Tirzepatide,a new glucagon-like peptide-1/glucose dependent insulin stimulating polypeptide(GLP-1/GIP)double receptor agonist,has been clinically shown to have a strong hypoglycemic effect and a very significant effect on reducing body mass.It can improve insulin sensitivity,and has superior cardiovascular protection and the effect of improving nonalcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH),with few side effects and good compliance.As a dual gut hor-mone agonist,tirzepatide shows strong potential to improve metabolic levels.This article reviews the mechanism of action and clini-cal studies of the GLP-1/GIP dual receptor agonist tirzepatide.

Objective:To compare the effects of different test meals on postprandial triglycerides and to optimize the standard meal composition and the blood sampling protocol for the oral fat tolerance test.Methods:This study is a prospective, open-label, randomized, cross-over trial. In March 2023, 36 volunteers were recruited in Hebei General Hospital. They underwent a health examination and oral glucose tolerance test. Twenty-six healthy volunteers(11 males and 15 females) were included in this study, with an average age of(39.08±4.56) years. Each volunteer received 75 g protein meal, 75 g fat meal, 700 kcal fixed-calorie high-fat mixed meal, and a high-fat mixed meal with energy adjusted based on 10 kcal/kg body weight. A one-week washout period of regular diet was applied before each trial. Blood was collected at fasting status and 1, 2, 3, 4, 5, and 6 hours after a meal to detect serum triglycerides, total cholesterol, low density lipoprotein-cholesterol(LDL-C), high density lipoprotein-cholesterol(HDL-C), glucose, and insulin. The variations of postprandial metabolic indicators over time following the consumption of different test meals were analyzed. The disparities in postprandial metabolic responses between the two types of mixed meals were compared.Results:The protein meal, fat meal, fixed-calorie high-fat mixed meal, and adjusted-calorie high-fat mixed meal resulted in postprandial triglyceride increases of 22.45%, 115.40%, 77.14%, and 63.63%, and insulin increase of 560.43%, 85.69%, 554.18%, and 598.97%, respectively, and with reductions in total cholesterol, LDL-C, and HDL-C ranging from 5.64%-21.81%, respectively. The blood glucose changed slightly. Changes in metabolic indicators mainly occured within 4 hours. The comparison of the characteristics of postprandial triglycerides between the two high-fat mixed meals showed no statistically significant differences( P>0.05). Conclusion:A standardize protocol with a 700 kcal fixed-calorie high-fat mixed meal as test meal, and blood lipid levels measured at fasting and at 1, 2, 3, and 4 hours after consumption, can serve as an optimized approach for oral fat tolerance test.

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Objective:To investigate the clinicopathological features of metastatic ovarian tumors from digestive system.Methods:The clinicopathological and follow-up data of 21 patients with metastatic ovarian tumor from digestive system were collected from April 2006 to January 2020 in the Maternity Hospital of Dalian Women and Children′s Medical Group. The pathological slides were reviewed, immunostained by EnVision method, and the clinicopathological features were summarized.Results:Twenty-one cases, aging from 26 to 66 years (average 41.5 years), were treated with chief complaint of abdominal pain, menstrual disorder or pelvic mass. The incidence of bilateral ovarian tumor was 81.0% (17/21), with a diameter of 0.2 to 20.0 cm. Most of tumors were solid and cystic, nodular or lobulated. Microscopically, tumor cells diffusely infiltrated ovarian stroma, accompanied with stromal proliferation and luteinization obviously. Metastatic gastric cancers were mainly signet-ring cell carcinomas, with cytokeratin 7 (CK7) positive, tail homeobox transcription factor 2 (CDX2) and cytokeratin 20 (CK20) partially positive, paired-box gene 8 (PAX8) and special AT-rich sequence binding protein 2 (SATB2) negative; metastatic colorectal cancers were mainly characterized by atypical glands, forming single cells or cribriform structure; metastatic appendix tumors were mostly low-grade tumor cells similar to ovarian borderline tumors and abundant extracellular mucinous, accompanied by peritoneal pseudomyxoma. The CK7 and PAX8 were negative, while the CK20, CDX2 and SATB2 were positive in patients with metastatic ovarian tumor from colorectal cancer and appendix tumor. The average follow-up time was 36 months, 18 patients relapsed within 5 years, 15 patients died; 3 patients were lost to follow-up.Conclusions:The ovarian metastatic tumors from digestive system are mostly bilateral, mainly solid and cystic. Microscopically, they show diffuse interstitial infiltration of tumor cells. The diagnosis should be combined with medical history, clinical symptoms, gross and histological features of tumor and immunohistochemistry, which should be mainly differentiated from primary mucinous ovarian tumor. The overall prognosis is poor.

