Evaluation of AJCC staging system and proposal of a novel stage grouping system in retroperitoneal liposarcoma: the Fudan Zhongshan experience.

Background: Overall survival (OS) varies significantly among individuals with heterogeneous retroperitoneal liposarcoma (RPLS), even among those with the same clinical stage. Improved staging of RPLS is a critical unmet need, given the disappointing results of external validations of the 8th American Joint Committee on Cancer (AJCC) TNM staging system. Methods: The cohort study included 220 consecutive patients who underwent surgical resection for primary RPLS at the largest sarcoma centre of Fudan University in China from September 2009 to August 2021, combined with 277 adult patients with RPLS in the SEER database from 1975 to 2020. Data analysis was performed from December 2021 to December 2022. Patients were retrospectively restaged according to the 8th and 7th editions of the TNM staging system as well as the new TNM (nTNM) staging system. The primary endpoint was overall survival (OS). Comparative analysis of postoperative survival was performed using the Kaplan-Meier method, and differences between subgroups were tested using the log-rank test. The OS prediction nomogram was generated based on baseline variables and tumour characteristics. Harrell's consistency index (C-index), area under the curve (AUC) of receiver operating characteristic curves (ROC), and calibration curves were used to evaluate the performance of the nomogram. Results: A total of 497 patients were enrolled in the study, including 282 (56.7%) male patients. The median follow-up was 51 months (interquartile range, IQR, 23-83), and the OS rates at 1, 3, and 5 years were 87.9%, 75.3%, and 64.9%, respectively. According to the staging distribution of the AJCC 7th edition, 6 patients were stage IA (1.2%), 189 patients were stage IB (38%), 12 patients were stage IIA (2.4%), 150 patients were stage IIB (30.1%), 131 patients were stage III (26.3%), and 9 patients were stage IV (1.8%). With the 8th edition staging, this distribution changed: 6 patients (1.2%) were stage IA, 189 patients (38%) were stage IB, 12 patients (2.4%) were stage II, 24 patients (4.8%) were stage IIIA, 257 patients (51.7%) were stage IIIB, and 9 patients (1.8%) were stage IV. 182 patients (36.6%) were reclassified according to the nTNM staging system with the new T stage classification. The C-index and log-rank score improved after implementation of nTNM implementation. The nTNM system was associated with improved identification of high-risk patients compared with the AJCC 7th and 8th TNM. The FNCLCC stage proved to be highly prognostic with significant intergroup differences in OS. The calibration curve shows a high degree of agreement between the actual OS rate and the nomogram estimated OS rate. Conclusion: Compared with 8th AJCC TNM, 7th AJCC TNM staging system showed a more homogeneous staging distribution and a slight improvement in the prognostic accuracy of RPLS. The revised T-stage and nTNM systems showed better risk stratification performance. The FNCLCC stage was found to have high prognostic value, further emphasising histological grade is the least negligible prognostic factor in predicting patient survival. The constructed nomogram model enables individualized prognostic analysis and helps to develop risk-adapted therapy for RPLS patients.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

Nicotine regulates abnormal macrophage polarization and trophoblast invasion associated with preterm labor via the α7nAChR/SIRT1 axis.

INTRODUCTION: Preterm birth (PTB) frequently results from the syndrome of preterm labor (PTL). PTL is linked to an atypical maternal inflammatory response, as well as intrauterine inflammation and/or infection. In this study, we explored the mechanisms involved in nicotine-mediated abnormal macrophage polarization and trophoblast invasion associated with PTL. METHODS: First, THP-1-M0 macrophages were generated by treating the human monocytic leukemia cell line (THP-1) with phorbol 12-myristate 13-acetate for a duration of 24 h. Afterward, nicotine treatment was administered, followed by coculturing with the HTR-8/SVneo trophoblast cell line (HTR-8) at a ratio of 1:1. Next, we transfected sh-α7nAChR and treated THP-1-M0 macrophages and HTR-8 cells with nicotine. In addition, we transfected THP-1-M0 macrophages with sh-NC or sh-SIRT1 or subjected them to 4 nM nicotinamide adenine dinucleotide (NAD) metabolic inhibitor FK866 treatment. Moreover, HTR-8 cells were treated with nicotine, after which THP-1-M0 macrophages were cocultured with HTR-8 cells. Finally, we constructed an in vivo RU486-induced PTL rat model to verify the effect of nicotine and the mechanisms involved. RESULTS: We found that nicotine affected polarization and α7nAChR expression in HTR-8 cocultured THP-1-M0 macrophages. Knocking down α7nAChR blocked the effect of nicotine on the proliferation and invasion of HTR-8 cells. Furthermore, nicotine activated the α7nAChR/SIRT1 axis to regulate THP-1-M0 macrophage polarization through the cholinergic anti-inflammatory pathway. Additionally, NAD metabolism mediated the role of the α7nAChR/SIRT1 axis in nicotine-induced polarization of HTR-8 cocultured THP-1-M0 macrophages. In vivo experiments demonstrated that nicotine alleviated inflammation in PTL rats, which involved the α7nAChR/SIRT1 axis. CONCLUSION: Nicotine regulated abnormal macrophage polarization and trophoblast invasion associated with PTL via the α7nAChR/SIRT1 axis.

