Nicotinamide N -methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma.

BACKGROUND AND AIMS: Nicotinamide N -methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood. APPROACH AND RESULTS: Here, we identified that NNMT can promote IL6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by decreasing the tri-methyl-histone H3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein, an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages and generation of myeloid-derived suppressor cells from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, GM-CSF, tumor-associated macrophage marker CD206, and myeloid-derived suppressor cell marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients. CONCLUSIONS: These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy.

Kyphoplasty is associated with reduced mortality risk for osteoporotic vertebral compression fractures: a systematic review and meta-analysis.

BACKGROUND: Vertebral augmentation, such as vertebroplasty (VP) or kyphoplasty (KP), has been utilized for decades to treat OVCFs; however, the precise impact of this procedure on reducing mortality risk remains a topic of controversy. This study aimed to explore the potential protective effects of vertebral augmentation on mortality in patients with osteoporotic vertebral compression fractures (OVCFs) using a large-scale meta-analysis. MATERIALS AND METHODS: Cochrane Library, Embase, MEDLINE, PubMed and Web of Science databases were employed for literature exploration until May 2023. The hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized as a summary statistic via random-effect models. Statistical analysis was executed using Review Manager 5.3 software. RESULTS: After rigorous screening, a total of five studies with substantial sample sizes were included in the quantitative meta-analysis. The total number of participants included in the study was an 2,421,178, comprising of 42,934 cases of vertebral augmentation and 1,991,244 instances of non-operative management. The surgical intervention was found to be significantly associated with an 18% reduction in the risk of mortality (HR 0.82; 95% CI 0.78, 0.85). Subgroup analysis revealed a remarkable 71% reduction in mortality risk following surgical intervention during short-term follow-up (HR 0.29; 95% CI 0.26, 0.32). Furthermore, KP exhibited a superior and more credible decrease in the risk of mortality when compared to VP treatment. CONCLUSIONS: Based on a comprehensive analysis of large samples, vertebral augmentation has been shown to significantly reduce the mortality risk associated with OVCFs, particularly in the early stages following fractures. Furthermore, it has been demonstrated that KP is more reliable and effective than VP in terms of mitigating mortality risk.

Astragalus (Astragalus mongholicus) Improves Ventricular Remodeling via ESR1 Downregulation RhoA/ROCK Pathway.

Astragalus (Astragalus mongholicus) alleviates myocardial remodeling caused by hypertension. However, the detailed molecular mechanism is unclear. This study aims to investigate the effect of Astragalus on ventricular remodeling in ovariectomized spontaneous hypertensive rats (OVX-SHR).Female SHR/NCrl rats were subjected to bilateral ovariectomy to establish the OVX-SHR model and treated with Astragalus extract by gavage. The hemodynamics and cardiac function parameters were measured. HE and Masson staining were used to detect the pathological structure of myocardial remodeling and observe the hyperplasia of myocardial collagen fibers. The immunohistochemistry tested the level of α-SMA. The expression levels of inflammatory cytokines, IκB, p65, Cleaved-Caspase3, RhoA, and ROCK1/2 were detected using Western blot. The method of qRT-PCR measured the expression of matrix metalloproteinase (MMP-2 and MMP-9).Hemodynamic and cardiac function parameters were significantly improved after a high dose of Astragalus extract and Valsartan treatment. The myocardial integrity of the model group was significantly reduced, arranged loosely, and disordered, while the expression of α-SMA was increased. However, Astragalus extract and Valsartan treatments significantly reduced the pathological damage and α-SMA. The levels of TNF-α, IL-1ß, IL-6, TGF-ß, MMP-2, and MMP-9 in the model group were increased but decreased after Astragalus extract treatment. Adding an ESR1 inhibitor attenuated the improvement effect of Astragalus extract on myocardial remodeling and restored the expression of RhoA and ROCK1/2.Astragalus extract attenuates the cardiac damage in OVX-SHR by downregulating the RhoA/ROCK pathway through ESR1.

Recharge of chondrocyte mitochondria by sustained release of melatonin protects cartilage matrix homeostasis in osteoarthritis.