Objective: To investigate the clinicopathological characteristics of primary ovarian mucinous adenocarcinoma. Methods: The clinical data of 28 patients with primary ovarian mucinous adenocarcinoma from April 2006 to December 2018 in Dalian Maternity Hospital Affiliated to Dalian Medical University were retrospectively analyzed. The pathological sections were reviewed, and the clinicopathological characteristics were analyzed by immunohistochemical staining. Results: Among 28 patients, the average age of patients was 46.5 (22 to 64) years. Ten cases were found by health examination, 15 cases showed lower abdominal discomfort, and 3 cases had irregular vaginal bleeding. Pelvic ultrasound examination showed heterogeneous internal echoes in adnexal region, and serum tumor marker levels did not significantly increase. The diameters of tumors were 8 to 32 cm, with an average of 16.5 cm. The unilateral ovarian tumor was in 26 cases, and bilateral ovarian tumor was in 2 cases. Most of tumors were solid-cystic with viscous liquid or jelly-like substance inside the cystic, accompanied with solid papillae or nodules. Microscopically, tumors were composed with gastrointestinal epithelium. Eighteen cases had borderline mucinous tumors with focal fusion infiltrating carcinoma; 10 cases had fusion infiltrating carcinoma dominant, while there were 2 cases whose tumor exhibited focal invasive infiltration. Immunohistochemical result showed that the positive rates of cytokeratin (CK) 7, CK20 and tail-type homeobox gene (CDX) 2 were 100.0% (28/28), 71.4% (20/28) and 53.6% (15/28); the positive rates of paired box gene (PAX) 8 and special AT-rich sequence-binding protein (SATB) 2 were 14.3%(4/28) and 10.7% (3/28). According to the ovarian carcinoma stage standard of International Federation of Gynecology and Obstetrics (FIGO) 2014, Ⅰ stage was in 21 cases, Ⅱstage in 4 cases, Ⅲ stage in 2 cases, and Ⅳ stage in 1 case. The patients were followed up for 3 to 120 months, with an average of 55 months. No recurrence or metastasis was in 17 cases (FIGO Ⅰ stage 16 cases, FIGO Ⅱ stage 1 case); recurrent within 2 years was in 5 cases (FIGO Ⅱ stage 2 cases, Ⅲ stage 2 cases, Ⅳ stage 1 case), of which 4 cases died within 5 years (FIGO Ⅱ stage 1 case, Ⅲ stage 2 cases, Ⅳ stage 1 case); lost to follow-up was in 6 cases (FIGO Ⅰ stage 5 cases, FIGO Ⅱ stage 1 case). Conclusions Primary ovarian mucinous adenocarcinoma is rare, and it has no specific clinical symptoms. It is mainly characterized by fusion infiltration. Immunohistochemical result shows that CK7 is always positive, the expressions of CK20 and CDX2 are different degree, and SATB2 and PAX-8 are mostly negative. Prognosis is closely related with FIGO stage, and the patients with FIGO Ⅰ stage have good prognoses, Ⅲ and Ⅳ stage have poor prognoses. It should be distinguished from ovarian metastatic mucinous tumor.