Clinical and surgical effectiveness of the multi-disciplinary standardized management model in the treatment of retroperitoneal liposarcoma: Evidence-based clinical practice experience from Fudan Zhongshan.

BACKGROUND: To assess the correlation between clinical outcomes and diagnostic accuracy of evaluations carried out by a preoperative multidisciplinary team versus standard surgical care for patients with retroperitoneal liposarcoma undergoing surgery. METHODS: This comparative study was conducted retrospectively at a specialist assessment center within Zhongshan Hospital, Fudan University, China, between April 2011 and March 2021. Patients were assigned to a multidisciplinary team or nonmultidisciplinary team cohort based on referral to the multidisciplinary team. The primary outcome measured was long-term clinical prognosis, with other outcomes including diagnostic accuracy, 30-day reoperation, duration of stay, perioperative mortality, and medical complications. To mitigate selection bias, we conducted propensity-score matching. Uni- and multivariable Cox proportional hazard models were then used to evaluate the effect of multidisciplinary teams on postoperative survival. The previously specified questionnaire was used to measure the enhancement of awareness and treatment adherence facilitated by multidisciplinary team management. Data analysis was carried out between January 2023 and August 2023. RESULTS: Of the 521 records that were screened, 139 patients were deemed eligible for inclusion and defined as the multidisciplinary team cohort. At the same time, 382 patients without multidisciplinary team management were also included during that period and defined as the nonmultidisciplinary team cohort. The multidisciplinary team cohort exhibited lower numbers of primary retroperitoneal liposarcoma but a higher tumor grade and a greater proportion of R2 resection. After propensity-score matching, the 1-, 3-, and 5-year overall survival rates were 89.5%, 70.5%, and 62.9%, respectively, in the multidisciplinary team cohort, and 77.1%, 49.8%, and 45.1% in the nonmultidisciplinary team cohort. The diagnostic consistency of the multidisciplinary team group was significantly superior to that of the nonmultidisciplinary cohort (92.5% vs 83.6%, P = .042). Although no significant links were shown with duration of stay (P = .232) and 30-day reoperation (P = .447), the multidisciplinary team participation was linked to a substantial decrease in perioperative mortality (P = .036) and postoperative complications (P = .002). Additionally, the multidisciplinary team group indicated stronger illness awareness and postoperative adherence among individuals with retroperitoneal liposarcoma. CONCLUSION: The study's findings indicate that multidisciplinary team management could result in improved clinical outcomes, higher diagnostic accuracy, and reduced duration of postoperative stays, complications, and perioperative mortality. The intervention may also enhance disease awareness and postoperative compliance in retroperitoneal liposarcoma patients who undergo surgery. However, evidence quality was deemed low, and prospective studies with robust designs are required. Nonetheless, these results are worth considering.

Recurrence of common bile duct stones after choledocholithotomy in elderly patients: risk factor analysis and clinical prediction model development.

