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AIM: To investigate the clinical value of serum vitamin A(Vit A)and basic fibroblast growth factor(bFGF)levels predicting retinopathy of prematurity(ROP).METHODS: Prospective cohort studies. A total of 411 premature or low birth weight infants with gestational age less than 37 wk or birth weight less than 2 500 g who were delivered in Hainan Branch, Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from January 2020 to December 2022 were selected as subjects. The Vit A and bFGF levels in peripheral blood were detected at 7 d and 35 d after birth, respectively.RESULTS: A total of 392 premature infants or low birth weight infants completed clinical study, including 51 cases in stage 1-2 ROP group, 23 cases in stage 3-5 ROP group and 318 cases in the group without ROP. At 7 d postnatal, the serum Vit A(0.44±0.17 μmol/L)and bFGF(0.53±0.16 ng/L)levels in stage 1-2 ROP group were lower than those in the group without ROP(0.50±0.12 μmol/L and 0.63±0.15 ng/L; all P<0.05). The serum Vit A(0.34±0.18 μmol/L)and bFGF(0.44±0.18 ng/L)levels in stage 3-5 ROP group were lower than those in the group without ROP(P<0.05). The serum Vit A and bFGF levels in stage 3-5 ROP group were lower than those in stage 1-2 ROP group(P<0.05). At 35d postnatal, the serum Vit A(0.33±0.19 μmol/L)and bFGF(0.39±0.19 ng/L)levels in stage 3-5 ROP group were lower than those in stage 1-2 ROP group(0.43±0.16 μmol/L and 0.48±0.17 ng/L; all P<0.05). According to the ROC curve drawn by serum Vit A, the AUC value was 0.853, the maximum Youden index was 0.68, the best sensitivity was 73%, and the best specificity was 95%. According to the ROC curve drawn by serum bFGF, the AUC value was 0.828, the maximum Youden index was 0.58, the best sensitivity was 90%, and the best specificity was 68%. According to the ROC curve drawn by serum Vit A combined with bFGF, the AUC value was 0.917, the maximum Youden index was 0.70, the best sensitivity was 70%, and the best specificity was 100%.CONCLUSION: Serum Vit A and bFGF levels are sensitive and effective indicators for predicting ROP. If the serum Vit A or bFGF levels are lower in premature infants or low birth weight infants, it may indicate the higher probability of ROP and its pathological stages. In addition, the clinica value of serum Vit A combined with bFGF in the diagnosis of ROP is higher than that of Vit A or bFGF alone, and the misdiagnosis rate is reduced.
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Lipoprotein(a) (Lp(a)) is a complex circulating lipoprotein, and increasing evidence has demonstrated its role as a risk factor for atherosclerotic cardiovascular disease and as a possible therapeutic target. Proprotein converting enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor significantly decreases the circulating level of Lp(a) and reduces the risk of cardiovascular events. Based on the research results in recent years, this review will systematically summarize the relevant mechanisms of PCSK9 inhibitor reducing Lp(a) synthesis and promoting its degradation. The mechanisms are influenced by whether statins used in combination and baseline levels of Lp(a). PCSK9 inhibitors decrease Lp(a) levels mainly by reducing Lp(a) synthesis. However, the importance of low-density lipoprotein receptor (LDLR) mediated enhancing Lp(a) degradation gradually increases when the LDL level decreases. Meanwhile, many other receptor pathways may also exist, including very low-density lipoprotein (VLDL) receptor, LDL receptor-related protein 1, CD36, toll-like receptor 2, scavenger receptor B1 and plasminogen receptor. At present, further studies are still needed to explore the mechanisms by which PCSK9 inhibitors reduce Lp(a) level, such as inhibition of Lp(a) synthesis and intracellular assembly, and LDLR-mediated Lp(a) degradation. In addition, whether the reduction of Lp(a) level by PCSK9 inhibitor is related to age, gender and race and whether the dose-effect relationship of reducing Lp(a) is influenced by background lipid level, all of which require in-depth exploration. In short, the cellular and molecular mechanisms underlying the regulation of Lp(a) synthesis and degradation is not completely clear. It is worth carrying out relevant research to provide a theoretical basis for better clinical application of such drugs.
