chloro-plasts, and etiolated leaves transition from the'sink"stage to the'source"stage. De-etiolation has been extensively studied in maize (Zea mays L.). However, little is known about how this transition is regulated. In this study, we described a quantitative proteomic and phosphoproteomic atlas of the de-etiolation process in maize. We identified 16,420 proteins in proteome, among which 14,168 pro-teins were quantified. In addition, 8746 phosphorylation sites within 3110 proteins were identified. From the combined proteomic and phosphoproteomic data, we identified a total of 17,436 proteins. Only 7.0％(998/14,168) of proteins significantly changed in abundance during de-etiolation. In con-trast, 26.6％ of phosphorylated proteins exhibited significant changes in phosphorylation level;these included proteins involved in gene expression and homeostatic pathways and rate-limiting enzymes involved in photosynthetic light and carbon reactions. Based on phosphoproteomic anal-ysis, 34.0％(1057/3110) of phosphorylated proteins identified in this study contained more than 2phosphorylation sites, and 37 proteins contained more than 16 phosphorylation sites, indicating that multi-phosphorylation is ubiquitous during the de-etiolation process. Our results suggest that plants might preferentially regulate the level of posttranslational modifications (PTMs) rather than protein abundance for adapting to changing environments. The study of PTMs could thus better reveal the regulation of de-etiolation.

Tooth preparation is the primary and core operation technique for dental esthetic restoration treatment, due to its effect of providing restoration space, bonding interfaces and marginal lines for dental rehabilitation after tooth tissue reduction. The concept of microscopic minimal invasive dentistry put forward the issue of conducting high-quality tooth preparation, conserve tooth-structure, protect vital pulp and periodontal tissue simultaneously. This study reviewed the concepts, physiology background, design and minimal invasive microscopic tooth preparation, and in the meantime, individualized strategies and the two core elements of tooth preparation (quantity and shape) are listed.
Dental Porcelain ; Dental Restoration, Permanent ; Esthetics, Dental ; Tooth Preparation

Insulin-like growth factor-1 receptor (IGF-1R) is involved in both glucose and bone metabolism. IGF-1R signaling regulates the canonical Wnt/β-catenin signaling pathway. In this study, we investigated whether the IGF-1R/ β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis (DOP). Serum from patients with or without DOP was collected to measure the IGF-1R level using enzyme-linked immunosorbent assay (ELISA). Rats were given streptozotocin following a four-week high-fat diet induction (DOP group), or received vehicle after the same period of a normal diet (control group). Dual energy X-ray absorption, a biomechanics test, and hematoxylin-eosin (HE) staining were performed to evaluate bone mass, bone strength, and histomorphology, respectively, in vertebrae. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to measure the total and phosphorylation levels of IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin. The serum IGF-1R level was much higher in patients with DOP than in controls. DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group. HE staining showed that the histomorphology of DOP vertebrae was seriously impaired, which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae. PCR analysis demonstrated that IGF-1R mRNA expression was significantly up-regulated, and western blotting detection showed that phosphorylation levels of IGF-1R, GSK-3β, and β-catenin were enhanced in DOP rat vertebrae. Our results suggest that the IGF-1R/β-catenin signaling axis plays a role in the pathogenesis of DOP. This may contribute to development of the underlying therapeutic target for DOP.
Aged ; Animals ; Bone Density ; Diabetes Mellitus, Experimental/complications* ; Diabetes Mellitus, Type 2/complications* ; Female ; Humans ; Male ; Middle Aged ; Osteoporosis/etiology* ; Rats ; Receptor, IGF Type 1/physiology* ; Signal Transduction ; Streptozocin ; beta Catenin/physiology*

BACKGROUND: Chinese medicine is effective for preventing and treating glucocorticoid-induced osteoporosis, however, the underlying mechanism remains unclear. DKK1, an inhibitor of Wnt/β-catenin signaling pathway, can be up-regulated by glucocorticoid. Thereafter, DKK1 is an important target in the prevention and treatment of osteoporosis. OBJECTIVE: To explore the regulatory effect of Zuogui pill on DKK1 in the prevention and treatment of glucocorticoid-induced osteoporosis. METHODS: Eighteen three-month-old female Sprague-Dawley rats were randomly divided into three groups: control group, model group and Zuogui pill group. Rats in the model and Zuogui pill groups received the subcutaneous injection of dexamethasone to establish the model of glucocorticoid-induced osteoporosis. The Zuogui pill group rats were administrated Zuogui pill extracts, and the control rats were given the same volume of normal saline. At 1 month after modeling, the lumbar vertebrae were removed to test the bone mass and microstructures by micro-CT scanning. The biomechanical properties were detected by compression test. The mRNA expression levels of DKK1, Runx2 and CTSK were determined by Qpcr. The serum alkaline phosphatase activity was tested. RESULTS AND CONCLUSION: Compared with the control group, in the model group, the volumetric bone mineral density, trabecular bone volume fraction, trabecular number, and trabecular thickness were significantly decreased (P ＜ 0.05), the trabecular separation and structure model index were significantly increased (P ＜ 0.05). The serum alkaline phosphatase activity was on a decline. The mRNA expression level of DKK1 showed a significant up-regulation (P ＜ 0.05). The mRNA expression level of Runx2 showed a down-regulated trend while mRNA expression level of CTSK showed an up-regulated trend. Compared with the model group, the Zuogui pill group showed significantly enhanced volumetric bone mineral density, trabecular bone volume fraction, and trabecular number (P ＜ 0.05); the structure model index was significantly decreased (P ＜ 0.05); the trabecular separation was reduced; the serum alkaline phosphatase activity was enhanced; the mRNA expression level of DKK1 showed a significant down-regulation (P ＜ 0.05); the mRNA expression level of Runx2 showed an up-regulated trend while mRNA expression level of CTSK showed a down-regulated trend. The vertebral compressive strength in the Zuogui pill group was significantly higher than that in the model group (P＜0.05). In summary, Zuogui pill prevents and treats glucocorticoid-induced osteoporosis possibly through the down-regulation of mRNA expression of DKK1.