Background: The reasons for the recurrence of common bile duct stones (CBDS) in elderly patients after choledocholithotomy are still unclear. This study aims to establish a prediction model for CBDS recurrence by identifying risk factors. Methods: We conducted a retrospective analysis of 1804 elderly patients aged 65 years and above who were diagnosed to have CBDS and were admitted to Nanjing First Hospital between January 1, 2010, and January 1, 2021. According to inclusion and exclusion criteria, 706 patients were selected for the final analysis. The patients were assigned to two groups according to the presence or absence of CBDS recurrence, and their clinical data were then statistically analyzed. Subsequently, a prediction model and nomogram were developed, evaluating effectiveness using the concordance index (C-index). Results: Of the 706 elderly patients, 62 patients experienced CBDS recurrence after surgery, resulting in a recurrence rate of 8.8%. The multivariate Cox analysis showed that prior history of cholecystectomy (hazard ratio [HR] = 1.931, 95% confidence interval [CI]: 1.051-3.547, p = 0.034), white blood cell (WBC) count ≥11.0 × 109/L (HR = 2.923, 95% CI: 1.723-4.957, p < 0.001), preoperative total bilirubin (TBIL) level ≥ 36.5 mmol/L (HR = 2.172, 95% CI: 1.296-3.639, p = 0.003), number of stones ≥2 (HR = 2.093, 95% CI: 1.592-5.294, p = 0.001), maximum stone diameter ≥ 0.85 cm (HR = 1.940, 95% CI: 1.090-3.452, p = 0.024), and T-tube drainage (HR = 2.718, 95% CI: 1.230-6.010, p = 0.013) were independent risk factors of CBDS recurrence in elderly patients after choledocholithotomy. A postoperative CBDS recurrence prediction model was constructed with a C-index value of 0.758 (95% CI: 0.698-0.818) and internal validation value of 0.758 (95% CI: 0.641-0.875). Conclusion: A history of cholecystectomy, WBC count ≥11.0 × 109/L, preoperative TBIL level ≥ 36.5 mmol/L, number of stones ≥2, maximum stone diameter ≥ 0.85 cm, and T-tube drainage are the independent risk factors of CBDS recurrence after choledocholithotomy in elderly patients. Our developed prediction model for CBDS recurrence has good predictive ability and can help predict the prognosis of patients with CBDS.

Insight of a lipid metabolism prognostic model to identify immune landscape and potential target for retroperitoneal liposarcoma.

Introduction: The exploration of lipid metabolism dysregulation may provide novel perspectives for retroperitoneal liposarcoma (RPLS). In our study, we aimed to investigate potential targets and facilitate further understanding of immune landscape in RPLS, through lipid metabolism-associated genes (LMAGs) based prognostic model. Methods: Gene expression profiles and corresponding clinical information of 234 cases were enrolled from two public databases and the largest retroperitoneal tumor research center of East China, including cohort-TCGA (n=58), cohort-GSE30929 (n=92), cohort-FD (n=50), cohort-scRNA-seq (n=4) and cohort-validation (n=30). Consensus clustering analysis was performed to identify lipid metabolism-associated molecular subtypes (LMSs). A prognostic risk model containing 13 LMAGs was established using LASSO algorithm and multivariate Cox analysis in cohort-TCGA. ESTIMATE, CIBERSORT, XCELL and MCP analyses were performed to visualize the immune landscape. WGCNA was used to identify three hub genes among the 13 model LMAGs, and preliminarily validated in both cohort-GSE30929 and cohort-FD. Moreover, TIMER was used to visualize the correlation between antigen-presenting cells and potential targets. Finally, single-cell RNA-sequencing (scRNA-seq) analysis of four RPLS and multiplexed immunohistochemistry (mIHC) were performed in cohort-validation to validate the discoveries of bioinformatics analysis. Results: LMS1 and LMS2 were characterized as immune-infiltrated and -excluded tumors, with significant differences in molecular features and clinical prognosis, respectively. Elongation of very long chain fatty acids protein 2 (ELOVL2), the enzyme that catalyzed the elongation of long chain fatty acids, involved in the maintenance of lipid metabolism and cellular homeostasis in normal cells, was identified and negatively correlated with antigen-presenting cells and identified as a potential target in RPLS. Furthermore, ELOVL2 was enriched in LMS2 with significantly lower immunoscore and unfavorable prognosis. Finally, a high-resolution dissection through scRNA-seq was performed in four RPLS, revealing the entire tumor ecosystem and validated previous findings. Discussion: The LMS subgroups and risk model based on LMAGs proposed in our study were both promising prognostic classifications for RPLS. ELOVL2 is a potential target linking lipid metabolism to immune regulations against RPLS, specifically for patients with LMS2 tumors.

Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis.

BACKGROUND & AIMS: Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS: We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS: We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5ß1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. CONCLUSIONS: CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

Damaged collagen detected by collagen hybridizing peptide as efficient diagnosis marker for early hepatic fibrosis.

Liver fibrosis is characterized by excessive synthesis and deposition of extracellular matrix (ECM) in liver tissues. However, it still has been lacking of early detection and diagnosis methods. The collagen hybridizing peptide (CHP) is a novel synthetic peptide that enables detection of collagen damage and tissue remodeling. Here, we showed that obvious CHP-positive staining could be detected in the liver while given CCl4 for only 3 days, which was significantly enhanced while given CCl4 for 7 days. However, H&E staining showed no significant changes in fibrous tissue, and sirius red-positive staining could only be observed while given CCl4 for 14 days. Moreover, CHP-positive staining enhanced initially at portal area which further extended into the hepatic lobule, which was increased more significantly than sirius red-positive staining in the model of 10 and 14 days. Further proteomic analysis of CHP-positive staining revealed that pathways associated with ECM remodeling were significantly increased, while retinol metabolism was downregulated. Meanwhile, proteins enriched in cellular gene transcription and signal transduction involved in fibrogenesis were also upregulated, suggesting that fibrosis occurred in CHP-positive staining. Our study provided evidence that CHP could detect the collagen damage in liver, which might be an efficient indicator for the diagnosis of liver fibrosis at a very early stage.

c-kit+VEGFR-2+ Mesenchymal Stem Cells Differentiate into Cardiovascular Cells and Repair Infarcted Myocardium after Transplantation.

Resent study suggests that c-kit+ cells in bone marrow-derived MSCs may differentiate toward cardiamyocytes. However, the properties of c-kit+ MSCs remain unclear. This study isolated c-kit+VEGFR-2+ cells from rat bone marrow-derived MSCs, and assessed potential of c-kit+VEGFR-2+ MSCs to differentiate towards cardiovascular cells and their efficiency of repairing the infarcted myocardium after transplantation. Gene expression profile of the cells was analyzed with RNA-sequencing. Potential of differentiation of the cells was determined after induction. Rat models of myocardial infarction were established by ligation of the left anterior descending coronary artery. The cells were treated with hypoxia and serum deprivation for four hours before transplantation. Improvement of cardiac function and repair of the infarcted myocardium were assessed at four weeks after transplantation. Gene expression profile revealed that c-kit+VEGFR-2+ MSCs expressed most smooth muscle-specific and myocardium-specific genes, while expression of endothelium-specific genes was upregulated significantly. After induction with VEGF or TGF-ß for two weeks, the cells expressed CD31 and α-SMA respectively. At three weeks, BMP-2-induced cells expressed cTnT. After transplantation of the cells, cardiac function was improved, scar size of the infarcted myocardium was decreased, and angiogenesis and myocardial regeneration were enhanced significantly. Moreover, paracrine in the myocardium was increased after transplantation. These results suggest that c-kit+VEGFR-2+ MSCs have a potential of differentiation towards cardiovascular cells. Transplantation of c-kit+VEGFR-2+ MSCs is effective for repair of the infarcted myocardium. c-kit+VEGFR-2+ MSCs may be a reliable source for cell therapy of ischaemic diseases.

Panax notoginseng attenuates hypoxia-induced glycolysis in colonic mucosal epithelial cells in DSS-induced colitis.