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Objective:To investigate the effect of roxadustat combined with levocarnitine in the treatment of renal anemia in hemodialysis patients with diabetic kidney disease (DKD), and its effects on iron metabolism, microinflammation status and microvascular complications.Methods:The clinical data of 89 hemodialysis renal anemia patients with DKD from January 2020 to October 2021 in Beijing Geriatric Hospital were retrospectively analyzed. Among them, 44 patients (control group)were treated with recombinant human erythropoietin and levocarnitine for renal anemia, and 45 patients (study group) were treated with recombinant human erythropoietin, levocarnitine and roxadustat for renal anemia. Both groups were treated for 3 months. The efficacy was compared between two groups. The laboratory indexes were measured before treatment and after 1, 3 months of treatment, including anemia related indexes such as hemoglobin, red blood cell count and mean corpuscular volume (MCV); iron metabolism indexes such as serum iron, ferritin and transferrin saturation (TSAT); inflammatory indexes such as interleukin-8 (IL-8), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α). The adverse reactions were recorded. The patients were followed up for 1 year after treatment, the incidence of diabetic microvascular complications, including diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR), was recorded.Results:The total effective rate in study group was significantly higher than that in control group: 93.33% (42/45) vs. 77.27% (34/44), and there was statistical difference ( χ2 = 4.60, P<0.05). There were no statistical differences in the laboratory indexes before treatment between two groups ( P<0.05); the hemoglobin, red blood cell count, MCV, serum iron, ferritin and TSAT after 1 and 3 months of treatment in study group were significantly higher than those in control group, the IL-8, CRP and TNF-α were significantly lower than those in control group, and there were statistical differences ( P<0.01 or <0.05). There was no significant difference in the incidence of adverse reactions between two groups ( P>0.05). After 1 year follow-up, 2 cases were lost in study group and 3 cases in the control group. The incidence of DR and DPN in study group were significantly lower than those in control group: 0 vs. 14.63% (6/41) and 2.33% (1/43) vs. 19.51% (8/41), and there were statistical differences ( χ2 = 4.75 and 4.81, P<0.05). Conclusions:Roxadustat combined with levocarnitine in the treatment of renal anemia in hemodialysis patients with DKD is reliable and safe, and can effectively relieve anemia symptoms, improve iron metabolism, reduce inflammatory response, and reduce the risk of diabetic microvascular complications.
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Objective To investigate the mechanism of Yes-associated protein 1(YAP1)ameliorating aristolochic acid 1(AAI)-induced liver injury in mice based on untargeted metabolomics techniques.Methods There were 83-week-old male hepatocyte-specific Yap1 gene knockout mice(genotyped as Yap1Flox/Flox,Albumin-Cre,aka.Yap1LKO)were randomly selected as the Yap1LKO+AAI group,and 8 Yap1Flox control mice as the Yap1Flox+AAI group.Both groups were injected intraperitoneally with AAI at a dose of 2.5 mg·kg-1·d-1 for 14 consecutive days.Genotypes were identified by tail PCR;serum alanine transaminase(ALT)and aspartate transaminase(AST)activities were determined by microplate assay;histopathological changes of liver tissue were observed by HE staining;and the protein expression of YAP1 in liver tissue was determined by immunohistochemistry.The untargeted metabolomics approach was used to analyze the liver tissue differential metabolites,and the samples were analyzed by ultra performance liquid chromatography-quadrupole-electrostatic field orbit trap high-resolution mass spectrometry,and the differential metabolites were screened by principal component analysis(PCA),Partial least square-discriminant analysis(PLS-DA),and orthogonal partial least squares-discriminant analysis(OPLS-DA);using HMDB database and METLIN database to identify metabolites,and the pathway enrichment of differential metabolites was analyzed by KEGG database.Results(1)After 14 days of AAI induction,the increase of body mass in Yap1LKO mice was lower than that in Yap1Flox mice,but there was no statistical significance(P＞0.05).On day 14,compared with the Yap1Flox+AAI group,the serum ALT and AST enzyme activities in the Yap1LKO+AAI group of mice were significantly increased(P＜0.05),and the histopathological damage of the liver was significantly aggravated.The livers of the Yap1Flox mice had a positive protein expression of YAP1,whereas the Yap1LKO mice did not have a positive protein expression of YAP1.(2)A total of 139 differential metabolites with significant changes(VIP＞1 and P＜0.05)were screened by metabonomic analysis;compared with Yap1LKO+ AAI group,62 liver metabolites in Yap1Flox+AAI group were up-regulated,including choline,taurine,hypotaurine,α-linolenic acid,eleostearic acid,chenodeoxycholic acid and so on.Seventy-seven metabolites were down-regulated including glycerophosphocholine,L-phosphatidylcholine,L-glutamine,L-serine,L-glutathione,5-methionine,phenylalanine,glucose 6-phosphate,lactic acid,uric acid glycosides,etc..KEGG-enriched pathways were mainly choline metabolism,glycerophospholipid metabolism,insulin resistance,glutathione metabolism,etc..Conclusion Hepatocyte-specific Yap1 gene knockout exacerbated AAI-induced liver injury in mice,and YAP1 was involved in the regulation of choline metabolism and glycerophospholipid metabolism through the up-regulation of unsaturated fatty acids,such as choline and taurine,which ameliorated AAI-induced liver injury in mice.
