Region-specific cellular and molecular basis of liver regeneration after acute pericentral injury.

Liver injuries often occur in a zonated manner. However, detailed regenerative responses to such zonal injuries at cellular and molecular levels remain largely elusive. By using a fate-mapping strain, Cyp2e1-DreER, to elucidate liver regeneration after acute pericentral injury, we found that pericentral regeneration is primarily compensated by the expansion of remaining pericentral hepatocytes, and secondarily by expansion of periportal hepatocytes. Employing single-cell RNA sequencing, spatial transcriptomics, immunostaining, and in vivo functional assays, we demonstrated that the upregulated expression of the mTOR/4E-BP1 axis and lactate dehydrogenase A in hepatocytes contributes to pericentral regeneration, while activation of transforming growth factor ß (TGF-ß1) signaling in the damaged area mediates fibrotic responses and inhibits hepatocyte proliferation. Inhibiting the pericentral accumulation of monocytes and monocyte-derived macrophages through an Arg-Gly-Asp (RGD) peptide-based strategy attenuates these cell-derived TGF-ß1 signalings, thus improving pericentral regeneration. Our study provides integrated and high-resolution spatiotemporal insights into the cellular and molecular basis of pericentral regeneration.

Study on the application of quality control circle activity in postoperative nursing of elderly dental implants.

BACKGROUND: To explore the application effect of "quality control circle" activity in postoperative nursing of elderly dental implants. METHODS: From January 2022 to December 2022, a total of 60 elderly patients were selected and divided into an experimental group and a control group, with 30 cases in each group using the random number table method. The elderly patients with dental implants received postoperative care under the supervision of a quality control circle. The control group was treated with conventional nursing methods. The success rate, postoperative complications, and satisfaction of the 2 groups were compared. RESULTS: By comparing the postoperative care effect of the 2 groups of patients, the satisfaction of the experimental group and the control group was 93.3% and 73.3%, respectively, showing the satisfaction of the experimental group was higher than the control group (P < .05). The planting success rate of the experimental and control groups were 96.7% and 66.7%, respectively, with the experimental group outperforming the control group (P < .05). The proportion of complications in the experimental was found to be fewer (6.7%) than in the control group (33.3%) (P < .05). CONCLUSION: Quality control circle activities can effectively improve the success rate of dental implants, reduce the occurrence of postoperative complications, improve patient satisfaction, and help medical staff in providing better treatment for patients.

Unveiling the power of microenvironment in liver regeneration: an in-depth overview.

The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.

The role of dietary fiber on preventing gestational diabetes mellitus in an at-risk group of high triglyceride-glucose index women: a randomized controlled trial.

BACKGROUND: Pregnant women with a high triglyceride-glucose (TyG) index during early pregnancy may increase the risk of gestational diabetes mellitus (GDM), and dietary fiber could play an important role in glucose and lipid metabolism. However, no trials have tested the effects of dietary fiber on preventing GDM in women with a high TyG index. This study aims to investigate whether GDM can be prevented by dietary fiber supplementation in women with a TyG index ≥8.5 during early pregnancy (<20 weeks). METHODS: A randomized clinical trial was performed among 295 women with a TyG index ≥8.5 before 20 weeks of gestation, divided into a fiber group (24 g dietary fiber powder/day) or a control group (usual care). The intervention was conducted from 20 to 24+6 gestational weeks, and both groups received guidance on exercise and diet. The primary outcomes were the incidence of GDM diagnosed by a 75 g oral glucose tolerance test at 25-28 gestational weeks, and levels of maternal blood glucose, lipids. Secondary outcomes include gestational hypertension, postpartum hemorrhage, preterm birth, and other maternal and neonatal complications. RESULTS: GDM occurred at 11.2% (10 of 89) in the fiber group, which was significantly lower than 23.7 (44 of 186) in the control group (P = 0.015). The mean gestational weeks increased dramatically in the fiber group compared with the control group (39.07 ± 1.08 vs. 38.58 ± 1.44 weeks, P = 0.006). The incidence of preterm birth was 2.3% (2 of 86) of women randomized to the fiber group compared with 9.4% (17 of 181) in the control group (P = 0.032). The concentrations of 2 h postprandial blood glucose showed statistically higher in the control group compared with the intervention group (6.69 ± 1.65 vs. 6.45 ± 1.25 mmol/L, P = 0.026). There were no other significant differences between groups in lipid profile values, or other secondary outcomes. CONCLUSION: An intervention with dietary fiber supplementation during pregnancy may prevent GDM and preterm birth in women with a TyG index ≥8.5 before 20 weeks of gestation.