Background: Colonic mucosal injuries are an important manifestation of ulcerative colitis (UC), which is related to hypoxia-induced glycolysis in colonic mucosal epithelial cells (cmECs). Panax notoginseng (PN) promotes the repair of colonic mucosal injuries by inhibiting hypoxia-induced glycolysis in cmECs; However, the mechanism by which this occurs is not completely clear. Here, we are to investigate the effects of PN on glucose metabolism in cmECs in colitis and the underlying mechanism. Methods: A model of dextran sulfate sodium-induced colitis rats was used in this research, and the severity of colitis was assessed by pathology, disease activity index (DAI), and weight changes. The content of intracellular pyruvate, intracellular lactate, adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial ROS (mtROS), myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, and inflammatory cytokines was detected by assay kits. The expression levels of proteins were detected by western blotting. The expression levels of the ATP4a gene were detected by quantitative polymerase chain reaction (QT-PCR). Results: The colonic mucosal injuries of the colitis rats were significantly worse than those of the control group. Specifically, the hypoxia-induced glycolysis and potential of hydrogen (pH) in the colonic lumen were increased, and the expression of ATP4a was downregulated in the colitis rats. PN (1.0 g/kg) promoted the repair of colonic mucosal injuries, and reversed the pH in the colonic lumen. Further, PN increased the expression of ATP4a proteins, the content of ATP, and the SOD activity, and decreased the expression of pyruvate dehydrogenase lipoamide kinase isozyme and hypoxia-inducible factor 1-alpha proteins, the content of ROS, and MPO activity in cmECs in colitis. PN also increased the expression of ATP4a, cytochrome P450 family 21 subfamily a member 2, and hydroxy-delta-5-steroid dehydrogenase, 3 beta and steroid delta-isomerase 2 proteins in the mitochondria, and decreased the content of mtROS in cmECs. Conclusions: PN alleviated the pH in the colonic lumen and hypoxia-induced glycolysis in cmECs by reducing the hypoxia-induced glycolysis caused by the downregulation of ATP4a protein, thereby promoting the repair of colonic mucosal injuries in colitis.

Implications of hydrogen peroxide on bromate depression during seawater ozonation.

The presence of hydrogen peroxide (H2O2) in ozonation process can resist the formation of carcinogenic bromate (BrO3¯) efficiently, and the bromate depression is closely related with background water qualities, especially in high bromide-containing seawater. In this study, the freshwater and seawater were selected to investigate the effects of H2O2 on ozone (O3) decomposition kinetics, bromide transformation and bromate depression, and the evolutions of BrO3¯ under different scavengers were explored to speculate the primary bromate formation pathways. The results showed that the initial O3 half-live period (t1/2-O3) in seawater was only one-sixth of that in freshwater, and its attenuation rate increased analogously with the increase of H2O2 concentration in both freshwater and seawater. The H2O2 could promote the formation of BrO3¯ via hydroxyl radical (•OH) based bromate pathways, nevertheless higher concentration of H2O2 facilitated the reduction of HOBr/OBr¯ back to Br¯, resulting in 87.0% and 73.2% of BrO3¯ retardment in freshwater and seawater, respectively. The suppression ratios of BrO3¯ were up to 48.4% and 35.3% in freshwater with the addition of •OH and •O2¯ scavengers, and the corresponding depressions in seawater decreased to 35.3% and 12.7%, indicating that •OH was dominant on bromate formation when the concentration of residual ozone was adequate to generate some bromine intermediates, meanwhile H2O2 and •O2¯ functioned as the key reductants for bromate depression. Based on these results, the Br¯ transformation mechanisms via O3, •OH, H2O2, and •O2¯ reactions were speculated, and the feasibility of H2O2-ozonation was verified for the treatment of high Br¯-containing seawater.

Effect of Postoperative Adverse Events on Hospitalization Expenditures and Length of Stay Among Surgery Patients in Taiwan: A Nationwide Population-Based Case-Control Study.

Background: The current study sought to determine the incidence of postoperative adverse events (AEs) based on data from the 2006 Taiwan National Health Insurance Research Database (NHIRD). Methods: This retrospective case-control study included patients who experienced postoperative AEs in 387 hospitals throughout Taiwan in 2006. The independent variable was the presence or absence of 10 possible postoperative AEs, as identified by patient safety indicators (PSIs). Results: A total of 17,517 postoperative AEs were identified during the study year. PSI incidence ranged from 0.1/1,000 admissions (obstetric trauma-cesarean section) to 132.6/1,000 admissions (obstetric trauma with instrument). Length of stay (LOS) associated with postoperative AEs ranged from 0.10 days (obstetric trauma with instrument) to 14.06 days (postoperative respiratory failure). Total hospitalization expenditures (THEs) ranged from 363.7 New Taiwan Dollars (obstetric trauma without instrument) to 263,732 NTD (postoperative respiratory failure). Compared to patients without AEs, we determined that the THEs were 2.13 times in cases of postoperative AE and LOS was 1.72 times higher. Conclusions: AEs that occur during hospitalization have a major impact on THEs and LOS.