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Helicobacter pylori is a common gram-negative bacterium, which is associated with a variety of gastroenteric diseases, such as gastritis, duodenal ulcer and gastric cancer. Recent studies suggested a potential role of Helicobacter pylori in the pathogenesis of common ocular diseases, such as central serous chorioretinopathy, glaucoma, anterior uveitis and ocular adnexal lymphoma. Helicobacter pylori might affect the pathophysiological process of ocular diseases through oxidative damage, circulatory disorders and immune injury. Some studies also suggested that eradication of Helicobacter pylori had certain effects on some ocular diseases. This review aims to summarize current evidence of the Helicobacter pylori in the pathogenesis of common ocular diseases, so as to encourage innovative approaches in the prevention and treatment of these ocular diseases.
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Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of childbearing age, which seriously affects women's reproductive health. In recent years, more and more studies have found that serum anti-Müllerian hormone (AMH) has certain significance in the diagnosis and treatment evaluation of PCOS. In addition, with the improvement of detection methods, more attention has been paid to the significance of female androgens and AMH in the evaluation of PCOS. This article reviews the recent research progress of serum AMH and androgens in the evaluation of PCOS.
Subject(s)
Female , Humans , Polycystic Ovary Syndrome/diagnosis , Androgens , Anti-Mullerian Hormone摘要
Objective: To explore the effect and mechanism of small GTP-binding protein GDP dissociation stimulator (SmgGDS) on the development of obesity. Methods: (1) 8-week-old C57BL/6J mice were randomly assigned to normal diet and high fat diet group, with 6 mice in each group. They were fed regular feed and a high fat diet containing 60% fat for 4 months, respectively. The expression of SmgGDS in epididymal adipose tissue (eWAT), liver, and skeletal muscle were measured using Western-blot. (2) 6-week-old wild-type (WT) and SmgGDS knockdown (KD) mice were divided into four groups, each receiving high fat diet for 4 months (7 in each group) and 7 months (9 in each group). Glucose tolerance test (GTT) and insulin tolerance test (ITT) were conducted; The weight, adipose tissue, and liver weight of mice were recorded; HE staining examined adipose tissue structural changes; Western-blot determined extracellular signal-regulated kinase (ERK) 1/2 phosphorylation levels in eWAT; Real time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect mRNA levels of CCAAT/enhancer binding protein α (C/EBPα), C/EBPβ and peroxisome proliferator activated receptor γ (PPARγ) in eWAT. (3) Mouse embryonic fibroblasts (MEFs) extracted from WT and KD mice were induced for differentiation. Oil red O staining and Western-blot were used to detect lipid droplet and expression of SmgGDS and phospho-ERK; C/EBPα, C/EBPβ and PPARγ mRNA levels were measured using RT-qPCR. (4) 10-week-old C57BL/6J mice were randomly assigned into two groups, with 7 mice in each group. Mice were infected with SmgGDS overexpressing adeno-associated virus (AAV-SmgGDS) or empty vector intraperitoneally, then fed with high fat diet. After 4 weeks, performed GTT and ITT; Recorded the weight and adipose tissue weight of mice; HE staining was