From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification.

OBJECTIVE: Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes. DESIGN: A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors. RESULTS: Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established. CONCLUSION: Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.

Accuracy of Microimplant Placement Using a 3D Guide Plate for Orthodontic Anchorage.

This study aimed to design a three-dimensional (3D) guide plate using computer-aided design and a 3D printing system for precise implantation of microimplants for orthodontic treatment and investigate the accuracy and feasibility of a 3D guide plate in clinical practice. A total of 30 microimplants were placed in 15 patients in the Department of Stomatology, Affiliated Hospital of Jiangnan University. Before surgery, DICOM data from cone-beam computed tomography (CBCT) scans and STereoLithography data from the 3D model scan were imported to 3Shape Dental System. Data fitting and matching were performed, and 3D guide plates were designed primarily focusing on the thickness of guide plates, amount of concave compensation, and dimensions of the ring. Assist implantation method was used to place the microimplants, and postoperative CBCT images were used to evaluate the position and implantation angle. The feasibility of placing microimplants and precise implantation guided by the 3D guide plate. CBCT data before and after the placement of microimplants were compared. Regarding the secure positioning of microimplants based on CBCT data, 26 implants were categorized as Grade i, four as Grade ii, and none as Grade iii. No loosening of microimplants 1 and 3 months after surgery was reported. The implantation of microimplants is more accurate under the guidance of a 3D guide plate. This technology can achieve accurate implant positioning, thus ensuring safety, stability, and improved success rates after implantation.

Associations of cholecystectomy with the risk of colorectal cancer: a Mendelian randomization study.

BACKGROUND: Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases, while the causal effects of cholecystectomy on colorectal cancer (CRC) and other complications are still unknown. METHODS: We obtained genetic variants associated with cholecystectomy at a genome-wide significant level ( P value <5 × 10 -8 ) as instrumental variables (IVs) and performed Mendelian randomization (MR) to identify the complications of cholecystectomy. Furthermore, the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy, and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis. The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines. RESULTS: The selected IVs explained 1.76% variance of cholecystectomy. Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC (odds ratio [OR] =1.543, 95% confidence interval [CI]: 0.607-3.924). Also, it was not significant in either colon or rectum cancer. Intriguingly, cholecystectomy might decrease the risk of Crohn's disease (OR = 0.078, 95% CI: 0.016-0.368) and coronary heart disease (OR = 0.352, 95% CI: 0.164-0.756). However, it might increase the risk of irritable bowel syndrome (IBS) (OR = 7.573, 95% CI: 1.096-52.318). Cholelithiasis could increase the risk of CRC in the largest population (OR = 1.041, 95% CI: 1.010-1.073). The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population (OR = 1.061, 95% CI: 1.002-1.125) after adjustment of cholecystectomy. CONCLUSIONS: The study indicated that cholecystectomy might not increase the risk of CRC, but such a conclusion needs further proving by clinical equivalence. Additionally, it might increase the risk of IBS, which should be paid attention to in clinical practice.

Effects of Dietary Fiber on the Risk of Gestational Diabetes Mellitus in Advanced Maternal Age Women: Study Protocol for a Randomized Controlled Trial.