Objective: To investigate the effect of metformin on autophagy in muscle cells exposed to palmitic acid, and to explore its mechanism. Methods: L6 rat myoblasts were incubated with palmitic acid at various concentrations(0.1, 0.2, 0.4, 0.6 mmol/L) and metformin(0.5, 1, 2, 5, 10 mmol/L) for 24 h. CCK8 method was used to detect the survival rate of muscle cells. After muscle cells were treated with palmitic acid and metformin for 24 h, mRNA and protein expressions of microtubule-associated protein11ight chain3(LC3Ⅱ), Beclin 1, p62, and silent mating type information regulation2 homolog-3(SIRT3) were detected by RT-PCR and Western blot, respectively. AMP-activated protein kinase(AMPK) phosphorylation level was detected by Western blot. Results: Palmitic acid dose-dependently decreased the survival rate of muscle cells, which was attenuated by metformin at the concentration of 2 mmol/L. After muscle cells were incubated with 0.4 mmol/L palmitic acid and 2 mmol/L metformin for 24 h, palmitic acid significantly reduced the mRNA and protein expressions of LC3Ⅱ, Beclin1, and SIRT3 as well as phosphorylation level of AMPK(all P<0.05), and increased p62 mRNA and protein expressions(P<0.05). Those effects were all antagonized by metformin(all P<0.05). Conclusions Metformin treatment may promote the autophagy of muscle cells exposed to palmitic acid through AMPK/STRT3 pathway.

Objective:To investigate the diagnosis and treatment of congenital leukemia and the main factors affecting its prognosis.Methods:Clinical data of children with congenital leukemia admitted to Zhengzhou Children′s Hospital from July 2007 to December 2017 were retrospectively collected.Their clinical characteristics, chemotherapy and factors affecting their long-term survival were analyzed.Results:A total of 23 cases of congenital leukemia were collected, who mostly complained of " increased white blood cells, skin nodules and skin hemorrhage" . Among them, 10 cases abandoned the treatment, who all died according to the follow-up results.Among the 13 treated cases, 7 cases were male, and 6 were female.One of the 13 cases was a twin.Eight cases were acute myeloid leukemia, and 5 cases were acute lymphoblastic leukemia.One case did not perform the fusion gene test. MLL gene was positive in 2 cases and negative in 10 cases.No other fusion genes were detected.Karyotype analysis showed that 1 case was 21-trisomy and 12 cases had a normal karyotype.All 13 patients received symptomatic and/or reduced chemotherapy.The median follow-up time was 4 years and 11 months.Six cases recovered and 7 cases died during the follow-up.One case was diagnosed with acute lymphoblastic leukemia on the 6 th day after the birth in another hospital.He was not treated timely and came to Zhengzhou Children′s Hospital with general contract blocks at the age of 32 days.After checking, he was diagnosed with center leukemia and testicular leukemia.He developed a severe infection in the lung and brain after strong chemotherapy, and died even after the remote consultation with Lurie Children′s Hospital of Chicago.The other 6 cases died of severe infection and multiple organ injuries after chemotherapy, and no one died of leukemia relapse. Conclusion:Reduction chemotherapy may be an important treatment to children with congenital leukemia.

Objective To investigate the application and clinical significance of human papilloma virus (HPV) E6/E7 mRNA detection in cervical atypical glandular cells (AGC). Methods Four hundred and forty-five cervical AGC patients diagnosed by thin-layer liquid-based cytology in the Maternity Affiliated Hospital of Dalian Medical University from January 2014 to March 2018 were collected. Histological follow-up data and HPV E6/E7 mRNA detection results were analyzed, and histological differences in HPV E6/E7 mRNA positive and negative patients were compared. Results The histological result of 445 patients with cervical AGC showed that negative was in 306 cases (68.76%), and clinical significant lesion was in 129 cases (28.99%). In 445 patients with cervical AGC, HPV E6/E7 mRNA result was positive in 121 cases (27.19%), among whom the positive rate of HPV 16 and 18/45 type was 54.55% (66/121); HPV E6/E7 mRNA result was negative in 324 cases (72.81% ), including 13 non-cervical lesions. The negative rate of histological results in HPV E6/E7 mRNA negative patients was significantly higher than that in HPV E6/E7 mRNA positive patients: 91.05% (295/324) vs. 9.09% (11/121), and there was statistical difference (P＜0.01); the rates of adenocarcinoma in situ (AIS), high-grade squamous intraepithelial lesion (HSIL) and cervical adenocarcinoma of histological result in HPV E6/E7 mRNA positive patients were significantly higher than those in HPV E6/E7 mRNA negative patients: 40.50% (49/121) vs. 1.23% (4/324), 44.63% (54/121) vs. 1.23% (4/324), 3.31% (4/121) vs. 0.31% (1/324), and there were statistical differences (P＜0.01). The sensitivity of HPV E6/E7 mRNA in detecting clinical significant lesion of cervical AGC patients was 82.95% (107/129), the specificity was 95.57% (302/316), positive predictive value was 88.43% (107/121), and negative predictive value was 93.21% (302/324). Conclusions The histological result of cervical AGC shows that the amount of negative patients is significantly higher than clinical significant lesion. For cervical AGC patients with HPV E6/E7 mRNA negative results, conservative follow-up can be adopted after excluding extracervical lesions and fully assessing the risk of cervical lesions. However, the cervical AGC patients with HPV E6/E7 mRNA positive results need further examination to detect lesion and choose treatment earlier.