used to analyze structural changes of eWAT; Western-blot was used to detect the phosphorylation level of ERK in eWAT. Results: (1) The expression of SmgGDS was significantly upregulated in eWAT of high fat diet fed mice (normal diet group: 0.218±0.037, high fat diet group:0.439±0.072, t=2.74, P=0.034). (2) At 4 months of high fat diet intervention, the glucose tolerance (60 minutes after glucose injection, WT group: 528 mg/dl±21 mg/dl, KD group: 435 mg/dl±17 mg/dl, t=3.47, P=0.030; 90 minutes, WT group: 463 mg/dl±24 mg/dl, KD group: 366 mg/dl±18 mg/dl, t=3.23, P=0.047;120 minutes, WT group: 416 mg/dl±21 mg/dl, KD group: 297 mg/dl±16 mg/dl, t=4.49, P=0.005) and insulin sensitivity (15 minutes after insulin injection, WT group: 77.79%±3.45%, KD group: 54.30%±2.92%, t=3.49, P=0.005; 30 minutes, WT group: 62.27%±5.31%, KD group: 42.25%±1.85%, t=2.978, P=0.024; 90 minutes, WT group: 85.69%±6.63%, KD group: 64.71%±5.41%, t=3.120, P=0.016) of KD mice were significantly improved compared to the WT group, with an increase in eWAT weight ratio (WT: 4.19%±0.18%, KD: 5.12%±0.37%, t=2.28, P=0.042), but a decrease in average adipocyte area (WT group: 5221 μm²±241 μm², KD group: 4410 μm²±196 μm², t=2.61, P=0.026). After 7 months of high fat diet, the eWAT weight ratio of KD mice decreased (WT: 5.02%±0.20%, KD: 3.88%±0.21%, t=3.92, P=0.001) and adipocyte size decreased (WT group: 6 783 μm²±390 μm², KD group: 4785 μm²±303 μm², t=4.05, P=0.002). The phospho-ERK1 in eWAT increased (WT group: 0.174±0.056, KD group: 0.588±0.147, t=2.64, P=0.025), and mRNA level of PPARγ significantly decreased (WT group: 1.018±0.128, KD group: 0.029±0.015, t=7.70, P=0.015). (3) The expression of SmgGDS was significantly increased in differentiated MEF (undifferentiated: 6.789±0.511, differentiated: 10.170±0.523, t=4.63, P=0.010); SmgGDS knock-down inhibited lipid droplet formation in MEF (WT group: 1.00±0.02, KD group: 0.88±0.02, t=5.05, P=0.007) and increased ERK1 (WT group: 0.600±0.179, KD group: 1.325±0.102, t=3.52, P=0.025) and ERK2 (WT group: 2.179±0.687, KD group: 5.200±0.814, t=2.84, P=0.047) activity, which can be reversed by ERK1/2 inhibitor. (4) SmgGDS over expression resulted in weight gain, increased eWAT weight (control group: 3.29%±0.36%, AAV-SmgGDS group: 4.27%±0.26%, t=2.20, P=0.048) and adipocyte size (control group: 3525 μm²±454 μm², AAV-SmgGDS group: 5326 μm²±655 μm², t=2.26, P=0.047), impaired insulin sensitivity(30 minutes after insulin injection, control group: 44.03%±4.29%, AAV-SmgGDS group: 62.70%±2.81%, t=3.06, P=0.019), and decreased ERK1 (control group: 0.829±0.077, AAV-SmgGDS group: 0.326±0.036, t=5.96, P=0.001)and ERK2 (control group: 5.748±0.287, AAV-SmgGDS group: 2.999±0.845, t=3.08, P=0.022) activity in eWAT. Conclusion: SmgGDS knockdown improves obesity related glucose metabolism disorder by inhibiting adipogenesis and adipose tissue hypertrophy, which is associated with ERK activation.
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Objective@#This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). @*Methods@#This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. @*Results@#Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199–0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269–0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324–0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. @*Conclusion@#PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.