SCOPE: To investigate whether dietary fiber supplementation may reduce the risk of gestational diabetes mellitus (GDM) in advanced maternal age Chinese women (≥35 years). Secondary outcomes include glucose metabolism, diet change, weight gain, and maternal and neonatal outcomes. METHODS AND RESULTS: In a randomized controlled trial, a dietary fiber group (19.56 g day-1 ) or control group (standard prenatal care) was conducted from 20 to 24+6 gestational weeks in advanced maternal age women. Dietary intakes were assessed using a validated 39-item Food Frequency Questionnaire (FFQ). GDM was diagnosed by a 75 g oral glucose tolerance test (OGTT) at 25-28 weeks. After intervention, the incidence of GDM was not significantly different between groups (21.6% vs 12.9%, p = 0.165). The mean increased in carbohydrate intake in the dietary fiber group is significantly lower than in the control group (-0.94 ± 92.12 g vs 32.27 ± 91.81 g, p = 0.032). In addition, the glucose tolerance, weight gain between 20 and 25 weeks, and preterm birth in the intervention group have improved compared to the control group. CONCLUSION: Supplementation with dietary fiber during pregnancy among advanced maternal age Chinese women do not lower the incidence of GDM, but improve glucose metabolism, gestational weight gain, and preterm birth.

Diet-derived antioxidants and nonalcoholic fatty liver disease: a Mendelian randomization study.

BACKGROUND: Whether supplementation with diet-derived antioxidants is beneficial for nonalcoholic fatty liver disease (NAFLD) is still controversial and we hope to answer this question using population-based genetic data. METHODS: A total of 8485 NAFLD cases and 658,849 healthy controls from four independent NAFLD genome-wide association studies were enrolled in this study. Genetic variants closely associated with the diet-derived antioxidants were selected to predict their circulating levels. A bi-directional Mendelian randomization (MR) design was employed to assess their causations. RESULTS: Genetic correlation analyses suggested inverse associations between diet-derived antioxidants and NAFLD. MR analyses indicated that the odds ratio (OR) of per standard deviation increase in genetically predicted toenail and blood selenium was 1.179 for NAFLD (95% confidence interval [1.083-1.284]). Also, the genetically elevated selenium level was causally associated with increased levels of C-reactive protein, fibrinogen, alkaline phosphatase and glycated hemoglobin. The OR of 1 µg/dL increase in genetically predicted serum lycopene was 1.082 (95%CI [1.051-1.113]). No other causal associations were found for NAFLD. However, we observed protective effects of genetically predicted ß-carotene (OR = 0.929[0.911-0.947]) and retinol (OR = 0.483[0.460-0.508]) on type 2 diabetes (T2D), and further they could reduce the serum levels of blood lipids and glucose. Reverse MR analysis suggested genetically predicated NAFLD status would not affect the levels of diet-derived antioxidants. CONCLUSION: Overall, we observed the positive associations of genetically predicted selenium and lycopene with NAFLD. However, the genetically predicted ß-carotene and retinol levels were inversely associated with the risk of T2D.

Examination on the risk factors of cholangiocarcinoma: A Mendelian randomization study.

Background: Several risk factors have been identified for CCA, however, whether such associations were causal remains unknown. Methods: Mendelian randomization (MR) has been applied to examine the causal relationship between 26 putative risk factors and CCA. The genetic variants for each risk factor were extracted from their corresponding genome-wide association study (GWAS) if they reached the genome-wide significance (p-value < 5 × 10-8). The genetic associations with CCA were obtained from the publicly available GWAS with the largest sample size. Mainly, inverse-variance weighted (IVW) has been adopted to estimate the causal effect on CCA. Both multivariable and mediation MR analyses were carried out to detect independent factors. Results: Three putative risk factors can causally elevate the risk of CCA after FDR correction, including liver fat content (LFC), non-alcoholic fatty liver disease (NAFLD), and cholelithiasis. The odds of CCA would increase per 1-SD increase in the liver fat content (LFC) (OR = 2.12 [1.66, 2.71]) and logOR of NAFLD. The genetic liability to cholelithiasis would increase the risk of CCA as well (OR = 2.17 [1.47, 3.20]). They were still significant in other methods. The multivariable MR analysis indicated that genetically-elevated LFC should increase the risk of CCA independently of cholelithiasis (OR = 1.88 [1.39, 2.55]). In the mediation MR analysis, the indirect effect was not significant when treating cholelithiasis as the mediator (indirect OR = 0.95 [0.85, 1.07]). Conclusion: This MR study identified that gallstone and liver fat accumulation are two independent risk factors of CCA, suggesting two modifiable ways of preventing CCA.