Recent evidence indicates that the mitochondrial functions of chondrocytes are impaired in the pathogenesis of osteoarthritis (OA). Melatonin can attenuate cartilage degradation through its antioxidant functions. This study aims to investigate whether melatonin could rescue the impaired mitochondrial functions of OA chondrocytes and protect cartilage metabolism. OA chondrocytes showed a compromised matrix synthesis capacity associated with mitochondrial dysfunction and aberrant oxidative stress. In vitro treatments with melatonin promoted the expression of cartilage extracellular matrix (ECM) components, improved adenosine triphosphate production, and attenuated mitochondrial oxidative stress. Mechanistically, either silencing of SOD2 or inhibition of SIRT1 abolished the protective effects of melatonin on mitochondrial functions and ECM synthesis. To achieve a sustained release effect, a melatonin-laden drug delivery system (DDS) was developed and intra-articular injection with DDS successfully improved cartilage matrix degeneration in a posttraumatic rat OA model. These findings demonstrate that melatonin-mediated recharge of mitochondria to rescue the mitochondrial functions of chondrocytes represents a promising therapeutic strategy to protect cartilage from OA.

Arctiin-reinforced antioxidant microcarrier antagonizes osteoarthritis progression.

Loss of extracellular matrix (ECM) of cartilage due to oxidative stress injury is one of the main characteristics of osteoarthritis (OA). As a bioactive molecule derived from the traditional Chinese Burdock, arctiin exerts robust antioxidant properties to modulate redox balance. However, the potential therapeutic effects of arctiin on OA and the underlying mechanisms involved are still unknown. Based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) tool, Burdock-extracted small molecule arctiin was identified as a potential anti-arthritic component. In vitro, treatment using arctiin rescued the interleukin (IL)-1ß-induced activation of proteinases and promoted the cartilage ECM synthesis in human chondrocytes. In vivo, intraperitoneal injection of arctiin ameliorated cartilage erosion and encountered subchondral bone sclerosis in the post-traumatic OA mice. Transcriptome sequencing uncovered that arctiin-enhanced cartilage matrix deposition was associated with restricted oxidative stress. Mechanistically, inhibition of nuclear factor erythroid 2-related factor 2 (NRF2) abolished arctiin-mediated anti-oxidative and anti-arthritic functions. To further broaden the application prospects, a gellan gum (GG)-based bioactive gel (GG-CD@ARC) encapsulated with arctiin was made to achieve long-term and sustained drug release. Intra-articular injection of GG-CD@ARC counteracted cartilage degeneration in the severe (12 weeks) OA mice model. These findings indicate that arctiin may be a promising anti-arthritic agent. Furthermore, GG-modified bioactive glue loaded with arctiin provides a unique strategy for treating moderate to severe OA.

Association between the second-stage duration of labor and perinatal outcomes in women with a prior cesarean delivery.

BACKGROUND: The cesarean delivery (CD) rate has been increasing globally. Trial of labor after cesarean delivery (TOLAC) has been used as a key method for the reduction of the CD rate. Little is known, however, about the association between the second-stage duration of TOLAC and adverse maternal and neonatal outcomes. This study evaluated the association between perinatal outcomes and the duration of second-stage labor in women undergoing TOLAC. METHODS: A 10-year retrospective cohort study was performed at the Department of Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, between January 2010 and January 2020. Women undergoing TOLAC who reached the second stage of labor were included in this study. Duration of the second stage of labor was examined as a categorical variable (group I: <0.5 h, group II: 0.5-2 h and group III: ≥2 h) and as a continuous variable to evaluate the association with adverse perinatal outcomes by using multivariable regression models and a Cox proportional hazards regression model adjusting for potential confounders. RESULTS: Of the 1,174 women who met the inclusion criteria, the median (interquartile range) length of the second stage was 0.5 h (0.3-0.9 h). Among them, 1,143 (97.4%) delivered vaginally and 31 underwent an unplanned CD. As the second-stage duration increased, operative vaginal delivery (OVD), CD, and postpartum hemorrhage (PPH) rates increased. Women in group III had higher risks of OVD (aOR = 11.34; 95% CI [5.06-25.41]), CD (aOR = 4.22; 95% CI [1.32-13.43]), and PPH (aOR = 2.43; 95% CI [1.31-4.50]) compared with group I. Correspondingly, blood loss and the oxytocin used to treat PPH increased significantly, while the postpartum hemoglobin reduced significantly in group III compared with group I. The incidence of uterine rupture, uterine atony, cervical laceration, red blood cell transfusion, and intensive care unit admission were similar in all three groups. Neonatal outcomes were not affected by the second-stage duration. CONCLUSIONS: Women undergoing TOLAC with second-stage duration of ≥2 h have higher odds of OVD, unplanned intrapartum CD, and PPH.