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Objective:To investigate the clinical value of different doses of paricalcitol combined with cinacalcet in the treatment of secondary hyperparathyroidism (SHPT) in patients with maintenance hemodialysis (MHD).Methods:The clinical data of 90 patients with MHD combined with SHPT from December 2020 to December 2022 in Beijing Geriatric Hospital were retrospectively analyzed. Among them, 30 patients were treated with cinacalcet (control group), 30 patients were treated with fixed dose paricalcitol combined with cinacalcet (experimental group A), and 30 patients were treated with adjusting dose of paricalcitol based on the level of intact parathyroid hormone (iPTH) combined with cinacalcet (experimental group B). All patients were continuously treated for 8 weeks. The blood calcium, blood phosphorus, iPTH, osteoprotegerin, osteocalcin, type Ⅰ collagen carboxy terminal peptide cross-linking (β-CTX), N-terminal medium molecule fragment of calcium (N-MID), fibroblast growth factor-23 (FGF-23) and Klotho protein before treatment and after 4 and 8 weeks of treatment were detected; coronary artery calcification (CAC) score and abdominal aortic calcification (AAC) score were evaluated. The adverse reactions were recorded.Results:There were no statistical differences in the indexes before treatment among three groups ( P>0.05). There were no statistical differences in blood calcium and blood phosphorus after 4 and 8 weeks of treatment among three groups ( P>0.05). After 4 and 8 weeks of treatment, the iPTH, β-CTX, osteoprotegerin, N-MID, osteocalcin and FGF-23 in experimental group A and experimental group B were significantly lower than those in control group, after 4 weeks of treatment: (936.99 ± 202.36) and (635.74 ± 135.44) ng/L vs. (1 028.56 ± 11.39) ng/L, (1.85 ± 0.32) and (1.50 ± 0.27) μg/L vs. (2.27 ± 0.69) μg/L, (71.18 ± 6.98) and (64.33 ± 7.87) ng/L vs. (80.15 ± 10.85) ng/L, (106.36 ± 14.42) and (92.64 ± 11.32) μg/L vs. (135.19 ± 15.18) μg/L, (66.17 ± 8.52) and (60.21 ± 7.85) μg/L vs. (73.15 ± 9.44) μg/L, (109.17 ± 11.24) and (98.50 ± 10.36) ng/L vs. (126.18 ± 15.64) ng/L; after 8 weeks of treatment: (632.17 ± 154.98) and (526.85 ± 98.45) ng/L vs. (819.85 ± 169.78) ng/L, (1.33 ± 0.15) and (1.15 ± 0.20) μg/L vs. (1.78 ± 0.27) μg/L, (65.78 ± 9.74) and (52.77 ± 7.18) ng/L vs. (74.26 ± 11.58) ng/L, (85.64 ± 11.62) and (70.25 ± 8.59) μg/L vs. (105.92 ± 19.17) μg/L, (48.17 ± 5.99) and (41.15 ± 6.44) μg/L vs. (59.24 ± 6.87) μg/L, (90.15 ± 11.25) and (82.58 ± 9.74) ng/L vs. (105.26 ± 14.35) ng/L, the indexes in experimental group B were significantly lower than those in experimental group A, and there were statistical differences ( P<0.05). After 4 and 8 weeks of treatment, the Klotho protein in experimental group A and experimental group B was significantly higher than that in control group, after 4 weeks of treatment: (124.25 ± 14.85) and (146.31 ± 16.85) U/L vs. (107.26 ± 11.36) U/L, after 8 weeks of treatment: (135.62 ± 16.87) and (150.24 ± 17.43) U/L vs. (115.56 ± 15.48) U/L, the Klotho protein in experimental group B was significantly higher than that in experimental group A, and there were statistical differences ( P<0.05). After 4 and 8 weeks of treatment, the CAC score and AAC score in experimental group A and experimental group B were significantly lower than those in control group, the indexes in experimental group B were significantly lower than those in experimental group A, and there were statistical differences ( P<0.05). There was no statistical difference in the incidence of adverse reactions among three groups ( P>0.05). Conclusions:Compared with the fixed dose of paricalcitol combined with cinacalcet therapy, the adjusting the dosage of paricalcitol combined with cinacalcet therapy based on iPTH level has more definite therapeutic effects in patients with MHD combined with SHPT, which can improve bone metabolism and reduce vascular calcification.