The effect of dietary fiber supplement on prevention of gestational diabetes mellitus in women with pre-pregnancy overweight/obesity: A randomized controlled trial.

Objective: To investigate the effect of dietary fiber intake during pregnancy on the prevention of gestational diabetes mellitus (GDM) in women who are overweight/obese prior to pregnancy. Methods: This randomized controlled trial was conducted in Shanghai General Hospital from June 2021 to March 2022. A total of 98 women who reported BMI≥24 kg/m2 prior to pregnancy were recruited before their 20th gestational week, and randomly (simple random allocation) assigned to the fiber supplement group (12 g of dietary fiber power twice daily) and the control group (standard prenatal care) from 20 to 24+6 gestational weeks. Both groups received nutrition education and dietary advice during the study. GDM diagnosis was performed by an oral glucose tolerance test (OGTT) at 25-28 weeks' gestation. Data are presented as means with SD, as medians with IQR, or as counts with percentages as appropriate. Comparisons were conducted using a t-test, Mann-Whitney U test, and χ2 test, respectively. Results: The incidence of GDM was significantly reduced in the fiber supplement group compared with the control group: 8.3 vs. 24.0% (χ2 = 4.40, p = 0.036). At OGTT, the mean fasting plasma glucose in the fiber supplement group was significantly lower than before the intervention (4.57 ± 0.38 mmol/L vs. 4.41 ± 0.29 mmol/L, p < 0.01) but not in the control group (4.48 ± 0.42 mmol/L vs. 4.37 ± 0.58 mmol/L, p = 0.150). Compared with the control group, the TG and TG/HDL-C ratio levels in the intervention group were significantly higher than those in the control group (2.19 ± 0.54 mmol/L vs. 2.70 ± 0.82 mmol/L and 1.19 ± 0.49 vs.1.63 ± 0.63, respectively, all P＜0.05). The body weight gain was significantly lower in the fiber supplement group than the control group (1.99 ± 1.09 kg vs. 2.53 ± 1.20kg, p = 0.022). None of the women randomized to the fiber supplement group experienced preterm birth (<37 weeks gestation) compared with 12.0% in the control group (p = 0.040). Excessive weight gain (total weight gain >11.5 kg for overweight, and >9.0 kg for obesity) occurred in 46.7% of women in the fiber supplement group compared with 68.0% in the control group (p = 0.035). There were no differences in other maternal and neonatal outcomes. Conclusion: Increased dietary fiber intake in pregnant women who were overweight/obese prior to pregnancy may reduce the risk of GDM, excessive weight gain, and preterm birth, but it did not improve blood lipids.

Precise extraction of impacted supernumerary tooth in the maxillary anterior region with a digital guide plate: A case report.

RATIONALE: Removal of impacted supernumerary teeth requires precision and accuracy to prevent iatrogenic injury to important anatomical structures during dental surgery and to improve postoperative healing. PATIENT CONCERNS: A 12-year-old girl visited our department for the assessment and management of her deviated front teeth. DIAGNOSIS: Impacted supernumerary tooth extraction in the maxillary anterior region. INTERVENTIONS: The digital guide plate was fabricated after the integration of cone beam computed tomography data with that obtained from scanning the patient's dental model. Impacted supernumerary tooth extraction was performed. OUTCOMES: The use of the digital guide plate and planting instruments made the removal of the impacted supernumerary tooth less invasive, faster, and more accurate, whereas the wound was smaller, and the patient experience more comfortable. LESSONS: Combining the digital guide plate with planting instruments offers a useful aid for the removal of impacted supernumerary teeth among the maxillary anterior region and is, thus, worth promoting.

Evaluation of the necessity of laparoscopic repair of a uterine scar defect for cesarean scar pregnancy.