Pentraxin 3 promotes the osteoblastic differentiation of MC3T3-E1 cells through the PI3K/Akt signaling pathway.

Osteoblast cells are responsible for synthesizing new bone tissue, and determining how to control osteoblastic differentiation is vital to the treatment of osteoporosis. In the present study, we show that pentraxin 3 (PTX3) signaling is involved in the regulation of osteoblastic differentiation in MC3T3-E1 cells. Our data reveal that PTX3 is abundantly expressed in MC3T3-E1 cells and that its expression is inducible by the introduction of osteogenic induction medium (OIM). Overexpression of PTX3 was observed to significantly increase the expression of four osteoblast signature genes, including Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN) and osterix (OSX), suggesting that the overexpression of PTX3 promotes osteoblastic differentiation. The relative level of gene expression between OIM and OIM plus overexpressed PTX3 was evaluated using the Affymetrix Gene Chip® mouse gene microarray. PTX3-related differentially expressed genes (DEGs) were screened. Gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathway enrichment analyses were performed, and the PI3K/Akt signaling pathway was primarily involved in the osteogenic differentiation of PTX3. Protein-protein interactions (PPIs) were also constructed, and the molecular complex detection (MCODE) plugin calculated modules of PPI networks. Moreover, we show that the effect of PTX3 is mediated by its induction of the PI3K/Akt signaling pathway. Mechanistically, we show that the action of PTX3 requires the activation of PI3K and Akt, and deactivation of PI3K by its inhibitor LY294002 weakens the PTX3-mediated induction of osteoblast signature genes, ALP and matrix mineralization. The present study revealed a new role played by PTX3 and suggest a potential mechanism governing the osteoblastic differentiation of MC3T3-E1 cells.

Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors.

Tumor-infiltrating tertiary lymphoid structures (TLS) are thought to have anti-tumor activity and are believed to indicate a favorable prognosis in cancer patients. However, the prognostic value of TLS in gastrointestinal stromal tumors (GIST) is unknown. We evaluated the prognostic value of TLS using two independent GIST cohorts. Pathological examinations identified TLS in 44.9% of patients in our discovery cohort (DC). TLS was significantly associated with smaller tumor size (P = .011), relatively well morphological classification (P < .001), lower NIH classification (P < .001), lower recurrence (P = .005), longer survival time (P < .001) and lower imatinib resistance (P = .006). Kaplan-Meier curves showed that TLS was remarkably associated with favorable survival (P = .0002) and recurrence (P = .0015) time. In addition, the presence of KIT mutations and the absence of TLS suggested worst prognosis both in terms of overall survival (OS) (P = .0029) and time to recurrence (TTR) (P = .0150), while the presence of PDGFRA mutations and TLS suggested optimal prognosis for OS and TTR. Multivariate analyzes demonstrated that TLS was an independent prognostic factor for OS (HR:0.180, P = .002) and TTR (HR:0.412, P = .023). These results were confirmed using our validation cohort. Multiplexed immunohistochemistry staining was used to determine the composition of TLS. Therapies designed to target TLS may be a novel therapeutic strategy for GIST patients with imatinib resistance.

Clinicopathological and prognostic implications of vessels encapsulate tumor clusters with PD-L1 in intrahepatic cholangiocarcinoma patients.

BACKGROUND: Frequently abnormal vascularization and immunologic derangement have been uncovered in malignant tumors. In present research, we evaluated prognostic characteristic and clinicopathological features of vessels encapsulate tumor clusters (VETC) and the immune checkpoint molecule, programmed cell death-ligand 1 (PD-L1) in patients diagnosed as intrahepatic cholangiocarcinoma (ICC). METHODS: VETC and PD-L1 were investigated in two cohort enrolling 412 ICC patients. VETC and PD-L1 was easily detectable in whole slides and tissue microarray (TMA). Prognostic analysis was performed through Kaplan-Meier cures, log-rank tests and nomograms. RESULTS: VETC+ was significantly associated with aggressive tumor features. VETC+ predicted a significantly unfavorable survival and higher metastasis and recurrence rates. Furthermore, nomograms integrated by the combination of VETC and PD-L1, that heralded better prognostic value compared to previous staging systems. CONCLUSIONS: Heterogeneous patterns of VETC phenotype and PD-L1 status were both illustrated to be an independent prognostic predictor for clinical outcomes. Therapies designed to target both vascularization and autoimmunity may open a novel direction for HCC. HCC should be replaced by ICC.