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Objective:To explore the therapeutic characteristics of population with gout achieving treat-to-target (T2T) indicators through real-world research and evaluate their safety.Methods:A total of 3 287 patients diagnosed with gout by rheumatologists in 21 first-class tertiary hospitals in 10 provinces, municipalities, and autonomous regions in China from January 2015 to December 2021 were included in this polycentric cross-sectional study. The database included patients′ general information, disease characteristics, and clinical application of traditional Chinese and Western medicine treatment measures. SPSS and Excel software were used for data analysis. Frequency analysis, cluster analysis, and factor analysis were used to summarize the characteristics and rules of treatment measures for patients with gout who achieved the target after treatment. The occurrence of adverse events (AE) was recorded during treatment.Results:After treatment, 691 visits (7%) achieved the serum urate (SUA) target, and the most frequent use of urate-lowering therapy (ULT) was febuxostat, followed by benzbromarone. The most common treatment options were following: GroupⅠ: traditional Chinese medicine (TCM) decoction-TCM external treatment-physical exercise-proprietary Chinese medicine; GroupⅡ: ferulic acid-nonsteroidal anti-inflammatory drugs (NSAIDs); Group Ⅲ: allopurinol-sodium bicarbonate-benzbromarone; Group Ⅳ: glucocorticoid-colchicine; Group Ⅴ: febuxostat. A total of 5 898 visits (60%) chieved manifestations of joint pain VAS scores target, and the most frequently used drug to control joint symptoms was NSAIDs. The frequency of use of drugs to control joint symptoms were 2 118 times (usage rate reached 35.9%), while the frequency of ULT were 2 504 times (usage rate reached 42.5%), which was higher than the joint symptom control drug. The most common treatment options were following: Group Ⅰ: proprietary Chinese medicine-TCM decoction-TCM external treatment-physical exercise; Group Ⅱ: NSAIDs-colchicine hormones; Group Ⅲ: allopurinol, Group Ⅳ: benzbromarone; Group Ⅴ: febuxostat. A total of 59 adverse events occurred during treatment.Conclusion:The proportions of gout patients who reach target serum urate level & good control of joint symptoms are both very low, and ULT and anti-inflammatory prescription patterns are very different from international guidelines, so it is necessary to strengthen the standardized management of gout patients. At the same time, life intervention measures account for a certain proportion of the treatment plans for the T2T population, and further exploration is needed.
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BACKGROUND@#Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.@*METHODS@#The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months.@*RESULTS@#Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group.@*CONCLUSION@#Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state.@*TRIAL REGISTRATION@#Chictr.org, ChiCTR2000039799.
Subject(s)
Humans , Quality of Life , China , Arthritis, Rheumatoid/drug therapy , Piperidines/therapeutic use , Treatment Outcome , Antirheumatic Agents/therapeutic use , Pyrroles/therapeutic use摘要
OBJECTIVE@#To investigate the effect of electroacupuncture (EA) at Neiguan (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHRs), and to explore the contribution of interleukin-1 β (IL-1 β), insulin-like growth factor 1 (IGF-1), and transforming growth factor β 1 (TGF- β 1) to the effects.@*METHODS@#Nine 12-weeks-old Wistar Kyoto (WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6 once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type I (Col I), collagen type 1 (Col 1) and the levels of IGF-1, 1L-1 β, TGF- β 1, matrix metalloproteinase (MMP)-2 and MMP-9 were examined in myocardial tissure respectively.@*RESULTS@#After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col I and Col 1 in myocardium tissue (P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group (P<0.01). Meanwhile, the increased levels of IL-1 β, IGF-1, TGF-β 1 in serum or myocardial tissue of SHRs, diminished MMP 9 mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment (P<0.05 or P<0.01). Furthermore, the contents of IL-1 β, IGF-1, TGF-β 1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively (P<0.01).@*CONCLUSION@#EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1 β/IGF-1-TGF- β 1-MMP9 pathway.
Subject(s)
Rats , Animals , Male , Rats, Inbred WKY , Electroacupuncture , Hypertension/therapy , Insulin-Like Growth Factor I , Interleukin-1beta , Rats, Inbred SHR , Essential Hypertension , Myocardium/pathology , Collagen Type I , Fibrosis摘要
AIM: To explore the mechanism of fructus lycii in treating dry eye based on network pharmacology and experimental verification.METHODS: Taking “fructus lycii” as key words, the active ingredients and target of fructus lycii were searched by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Gene targets related to dry eye(DE)were searched by GeneCards and OMIM databases. The target genes of fructus lycii and DE were imported into Venn software to obtain the intersection target map of them. After that, the data were imported into the String database to obtain the PPI protein-protein interaction network diagram. Using Cytoscape3.7.2 software, the PPI protein-protein interaction network diagram was constructed for active ingredients, target sites and related diseases of fructus lycii. The Bioconductor platform and R language were used for gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis. And the key targets in the pathogenesis of DE were verified by experiments.RESULTS: Through TCMSP, 45 types of effective chemical components of fructus lycii, 174 target genes corresponding to active components and 131 common target genes with DE were screenedout. In accordance with the network topology of “drug-composition-disease-target”, 27 main effective components of fructus lycii were found in the treatment of DE. The PPI network was analyzed according to the high degree value, which is the key targets of fructus lycii for DE treatment, mainly including AKT1, VEGFA, CASP3, IL1B, JUN, PTGS2, CXCL8, etc. According to GO enrichment analysis, 166 biological functions and processes of fructus lycii for DE treatment were obtained. KEGG enrichment analysis showed that 31 signaling pathways were involved. Additionally, experimental verification displayed that the protein expressions of AKT1, interleukin-6(IL-6), tumor necrosis factor(TNF-α)and IL-17 in conjunctiva tissue of the DE model group were significantly increased.CONCLUSIONS: Through network pharmacology, this study confirmed that the treatment of DE by fructus lycii is a complex process involving multi-components, multi-targets and multi-pathways, and that the treatment of DE by fructus lycii is mainly regulated by anti-inflammatory and apoptosis-related molecules.