OBJECTIVE: This study aimed to determine the risk factors associated with the necessity of laparoscopic scar defect repair for cesarean scar pregnancy (CSP). METHODS: We retrospectively analyzed 237 patients with CSP who were treated by ultrasound-guided suction curettage and/or laparoscopy in our hospital from April 2012 to November 2019. A total of 199 of these patients underwent ultrasound-guided suction curettage without uterine scar defect repair, while 38 of these patients underwent laparoscopic resection and uterine scar defect repair. We analyzed various clinical variables and compared the efficacy of treatment between the two groups. RESULTS: Gestational age, the maximum transverse diameter (MTD) of the gestational sac, myometrial thickness, the operation time, intraoperative blood loss, and the duration of the hospital stay were significantly different between the two groups. Gestational age, the MTD of the gestational sac, and myometrial thickness were independent risk factors for laparoscopic repair. CONCLUSIONS: Gestational age, the MTD of the gestational sac, and myometrial thickness are important factors associated with the necessity for laparoscopic repair of a uterine scar defect.

Effect of exposure to antibiotics on the gut microbiome and biochemical indexes of pregnant women.

INTRODUCTION: Exposure to antibiotics (ABX) during pregnancy can have a systematic effect on both fetal and maternal health. Although previous biomonitoring studies have indicated the effects on children of extensive exposure to ABX, studies on pregnant women remain scarce. To explore the effect on pregnant women of environmental exposure to ABX through accidental ingestion and identify potential health risks, the present study investigated 122 pregnant women in East China between 2019 and 2020. RESEARCH DESIGN AND METHODS: The presence of six categories of ABX (quinolones, sulfonamides, lincosamides, tetracyclines, amide alcohol ABX, and ß-lactams) in plasma samples taken from the pregnant women was investigated using an ABX kit and a time-resolved fluorescence immunoassay. RESULTS: All six ABX were detected in the plasma, with a detection rate of 17.2%. It was discovered that the composition of intestinal flora in pregnant women exposed to ABX was different from that of pregnant women who had not been exposed to ABX. The intestinal flora of pregnant women exposed to ABX also changed at both the phylum and genus levels, and several genera almost disappeared. Furthermore, the metabolic levels of glucose and insulin and the alpha diversity of pregnant women exposed to ABX were higher than those of pregnant women not exposed to ABX. CONCLUSION: Pregnant women are potentially at higher risk of adverse microbial effects. Glucose metabolism and insulin levels were generally higher in pregnant women exposed to ABX than in unexposed women. Also, the composition and color of the gut microbiome changed.

The characteristics of intestinal flora in overweight pregnant women and the correlation with gestational diabetes mellitus.

OBJECTIVE: To investigate the characteristics of intestinal flora in overweight pregnant women and the correlation with gestational diabetes mellitus (GDM). METHODS: A total of 122 women were enrolled and divided into four groups according to their pre-pregnancy BMI and the presence of GDM: group 1 (n = 71) with a BMI <24 kg/m2, without GDM; group 2 (n = 27) with a BMI <24 kg/m2, with GDM; group 3 (n = 17) with a BMI ≥24 kg/m2, without GDM; and group 4 (n = 7) with a BMI ≥24 kg/m2 with GDM. Feces were collected on the day that the oral glucose tolerance test was conducted. The V3-V4 variable region of 16S rRNA was sequenced using the Illumina Hiseq 2500 platform, and a bioinformatics analysis was conducted. RESULTS: There were differences between the four groups in the composition of intestinal flora, and it was significantly different in group 4 than in the other three groups. Firmicutes accounted for 36.4% of the intestinal flora in this group, the lowest among the four groups, while Bacteroidetes accounted for 50.1%, the highest among the four groups, making ratio of these two bacteria approximately 3:5, while in the other three groups, this ratio was reversed. In women with a BMI <24 kg/m2, the insulin resistance index (homeostatic model assessment for insulin resistance (HOMA-IR)) in pregnant women with GDM was higher than in those without (P3 = 0.026). CONCLUSION: The composition of the intestinal flora of pregnant women who were overweight or obese before pregnancy and suffered from GDM was significantly different than women who were not overweight or did not suffer from GDM.