Comprehensive Characterization of Immunological Profiles and Clinical Significance in Hepatocellular Carcinoma.

BACKGROUND: Therapies targeting immune molecules have rapidly been adopted and advanced the treatment of hepatocellular carcinoma (HCC). Nonetheless, no studies have reported a systematic analysis between immunological profiles and clinical significance in HCC. METHODS: We comprehensively investigated immune patterns and systematically correlated 22 types of both adaptive and innate immune cells with genomic characteristics and clinical outcomes based on 370 HCC patients from The Cancer Genome Atlas (TCGA) database through a metagene approach (known as CIBERSORT). Based on the Quantitative Pathology Imaging and Analysis System coupled with integrated high-dimensional bioinformatics analysis, we further independently validated six immune subsets (CD4+ T cells, CD8+ T cells, CD20+ B cells, CD14+ monocytes, CD56+ NK cells, and CD68+ macrophages), and shortlisted three (CD4+ T cells, CD8+ T cells, and CD56+ NK cells) of which to investigate their association with clinical outcomes in two independent Zhongshan cohorts of HCC patients (n = 258 and n = 178). Patient prognosis was further evaluated by Kaplan-Meier analysis and univariate and multivariate regression analysis. RESULTS: By using the CIBERSORT method, the immunome landscape of HCC was constructed based on integrated transcriptomics analysis and multiplexed sequential immunohistochemistry. Further, the patients were categorized into four immune subgroups featured with distinct clinical outcomes. Strikingly, significant inter-tumoral and intra-tumoral immune heterogeneity was further identified according to the in-depth interrogation of the immune landscape. CONCLUSION: This work represents a potential useful resource for the immunoscore establishment for prognostic prediction in HCC patients.

Correlation between potentially inappropriate medication and Alzheimer's disease among the elderly.

PURPOSE: This study is conducted to explore the association between potentially inappropriate medication (PIM) and Alzheimer's disease (AD) among the elderly. METHODS: We used Taiwan's National Health Insurance Research Database (NHIRD) to conduct a nationwide case-control study. Elderly individuals (over 65 years of age) who had been diagnosed with AD (ICD-9-CM: 331.0) for the first time in 2011 were selected as subjects for the case group. A control group was formed by selecting elderly patients without AD using 1:1 propensity score matching. Control variables included sex, age, health status, and 31 Elixhauser comorbidities. All analyses were performed using the Resource Utilization Band (Adjusted Clinical Groups software). All health utilization data associated with PIM were traced back for a period of 5 years. We examined the odds ratio (OR) and 95% confidence interval (CI) for PIM in relation to AD. RESULTS: We identified 5264 patients with AD (case group) and 5264 non-AD controls. After adjustment for confounding factors, proportion of all PIM (adjusted OR: 1.006, 95%CI: 1.002-1.010, p-value = 0.009) was significantly associated with AD. CONCLUSION: In conclusion, we observed a significant positive correlation between PIM and AD among elderly population.

Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C.

Impairment of cardiac lymphatic vessels leads to cardiac lymphedema. Recent studies have suggested that stimulation of lymphangiogenesis may reduce cardiac lymphedema. However, effects of lymphatic endothelial progenitor cells (LEPCs) on cardiac lymphangiogenesis are poorly understood. Therefore, this study investigated effectiveness of LEPC transplantation and VEGF-C release with self-assembling peptide (SAP) on cardiac lymphangiogenesis after myocardial infarction (MI). CD34+VEGFR-3+ EPCs isolated from rat bone marrow differentiated into lymphatic endothelial cells after VEGF-C induction. VEGF-C also stimulated the cells to incorporate into the lymphatic capillary-like structures. The functionalized SAP could adhere with the cells and released VEGF-C sustainedly. In the condition of hypoxia and serum deprivation or abdominal pouch assay, the SAP hydrogel protected the cells from apoptosis and necrosis. At 4 weeks after intramyocardial transplantation of the cells and VEGF-C loaded with SAP hydrogel in rat MI models, cardiac lymphangiogenesis was increased, cardiac edema and reverse remodeling were reduced, and cardiac function was improved significantly. Delivery with SAP hydrogel favored survival of the engrafted cells. VEGF-C released from the hydrogel promoted differentiation and incorporation of the cells as well as growth of pre-existed lymphatic vessels. Cardiac lymphangiogenesis was beneficial for elimination of the inflammatory cells in the infarcted myocardium. Moreover, angiogenesis and myocardial regeneration were enhanced after reduction of lymphedema. These results demonstrate that the combined delivery of LEPCs and VEGF-C with the functionalized SAP promotes cardiac lymphangiogenesis and repair of the infarcted myocardium effectively. This study represents a novel therapy for relieving myocardial edema in cardiovascular diseases.