Proteomic comparison between physiological degeneration and needle puncture model of disc generation disease.

BACKGROUND: The completeness of the intervertebral disc proteome is fundamental to the integrity and functionality of the intervertebral disc. METHODS: The 20 experimental rats were placed into two groups randomly, normal group (NG) and acupuncture pathological degeneration group-2 weeks (APDG-2w). The ten 24-month-old rats were grouped into physiological degeneration group (PDG). Magnetic resonance imaging, X-ray examination, histological staining (hematoxylin & eosin, safranin-O cartilage, and alcian blue staining), and immunohistochemical examination were carried out for assessing the degree of disc degradation. Intervertebral disc was collected, and protein composition was determined by LC- MS, followed by bioinformatic analysis including significance analysis, subcellular localization prediction, protein domain prediction, GO function and KEGG pathway analysis, and protein interaction network construction. LC-PRM was done for protein quantification. RESULTS: Physiological degeneration and especially needle puncture decreased T2 signal intensity and intervertebral disc height. Results from hematoxylin & eosin, safranin-O, and alcian blue staining revealed that the annulus fibrosus apparently showed the wavy and collapsed fibrocartilage lamellas in APDG-2w and PDG groups. The contents of the nucleus pulposus were decreased in physiological degeneration group and APDG-2w group compared with NG. Results from immunohistochemical analysis suggested the degeneration of intervertebral disc and inflammation in APDG-2w and PDG groups. The protein composition and expression between needle puncture rat models and the physiological degeneration group showed significant difference. CONCLUSIONS: Our studies produced point-reference datasets of normal rats, physiological degeneration rats, and needle puncture rat models, which is beneficial to subsequent pathological studies. There is differential expression of protein expression in degenerative discs with aging and acupuncture, which may be used as a potential discriminating index for different intervertebral degenerations.

Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection.

The aim of this study was to identify predictive immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation (EMT)-related biomarkers, pathways and new drugs in allograft rejection in kidney transplant patients. First, gene expression data were downloaded followed by identification of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis. Second, diagnostic model was construction based on key genes, followed by correlation analysis between immune/hypoxia/ferroptosis/EMT and key diagnostic genes. Finally, drug prediction of diagnostic key genes was carried out. Five diagnostic genes were further identified, including CCR5, CD86, CD8A, ITGAM, and PTPRC, which were positively correlated with allograft rejection after the kidney transplant. Highly infiltrated immune cells, highly expression of hypoxia-related genes and activated status of EMT were significantly positively correlated with five diagnostic genes. Interestingly, suppressors of ferroptosis (SOFs) and drivers of ferroptosis (DOFs) showed a complex regulatory relationship between ferroptosis and five diagnostic genes. CD86, CCR5, and ITGAM were respectively drug target of ABATACEPT, MARAVIROC, and CLARITHROMYCIN. PTPRC was drug target of both PREDNISONE and EPOETIN BETA. In conclusion, the study could be useful in understanding changes in the microenvironment within transplantation, which may promote or sustain the development of allograft rejection after kidney transplantation.

Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer.

BACKGROUND & AIMS: Our previous genomic whole-exome sequencing (WES) data identified the key ErbB pathway mutations that play an essential role in regulating the malignancy of gallbladder cancer (GBC). Herein, we tested the hypothesis that individual cellular components of the tumor microenvironment (TME) in GBC function differentially to participate in ErbB pathway mutation-dependent tumor progression. METHODS: We engaged single-cell RNA-sequencing to reveal transcriptomic heterogeneity and intercellular crosstalk from 13 human GBCs and adjacent normal tissues. In addition, we performed WES analysis to reveal the genomic variations related to tumor malignancy. A variety of bulk RNA-sequencing, immunohistochemical staining, immunofluorescence staining and functional experiments were employed to study the difference between tissues with or without ErbB pathway mutations. RESULTS: We identified 16 cell types from a total of 114,927 cells, in which epithelial cells, M2 macrophages, and regulatory T cells were predominant in tumors with ErbB pathway mutations. Furthermore, epithelial cell subtype 1, 2 and 3 were mainly found in adenocarcinoma and subtype 4 was present in adenosquamous carcinoma. The tumors with ErbB pathway mutations harbored larger populations of epithelial cell subtype 1 and 2, and expressed higher levels of secreted midkine (MDK) than tumors without ErbB pathway mutations. Increased MDK resulted in an interaction with its receptor LRP1, which is expressed by tumor-infiltrating macrophages, and promoted immunosuppressive macrophage differentiation. Moreover, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on regulatory T cells was induced in GBC with ErbB pathway mutations. Elevated MDK was correlated with poor overall survival in patients with GBC. CONCLUSIONS: This study has provided valuable insights into transcriptomic heterogeneity and the global cellular network in the TME, which coordinately functions to promote the progression of GBC with ErbB pathway mutations; thus, unveiling novel cellular and molecular targets for cancer therapy. LAY SUMMARY: We employed single-cell RNA-sequencing and functional assays to uncover the transcriptomic heterogeneity and intercellular crosstalk present in gallbladder cancer. We found that ErbB pathway mutations reduced anti-cancer immunity and led to cancer development. ErbB pathway mutations resulted in immunosuppressive macrophage differentiation and regulatory T cell activation, explaining the reduced anti-cancer immunity and worse overall survival observed in patients with these mutations.