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The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.
摘要
Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.
Subject(s)
Pregnancy , Female , Humans , Adult , Hyperplasia , Progestins , Fertility Preservation , Endometrial Neoplasms/pathology , Endometrial Hyperplasia/surgery , Treatment Outcome , Precancerous Conditions , Fertility , Class I Phosphatidylinositol 3-Kinases , Retrospective Studies摘要
This study aims to investigate the efficacy and possible mechanism of Liuwei Dihuang Pills in the treatment of diminished ovarian reserve(DOR) by using proteomic techniques. Firstly, cyclophosphamide(60 mg·kg~(-1)) combined with busulfan(6 mg·kg~(-1)) was injected intraperitoneally to establish the mouse model of DOR. After drug injection, the mice were continuously observed and the success of modeling was evaluated by the disturbance of the estrous cycle. After successful modeling, the mice were administrated with the suspension of Liuwei Dihuang Pills by gavage for 28 days. At the end of the gavage, four female mice were selected and caged together with males at a ratio of 2∶1 for the determination of the pregnancy rate. Blood and ovary samples were collected from the remaining mice on the next day after the end of gavage. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were then employed to observe the morphological and ultrastructural changes in the ovaries. The serum levels of hormones and oxidation indicators were measured by enzyme-linked immunosorbent assay. Quantitative proteomics techniques were used to compare the ovarian protein expression before and after modeling and before and after the intervention with Liuwei Dihuang Pills. The results showed that Liuwei Dihuang Pills regulated the estrous cycle of DOR mice, elevated the serum levels of hormones and anti-oxidation indicators, promoted follicle development, protected the mitochondrial morphology of ovarian granulosa cells, and increased the litter size and survival of DOR mice. Furthermore, Liuwei Dihuang Pills negatively regulated the expression of 12 differentially expressed proteins associated with DOR, which were mainly involved in lipid catabolism, inflammatory response, immune regulation, and coenzyme biosynthesis. These differentially expressed proteins were significantly enriched in sphingolipid metabolism, arachidonic acid metabolism, ribosomes, ferroptosis, and cGMP-PKG signaling pathway. In summary, the occurrence of DOR and the treatment of DOR with Liuwei Dihuang Pills are associated with multiple biological pathways, mainly including oxidative stress response, inflammatory response, and immune regulation. "Mitochondria-oxidative stress-apoptosis" is the key to the treatment of DOR by Liuwei Dihuang Pills. YY1 and CYP4F3 may be the key upstream targets that trigger mitochondrial dysfunction and ROS accumulation, and the metabolism of arachidonic acid is the main signaling pathway of drug action.
Subject(s)
Female , Male , Pregnancy , Animals , Mice , Arachidonic Acid , Ovarian Reserve , Proteomics , Ovary , Lipid Metabolism摘要
OBJECTIVE@#To observe the effect of electroacupuncture (EA) at "Neiguan" (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHR), and explore preliminarily the mediating role of cholinergic anti-inflammatory pathway (CAP) and its downstream nuclear factor κB (NF-κB) signaling pathway.@*METHODS@#Six 12-week-old WKY male rats were employed as the normal group. Eighteen 12-week-old SHR were randomly divided into 3 groups, i.e. a model group, an EA group and a blocking group (EA after blocking α7 nicotinic acetylcholine receptor [α7nAchR]), with 6 rats in each one. In the EA group, EA was delivered at "Neiguan"(PC 6) and the site 0.5 cm from its left side, with disperse-dense wave, 2 Hz/15 Hz in frequency and 1 mA in current intensity. One intervention took 30 min and was given once every 2 days, lasting 8 weeks. In the blocking group, prior to each EA, the α7nAchR specific blocker, α-bungartoxin was injected intravenously in the tails of the rats. After EA intervention, the systolic blood pressure (SBP), the diastolic blood pressure (DBP) and the mean arterial pressure (MAP) were measured with non-invasive blood pressure monitor. Using echocardiogram, the left ventricular (LV) anterior wall end-diastolic thickness (LVAWd) , LV posterior wall end-diastolic thickness (LVPWd) and the LV end-diastolic internal diameter (LVIDd) were measured. The level of hydroxyproline (Hyp) in the myocardial tissue was determined by using alkaline hydrolysis, and that of acetylcholine (Ach) was detected by ELISA. With the real-time PCR adopted, the mRNA expression of NF-κB p65, tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 were determined.