Development of Alzheimer disease in old major depressive patients based upon their health status: A retrospective study in Taiwan.

This study is conducted to investigate the association between major depressive disorder and the subsequent development of Alzheimer disease (AD) in elderly patients with different health statuses using Taiwan's National Health Insurance Research Database (NHIRD).A retrospective cohort study was performed on subjects over 65 years old from 2002 to 2006 using a random sampling from the 1 million beneficiaries enrolled in the NHI. Patients who were diagnosed with major depressive disorder were selected as the case group. Subjects in the control group were selected from elderly patients who did not have depression during the study period by matching age, sex, and index date of depression with subjects in the case group using a ratio of 1:4 (case:control). Both groups of patients were checked annually over a period of 7 years to observe whether they subsequently developed AD.A total of 1776 subjects were included in the case group while 7104 subjects were in the control group. After the follow-up period, 59 patients (3.3%) with depression developed AD while 96 patients (1.4%) without depression developed AD. The Kaplan-Meier curves showed that the incidence rate of AD in both groups varied significantly depending on different health statuses (log-rank P < .001). Results of the generalized estimating equation model found that patients with depression (hazard ratio [HR] = 1.898; 95% confidence interval [CI] = 1.451-2.438), very severe health status (HR = 1.630; 95% CI = 1.220-2.177), or artery diseases (HR = 1.692; 95% CI = 1.108-2.584) were at a higher risk of developing AD than other groups.The association between major depressive disorder and the later development of AD varied depending on the health statuses of elderly patients. Clinicians should exercise caution when diagnosing and treating underlying diseases in elderly depressed patients, and then attempt to improve their health status to reduce the incidence rate of subsequent AD development.

Anterior decompression and fusion versus laminoplasty for cervical myelopathy due to ossification of posterior longitudinal ligament: A meta-analysis.

BACKGROUND: Both anterior decompression and fusion (ADF) and laminoplasty (LAMP) are frequently used for the treatment of cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL). However, some controversies still remained in surgical options. We investigated whether ADF had better neurological outcome than LAMP in the treatment of cervical myelopathy due to OPLL. Secondary outcomes included operation time, blood loss, rate of complication and reoperation. METHODS: PubMed, EMBASE and the Cochrane Register of Controlled Trials database were searched to identify potential clinical studies compared ADF with LAMP for treatment of cervical myelopathy owing to OPLL. We also manually searched the reference lists of articles and reviews for possible relevant studies. Quality assessment was performed according to Cochrane Handbook and meta-analysis was conducted using Stata 12.0 software. RESULTS: Nine studies involving 712 patients were finally included in this analysis. Compared with LAMP, ADF was associated with an increase of the Japanese Orthopaedic Association (JOA) score (WMD = 1.86, 95% CI 0.43 to 3.29, P = .011) and recovery JOA score at final follow-up (WMD = 30.94, 95% CI 20.56 to 41.33, P = .000). And, ADF was associated with a decrease of the late neurologic deterioration than LAMP group (RR = 0.34, 95% CI 0.12 to 0.92, P = .003). However, ADF was associated with an increase of the postoperative cervical lordosis (WMD = 4.47, 95% CI 1.58 to 7.36, P = .002) than LAMP. There was no significant difference between the complication, reoperation rate (P > .05). What's more, ADF was associated with an increase of the operation time than LAMP (P < .05). CONCLUSIONS: ADF yields better neurological improvement, but higher cervical lordosis and longer operation time compared with LAMP for cervical myelopathy caused by OPLL. No significant difference was found in the complication and re-operation rate.