Objective To investigate the clinicopathological features of ovarian malignant tumor with thyroid components. Methods The clinical and pathological data of ovarian malignant tumor withthyroid component were collected from May 2006 to March 2018, including four cases of stroumal carcinoid and one case of metastatic thyroid follicular carcinoma, and the related literature was also reviewed. Results Ages of 5 cases ranged from 25 to 65 years old, and pelvic mass or abdominal discomfort was presented in physical examination. Tumors were unilateral, and mainly on the left side. The diameter of tumors was 5 to 13 cm with cyst or solid mainly. The strumal and carcinoid components were seen in strumal carcinoid. The insular and trabecular carcinoid were the common types of carcinoid. The synaptophysin (Syn) and chromogranin (CgA) were positive by immunohistochemistry. The patient with metastatic thyroid follicular carcinoma of ovary had a history of thyroid nodules for 13 years and the tumor grew rapidly in a short time. Under the microscope, dense thyroid follicles were arranged in papillary or diffuse distribution. Tumor cells were rich in eosinophilic cytoplasm and accompanied by follicular cell tumor-like hyperplasia. Conclusions Papillary tumor and strumal carcinoid are the most common primary malignant tumors of ovary with thyroid component, which both presented low malignancy and good prognosis. Ovarian metastasis from thyroid cancer is extremely rare and needs to be differentiated from primary ovarian thyroid cancer.

Objective To investigate the role of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) in high-fat diet-induced insulin resistance (IR) and mitochondrial degeneration in skeletal muscle.Methods Wistar rats were randomly divided into a normal chow (NC)group (n =10) and a high-fat diet(HFD)group (n =10).After eight weeks,fasting plasma glucose(FBG) levels,fasting insulin(FINS) levels and glucose infusion rates (GIR) in each group were measured (n=3).Samples of rat skeletal muscle were harvested.L6 myoblasts were divided into a control group,a PA group (cells were cultured in palmitic acid),a pcDNA3 group (cells were transfected by the plasmid pcDNA3)and a pcDNA3-PGC1α group (cells were transfected by the PGC1α-overexpressiorn plasmid).Expression levels of PGC1α,nuclear respiratory factor 1 (NRF1),uncoupling protein 3 (UCP3),and cytochrome C oxidase 1 (COX1) in skeletal muscle and L6 myoblasts were measured by real-time PCR and Western blotting.Results Levels of FBG and insulin were higher and those of GIR were lower in the HFD group than in the NC group,(6.0±0.7)mmol/L vs.(5.0±0.4)mmol/L、(23.3±3.0)mU/L vs.(12.9±1.8)mU/L、(14.2±1.8)％ vs.(22.6±2.4)％ (t =-3.578,-6.679,6.265,respectively,P ＜ 0.05).Expression levels of PGC1α,NRF1,UCP3,and COX1 were down in skeletal muscle in the HFD group compared with those in the NC group(P ＜0.05).In L6 myoblasts cultured with palmitic acid,the expression of PGC1 α,NRF1,UCP3,and COX1 were down compared with their expression in the NC group (P ＜ 0.05).However,the altered expression of PGC1α,NRF1,UCP3,and COX1 was reversed by transfecting with PGC1α-overexpression plasmids (F =30.079,96.883,226.772,respectively,P ＜ 0.001).Conclusions High-fat diets can lead to insulin resistance and decreased expression of mitochondrial energy metabolism-related genes,which can be reversed by PGC1α.The decreased expression of PGC1α may mediate the high-fat diet-induced mitochondrial dysfunction and IR.