@*RESULTS@#Compared with the normal group, SBP, DBP, MAP, LVAWd and LVPWd were increased (P<0.01), and LVIDd was decreased (P<0.01) in the rats of the model group. SBP, DBP, MAP and LVAWd were dropped (P<0.01, P<0.05), and LVIDd rose (P<0.01) in the EA group when compared with those in the model group. The differences in the above indexes were not statistically significant between the blocking group and the model group (P>0.05). Compared with the normal group, Hyp level and the mRNA expression of NF-κB p65, TNF-α, IL-1β and IL-6 in the myocardial tissue increased (P<0.01, P<0.05) and Ach level decreased (P<0.01) in the model group. Hyp level, the mRNA expression of NF-κB p65, TNF-α, IL-1β and IL-6 in the myocardial tissue were reduced (P<0.05, P<0.01) and Ach level rose (P<0.01) in the EA group when compared with those in the model group. These indexes were not different statistically between the blocking group and the model group (P>0.05).@*CONCLUSION@#CAP may be involved in ameliorating the pathological damage of myocardial fibrosis during EA at "Neiguan"(PC 6). The underlying effect mechanism is associated with up-regulating the neurotransmitter, Ach and down-regulating mRNA expression of NF-κB p65 and pro-inflammatory factors such as TNF-α, IL-1β and IL-6 in myocardial tissue.
Subject(s)
Rats , Male , Animals , Rats, Inbred SHR , NF-kappa B/metabolism , Rats, Inbred WKY , Electroacupuncture , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , Neuroimmunomodulation , alpha7 Nicotinic Acetylcholine Receptor , Acetylcholine , Fibrosis , RNA, Messenger摘要
AIM: To analyze the application value of spectral domain-optical coherence tomography(SD-OCT)parameters on evaluating visual acuity improvement after internal limiting membrane peeling of macular hole.METHODS: The retrospective analysis was performed on the clinical data of 82 patients(82 eyes)with idiopathic macular hole(IMH)who underwent vitrectomy + internal limiting membrane peeling + long-acting gas tamponade in the hospital between May 2019 and February 2021. The correlation between IMH closure and SD-OCT parameters at 3mo after surgery was analyzed, and the risk factors for poor postoperative visual acuity improvement were evaluated.RESULTS: Spearman rank correlation coefficient analysis showed that IMH closure at 3mo after operation was positively correlated with preoperative external limiting membrane(ELM)defect diameter(rs=0.308, P<0.05), and it was negatively correlated with preoperative macular hole index(MHI; rs=-0.266, P<0.05). Logistic regression analysis revealed that preoperative MHI≥0.5 was a protective factor affecting poor postoperative visual acuity improvement(OR=0.691, P<0.05).CONCLUSION: SD-OCT can predict the surgical efficacy by detecting the preoperative MHI and ELM defect diameter, and it is beneficial to judging the improvement of visual function.
摘要
Takayasu′s arteritis (TAK) mainly involves the aorta and its major branches, which is characterized as a chronic, progressive and inflammatory disease. China belongs to one of the regions with a high prevalence of TAK referring to its global distribution. However, it is insufficient for the spread and update of standardized diagnosis and treatment of TAK. Based on the evidence and guidelines from China and other countries, Chinese Rheumatology Association developed the standardized diagnosis and treatment of TAK in China. The purpose is to standardize the methods for diagnosis of TAK, assessment of disease activity and disease severity, strategies of internal treatment and timing of surgical intervention, and further leading to protect the function of important organs and improve the disease prognosis.
摘要
Objective@#The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). @*Methods@#A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. @*Results@#Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%–97.9%) and 76.5% (95% CI=68.1%–84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%–15.2%) in patients with grade 1–2 endometrial cancer and 11.8% (95% CI=8.1%–16.1%) in patients with grade 1–3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%–100%) in studies that included grade 1–2 endometrial cancer and 99.2% (95% CI=97.9%–99.9%) in studies that also included grade 3. @*Conclusion@#SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediate-risk endometrial cancer.