Identification of genes and miRNAs in paclitaxel treatment for breast cancer.

AIM: Paclitaxel is a microtubule-stabilizing drug that has therapeutic effect on breast cancer. However, the molecular mechanism of paclitaxel on breast cancer has not been elucidated. MATERIALS AND METHODS: Microarray data of GSE114403, including 50 pretreatment and 50 posttreatment samples, were downloaded from public database. The differentially expressed genes (DEGs) between pretreatment and posttreatment were identified, followed by functional enrichment analysis. Then, protein-protein interaction (PPI) network and transcription factor (TF)-miRNA-mRNA network were constructed. Finally, the survival analysis of hub genes was performed. RESULTS: A total of 107 DEGs were screened from pretreatment versus posttreatment. Genes were significantly enriched in GO terms such as inflammatory response, and pathways like cytokine-cytokine receptor interaction pathway. CXCL2, PTGS2, and ATF3 were considered as hub genes in PPI network. TFs such as FOXA2, NFE2L2, as well as miRNAs like has-miR-508-3p and has-miR-584 also played role in the paclitaxel treatment. Additionally, survival analysis revealed that breast cancer patients with high expression level of CXCL2, PTGS2, and ATF3 had longer survival time. CONCLUSION: In summary, we demonstrated that CXCL2, PTGS2, and ATF3 might be diagnostic and therapeutic molecular biomarkers for breast cancer. These findings might provide further insights into the pathophysiology of breast cancer, as well as enhance our understanding of the anticancer effects of paclitaxel.

The effects of dementia on the prognosis and mortality of hip fracture surgery: a systematic review and meta-analysis.

OBJECTIVES: Dementia is a common mental disorder that affects the life quality in elders. Recently, emerging studies reported the negative impacts of dementia on prognosis after hip surgeries. However, the integrated and reliable role of dementia in hip surgery is not illustrated. METHODS: We searched the relevant literatures before June 2020 and extracted the data that met the inclusion criteria. The influence of dementia on postoperative walking ability, complications including infection, cardiovascular complications, hip dislocation, delirium, and respiratory complications, and survival rate at different periods were evaluated. Qualitative and quantitative analysis were conducted using Review Manager Version 5.3. RESULTS: The meta-analysis enrolled a total of 30 studies with 1,037,049 patients. The pooled results revealed that there were significant negative impacts of dementia on the recovery of postoperative walking ability, postoperative infection, hip dislocation, delirium and respiratory complications and mortality at different periods. CONCLUSIONS: Dementia is a crucial risk factor for the poor prognosis after hip fracture surgery. Therefore, when making clinical strategies for hip fracture patients with dementia, countermeasures for possible complications should be generated.

miR-139-5p mediates the palmitate-induced inhibition of insulin secretion by targeting neuronal pentraxin 1 in INS-1 cells.