Alterations of gut microbiota in gestational diabetes patients during the second trimester of pregnancy in the Shanghai Han population.

BACKGROUND: The causes of gestational diabetes mellitus (GDM) are still unclear. Recent studies have found that the imbalance of the gut microbiome could lead to disorders of human metabolism and immune system, resulting in GDM. This study aims to reveal the different gut compositions between GDM and normoglycemic pregnant women and find the relationship between gut microbiota and GDM. METHODS: Fecal microbiota profiles from women with GDM (n = 21) and normoglycemic women (n = 32) were assessed by 16S rRNA gene sequencing. Fasting metabolic hormone concentrations were measured using multiplex ELISA. RESULTS: Metabolic hormone levels, microbiome profiles, and inferred functional characteristics differed between women with GDM and healthy women. Additionally, four phyla and seven genera levels have different correlations with plasma glucose and insulin levels. Corynebacteriales (order), Nocardiaceae (family), Desulfovibrionaceae (family), Rhodococcus (genus), and Bacteroidetes (phylum) may be the taxonomic biomarkers of GDM. Microbial gene functions related to amino sugar and nucleotide sugar metabolism were found to be enriched in patients with GDM. CONCLUSION: Our study indicated that dysbiosis of the gut microbiome exists in patients with GDM in the second trimester of pregnancy, and gut microbiota might be a potential diagnostic biomarker for the diagnosis, prevention, and treatment of GDM.

Construction of a ceRNA network of hub genes affecting immune infiltration in ovarian cancer identified by WGCNA.

BACKGROUND: Ovarian cancer is the leading cause of death among gynecological malignancies. Immunotherapy has demonstrated potential effects in ovarian cancer. However, few studies on immune-related prognostic signatures in ovarian cancer have been reported. This study aimed to identify hub genes associated with immune infiltrates to provide insight into the immune regulatory mechanisms in ovarian cancer. METHODS: Raw data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and University of California, Santa Cruz (UCSC) Xena websites. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Kaplan-Meier analysis and differential expression analysis were applied to explore the real hub genes. RESULTS: Through ssGSEA and WGCNA, 7 hub genes (LY9, CD5, CXCL9, IL2RG, SLAMF1, SLAMF6, and SLAMF7) were identified. Finally, LY9 and SLAMF1 were recognized as the real hub genes in immune infiltrates of ovarian cancer. LY9 and SLAMF1 are classified as SLAM family receptors involved in the activation of hematopoietic cells and the pathogenesis of multiple malignancies. Furthermore, 12 lncRNAs and 43 miRNAs significantly related to the 2 hub genes were applied to construct a lncRNA-miRNA-mRNA ceRNA network. The lncRNA-miRNA-mRNA ceRNA network shows upstream regulatory sites of the 2 hub genes. CONCLUSIONS: These findings improve our understanding of the regulatory mechanism of and reveal potential immune checkpoints for immunotherapy for ovarian cancer.

Improved osteogenesis and angiogenesis of a novel copper ions doped calcium phosphate cement.

Improving the angio1genesis potential of bone-repairing materials is vital for the repair of cancerous bone defects. It can further facilitate the delivery of active substances with osteogenesis and anti-tumor functions, ultimately promoting the formation of new bone tissues. Copper ions (Cu2+) have been proved to be beneficial to angiogenesis. This study developed a new type of Cu-containing calcium phosphate cement (Cu-CPC) by incorporating with copper phosphate (CuP) nanoparticles with a photothermal anti-tumor effect. The results revealed that the main phases of all hydrated CPCs were hydroxyapatite, unreacted tricalcium phosphate and calcium carbonate. But the hydration products of CPC became thinner after the incorporation of Cu2+. With the increase of CuP concentration, the setting time of CPC was prolonged while the injectability and the compressive strength were increased. The release concentration of Cu2+in vitro was among 0.01 to 0.74 mg/mL, which showed a positive relation with CuP content. Mouse bone marrow stromal cells (mBMSCs) displayed higher adhesion activity, proliferation performance and expression of osteogenic genes and proteins on CPC with 0.01 wt% CuP (0.01Cu-CPC) and 0.05 wt% CuP (0.05Cu-CPC). When human umbilical vein endothelial cells were co-cultured with 0.01Cu-CPC and 0.05Cu-CPC extracts, the proliferation and angiogenesis-related gene and protein expression were significantly increased, and the in vitro tube formation capacity was promoted. However, higher CuP content inhibited the proliferation of mBMSCs. In conclusion, CPC with 0.01 wt% and 0.05 wt% CuP nanoparticles has the potential to promote bone formation around cancerous bone defects, which would be promising for bone regeneration and treatment of bone tumors.