High fatty acid reduces insulin secretion in pancreatic ß-cells and miR-139-5p is increased in diabetic pancreatic tissues and induces islet ß-cell apoptosis. However, to date, there is no study exploring whether or not miR-139-5p is involved in high fatty acid-induced insulin secretion. In the present study, INS-1 cells were exposed to different concentrations (0.1, 0.2, and 0.4 mM) of palmitate for different time periods (12, 24, and 48 h). The expression levels of miR-139-5p and neuronal pentraxin 1 (NPTX1) were evaluated by real-time PCR and western blot analysis. The regulation of NPTX1 by miR-139-5p was examined by luciferase assay. Cell transfection was conducted using Lipo8000 or Lipofectamine RNAiMAX. Potassium or glucose-stimulated insulin secretion levels were used to verify the function of miR-139-5p or NPTX1 in insulin secretion. Insulin secretion levels were detected by radioimmunoassay. We found that miR-139-5p was increased in INS-1 cells stimulated with palmitate. In addition, miR-139-5p was also elevated in islets of high-fat diet-fed mice and db/db mice compared to those in islets of normal diet-fed mice and wild-type mice. Knockdown of miR-139-5p could reverse high fatty acid-induced insulin secretion defects in INS-1 cells. Furthermore, we demonstrated that NPTX1 is a target of miR-139-5p. miR-139-5p mediated palmitate-induced insulin secretion defects by targeting NPTX1. Moreover, palmitate treatment declined the expression of NPTX1 and the NPTX1 expression was also decreased in islets of high-fat diet-fed mice and db/db mice. Impaired NPTX1 expression is involved in fatty acid-induced insulin secretion defects. Collectively, our results illustrate that the induction of ß-cell insulin secretion defects by fatty acids is mediated, at least in part, by miR-139-5p via downregulation of NPTX1 expression.

Predictors of postoperative delirium in elderly patients following total hip and knee arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Postoperative delirium (POD) is widely reported as a common postoperative complication following total joint arthroplasty (TJA) of the hip and knee in elderly patients, leading to many adverse effects. We sought to investigate predictors of delirium after TJA. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched up to 2020 for studies examining POD following TJA in elderly patients. Pooled odds ratio (OR) and mean difference (MD) of those who experienced delirium compared to those who did not were calculated for each variable. The Newcastle-Ottawa Scale (NOS) was used for the study quality evaluation. RESULTS: Fifteen studies with 31 potential factors were included. In the primary analysis, 9 factors were associated with POD, comprising advanced age (MD 3.81; 95% confidence interval (CI) 1.80-5.83), dementia (OR 24.85; 95% CI 7.26-85.02), hypertension (OR 2.26; 95% CI 1.31-3.89), diabetes (OR 2.02; 95% CI 1.15-3.55), stroke (OR 14.61; 95% CI 5.26-40.55), psychiatric illness (OR 2.72; 95% CI 1.45-5.08), use of sedative-hypnotics (OR 6.42; 95% CI 2.53-16.27), lower preoperative levels of hemoglobin (MD - 0.56; 95% CI - 0.89-- 0.22), and lower preoperative mini-mental state examination score (MD - 0.40; 95% CI - 0.69-- 0.12). Twelve studies were included in the systematic review, of which 24 factors were additionally correlated with POD using single studies. CONCLUSIONS: Strategies and interventions should be implemented for the elderly patients receiving TJA surgeries with potential predictors identified in this meta-analysis.

Computer-aided assessment of the chemokine receptors CXCR3, CXCR4 and CXCR7 expression in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is a vicious and invasive disease. The major challenge in the clinical treatment of GBC is the lack of a suitable prognosis method. Chemokine receptors such as CXCR3, CXCR4 and CXCR7 play vital roles in the process of tumour progression and metastasis. Their expression levels and distribution are proven to be indicative of the progression of GBC, but are hard to be decoded by conventional pathological methods, and therefore, not commonly used in the prognosis of GBC. In this study, we developed a computer-aided image analysis method, which we used to quantitatively measure the expression levels of CXCR3, CXCR4 and CXCR7 in the nuclei and cytoplasm of glandular and interstitial cells from a cohort of 55 GBC patients. We found that CXCR3, CXCR4 and CXCR7 expressions are associated with the clinicopathological variables of GBC. Cytoplasmic CXCR3, nuclear CXCR7 and cytoplasmic CXCR7 were significant predictive factors of histology invasion, whereas cytoplasmic CXCR4 and nuclear CXCR4 were significantly correlated with T and N stage and were associated with the overall survival and disease-free survival. These results suggest that the quantification and localisation of CXCR3, CXCR4 and CXCR7 expressions in different cell types should be considered using computer-aided assessment to improve the accuracy of prognosis in GBC.

Comparison of cervical disc arthroplasty and anterior cervical discectomy and fusion for the treatment of cervical disc degenerative diseases on the basis of more than 60 months of follow-up: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis was designed to investigate the long-term efficacy and safety between cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF) in treating cervical disc degenerative diseases (CDDDs). METHODS: Literature search was performed on Pubmed, Embase, Cochrane Library, and Web of Science before Jan 2019. Surgical details, clinical outcomes, range of motion (ROM), complications, and reoperation rates between CDA and ACDF groups were compared and analyzed. A fixed- or random-effects model was applied based on different heterogeneity. STATA (Version 11.0) software was used to perform data analysis. RESULTS: A total of 13 randomized controlled trial studies with more than 60 months of follow-up (mean 83.1 months) were enrolled in this meta-analysis. Pool results indicated that the CDA group exhibited significantly better outcomes in clinical scores (odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.15-2.08, p = 0.004) and preservation of ROM (mean difference = 1.77, 95% CI: 1.60-1.95, p < 0.001) than the ACDF group. Meanwhile, the incidence of adjacent segment disease (ASD) (OR = 0.51, 95% CI: 0.35-0.76, p = 0.001) and occurrence of reoperation (OR = 0.41, 95% CI: 0.25-0.69, p = 0.001) were lower in the CDA group than in the ACDF group. CONCLUSIONS: At long-term follow-up, CDA showed better efficacy in terms of clinical outcomes, ROM, ASD, and reoperation than ACDF for treating CDDDs. However, our results require further validation in large-sample and high-quality studies.

Safety and efficacy of percutaneous kyphoplasty assisted with O-arm navigation for the treatment of osteoporotic vertebral compression fractures at T6 to T9 vertebrae.

PURPOSE: To evaluate the safety and efficacy of PKP under O-arm navigation system guidance for treating middle thoracic OVCF (T6~T9). METHODS: A retrospective study was conducted for 44 consecutive T6~T9 OVCF patients who received PKP assisted with O-arm navigation (n = 20) or fluoroscopy (n = 24) from January 2016 to December 2017. Demographic data, radiographic parameters, and clinical outcomes were collected and analyzed at pre-operative, post-operative, and final follow-up period. Complications including tissue lesion, needle malposition, and leakage of bone cement were also recorded amid operation. RESULTS: A total of 44 patients (4 males and 40 females, with mean age of 71.1 ± 8.7) were enrolled in this study, and the mean follow-up time was 14.4 months. In surgical details, navigation system could obtain more satisfactory volume of injected cement and less loss of blood, as well did not increase surgical time compared with fluoroscopy. Both radiological and clinical outcomes improved significantly at post-operative and final follow-up, while did not differed between two groups. For adverse events, the incidence of cement leakage was similar between two groups. However, O-arm navigation can achieve lower rate of complications than fluoroscopy. CONCLUSION: Our preliminary study demonstrated that PKP assisted with O-arm navigation is a safe and effective procedure that applied for middle thoracic OVCF (T6~T9), which can achieve favourable radiological and clinical outcomes, and low rate of complications.

Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis.

OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results.

Long noncoding RNA HOXA-AS2 regulates the expression of SCN3A by sponging miR-106a in breast cancer.

Breast cancer is the most commonly diagnosed cancer that affects women worldwide. This study aimed to investigate the competing endogenous RNAs (ceRNAs) mechanism in breast cancer. Microarray data were downloaded from the University of California Santa Cruz (UCSC) Xena database. The limma package was used to screen the differentially expressed messenger RNAs (DEMs) and differentially expressed long noncoding RNAs (DELs). Subsequently, functional analysis was performed using DAVID tool. After constructing the protein-protein interaction (PPI) network, we identified the major gene modules using the Cytoscape software. Univariate survival analysis in the survival package was performed. Finally, the ceRNA regulatory network was constructed to identify the critical genes. A total of 1380 DEMs and 345 DELs were identified in breast cancer samples compared with normal samples. Functional enrichment analysis showed that DEMs were mainly involved in cell division, and cell cycle. We screened four major gene modules and identified the hub nodes in these functional modules. Several DEMs (including FABP7, C4BPA, and LAMB3) and three long noncoding RNAs (lncRNAs) (LINC00092, SLC26A4.AS1, and COLCA1) exhibited significant correlation with patients' survival outcomes. In the ceRNA network, the lncRNA HOXA-AS2 regulated the expression level of SCN3A by interacting with hsa-miR-106a-5p. Thus, our study investigated the ceRNA mechanism in breast cancer. The results showed that lncRNA HOXA-AS2 might modulate the expression of SCN3A by sponging miR-106a in breast cancer.

LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis.

BACKGROUNDS: Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. METHODS: The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. RESULTS: We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. CONCLUSIONS: Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.

LncRNA-PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC Functional analysis indicates that lncRNA-PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.