Cav-1 participates in the development of diabetic neuropathy pain through the TLR4 signaling pathway.

This study aims to determine whether caveolin-1 (Cav-1) participates in the process of diabetic neuropathic pain by directly regulating the expression of toll-like receptor 4 (TLR4) and the subsequent phosphorylation of N-methyl-D-aspartate receptor 2B subunit (NR2B) in the spinal cord. Male Sprague-Dawley rats (120-150 g) were continuously fed with high-fat and high-sugar diet for 8 weeks, and received a single low-dose of intraperitoneal streptozocin injection in preparation for the type-II diabetes model. Then, these rats were divided into five groups according to the level of blood glucose, and the mechanical withdrawal threshold and thermal withdrawal latency values. The pain thresholds were measured at 3, 7, and 14 days after animal grouping. Then, eight rats were randomly chosen from each group and killed. Lumbar segments 4-6 of the spinal cord were removed for western blot analysis and immunofluorescence assay. Cav-1 was persistently upregulated in the spinal cord after diabetic neuropathic pain in rats. The downregulation of Cav-1 through the subcutaneous injection of Cav-1 inhibitor daidzein ameliorated the pain hypersensitivity and TLR4 expression in the spinal cord in diabetic neuropathic pain (DNP) rats. Furthermore, it was found that Cav-1 directly bound with TLR4, and the subsequent phosphorylation of NR2B in the spinal cord contributed to the modulation of DNP. These findings suggest that Cav-1 plays a vital role in DNP processing at least in part by directly regulating the expression of TLR4, and through the subsequent phosphorylation of NR2B in the spinal cord.

Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy.

PURPOSE: The aim of the present study was to further elucidate the role of JAK2/STAT3-CAV-1-NR2B on painful diabetic neuropathy. METHODS: In vivo, the mechanical withdrawal threshold and thermal withdrawal latency were measured to evaluate neuropathic pain behaviors (n= 8), while western blot (n= 5) and an immunofluorescence double staining experiment (n= 6) were performed to understand the molecular mechanism. In vitro, the individual culture of BV2 mouse microglia cell lines, the co-culture of BV2 mouse microglia cell lines and PC12 rat neuron cell lines, and western blot analysis were performed to understand the molecular mechanism between microglia and neurons. RESULTS: The expression of p-JAK2, p-STAT3, t-CAV-1, and p-NR2B was upregulated in the dorsal horn of DNP rats throughout the experiment. Through the immunofluorescence double staining experiment, it was found that p-STAT3 was mainly expressed in activated microglia, and this condition can be stably maintained for approximately 2 weeks after the establishment of the DNP model. The intrathecal injection of JAK2 inhibitor AG490 can relieve the abnormal expression of p-JAK2, p-STAT3, t-CAV-1, and p-NR2B, and relieve pain. The remission of AG490 began on the third day, and it could be stably sustained for 14 days. In vitro high-glucose induced the activation of p-STAT3 in microglia, thereby upregulating the expression of p-CAV-1 and p-NR2B in neurons in the co-culture system. JAK2 inhibitor AG490 can alleviate the abnormal expression of these proteins in the JAK2/STAT3-CAV-1-NR2B signaling pathway in vitro. CONCLUSIONS: Microglial JAK2/STAT3 signaling probably contributes to neuropathic pain by activating the CAV-1-NR2B pathway.