Search

Shuo Chen, Kai-Xuan Sun, Miao-Xiao Feng, Xiu-Bo Sang, Bo-Liang Liu, Yang Zhao Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China Background: Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays an important role in cancer tumorigenesis and progression. We investigated the role of the GSK-3β inhibitor AZD1080 in ovarian cancer cell lines. Methods: A2780 and OVCAR3 ovarian cancer cell lines were exposed to AZD1080, after which cell proliferation, cell cycle, invasion, and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction and Western blot were used to assess the respective mRNA and protein expression levels of GSK-3β, CDK2, CDK1, cyclin D1, matrix metalloproteinase-9 (MMP9), and Bcl-xL. Results: AZD1080 exposure suppressed ovarian cancer cell proliferation, invasion, migration, and lamellipodia formation, and induced G1 arrest, which was concentration dependent. AZD1080 also significantly downregulated GSK-3β, CDK2, CDK1, cyclin D1, MMP9, and Bcl-xL expression at both mRNA and protein levels. Conclusion: Taken together, our results demonstrate that the GSK-3β inhibitor AZD1080 suppresses ovarian cancer development and therefore may indicate a new direction for ovarian cancer treatment. Keywords: ovarian cancer, GSK-3β inhibitor, AZD1080, tumorigenesis, progression

Objective: In order to synthesize available results regarding human immunodeficiency virus (HIV) infection and inflammatory bowel disease (IBD), we conducted a systematic review and meta-analysis to provide quantitative estimates of associated risk., Methods: A systematic search of four scientific databases, PubMed, the Cochrane Library, EMBASE, and Scopus, was performed. The overall odds ratio (OR) with the corresponding 95% CI was calculated via a random effects model. Sensitivity analyses and tests for publication bias were then performed., Results: Of the 3046 articles retrieved, seven studies with a cumulative sample size greater than 57,000,000 were included in our analysis. A subsequent meta-analysis based on a random effects model (heterogeneity test, I 2  = 99.9) revealed an association between HIV infection and IBD: OR = 2.68 (95% CI: 1.17, 6.13). The funnel plot of this meta-analysis was asymmetric (Egger's test: P = 0.01), and significant publication bias was found. Sensitivity analysis of the 3 dimensions revealed that the results of this meta-analysis were relatively stable., Conclusions: A significant correlation may exist between HIV infection and intestinal disease, and more large-scale studies are needed to draw firm conclusions. It is recommended that HIV patients be screened for intestinal diseases., (© 2024. The Author(s).)

Background: The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and pharmaceuticals. However, no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in humans. This study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide poisoning., Methods: This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July 2022. The entire course of the incidents was described in detail. Blood 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass spectrometer. Hematoxylin and eosin staining was performed to assess liver injury, and immunofluorescence was used to evaluate hepatic mitophagy., Results: The 2-amino-5-chloro-N,3-dimethylbenzamide powder (99% purity) entered the human body mainly via the skin and respiratory tract due to poor personal protective measures. The typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency, rash, fever, organic damage, and recovery phases in accordance with the clinical evolution. Rash and fever may be the important premonitory symptoms for further organ injuries. The chemical was detected in the blood of all patients and caused multiple organ injuries, predominantly liver injury, including kidney, myocardium, and microcirculation. Three patients recovered smoothly after comprehensive treatments, including artificial liver therapy, continuous renal replacement therapy, glucocorticoids, and other symptomatic and supportive treatments. One patient survived by liver transplantation. The postoperative pathological findings of the removed liver showed acute liver failure, and immunofluorescence staining confirmed the abundance of mitophagy in residual hepatocytes., Conclusions: This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. The chemical enters the body through the respiratory tract and skin during industrial production. The 2-amino-5-chloro-N,3-dimethylbenzamide poisoning causes multiple-organ dysfunction with a predominance of liver injury. Liver transplantation may be an effective option for patients with severe liver failure. The mechanisms of liver injury induced by 2-amino-5-chloro-N,3-dimethylbenzamide might involve abnormal mitochondrial function and mitophagy., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression., Methods: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells., Results: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis., Conclusions: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the effect and underlying mechanism of increased expression of M-type phospholipase A 2 receptor (PLA 2 R) on podocyte membrane induced by hepatitis B virus X protein (HBx) on podocyte pyroptosis in hepatitis B virus-associated glomerulonephritis (HBV-GN). Methods: Transfection of the HBx gene into human kidney podocytes was used to mimic the HBV-GN pathogenesis process. Subsequently, podocytes were divided into the following eight groups: normal control plus secretory phospholipase A 2 -ⅠB (sPLA 2 -ⅠB) group, empty plasmid plus sPLA 2 -ⅠB group, HBx group, HBx plus sPLA 2 -ⅠB group, HBx plus sPLA 2 -ⅠB plus PLA 2 R control siRNA group, HBx plus sPLA 2 -ⅠB plus PLA 2 R-siRNA group, HBx plus sPLA 2 -ⅠB plus ROS control siRNA group, and HBx plus sPLA 2 -ⅠB plus ROS-siRNA group. Podocyte morphology was observed under a transmission electron microscope, and PLA 2 R expression was detected under a fluorescence microscope. Podocyte pyroptosis and reactive oxygen species (ROS) expression were analyzed by flow cytometry, and the mRNA and protein expression of PLA 2 R, nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin (IL)-1β and IL-18 were determined by real-time fluorescence quantitative PCR and Western blot. Results: Compared with the control group, the expression of PLA 2 R on podocyte membrane significantly increased after transfection with HBx plasmid in vitro (4.07±0.41 vs 1.01±0.17, P <0.001). Transmission electron microscope and fluorochrome-labeled inhibitor of caspases/propidium iodide (FLICA/PI) double staining suggested that overexpressed PLA 2 R combined with sPLA 2 -ⅠB caused aggravated podocyte injury and increased pyroptosis (20.22%±0.36% vs 7.86%±0.28%, P <0.001). Moreover, the expression levels of ROS (4 324 515±222 764 vs 12 920±46, P <0.001), NLRP3 (48.30±2.73 vs 1.00±0.11, P <0.001), ASC (4.02±0.84 vs 1.01±0.15, P <0.001), caspase-1 (3.99±0.42 vs 1.00±0.11, P <0.001), IL-1β (9.08±0.75 vs 1.00±0.09, P <0.001) and IL-18 (19.20±0.70 vs 1.00±0.02, P <0.001) increased when PLA 2 R was overexpressed. In contrast, with the addition of PLA 2 R-siRNA or ROS-siRNA to knockdown the expression of related substances, podocyte injury was alleviated and the degree of pyroptosis decreased, and the expressions of genes related to the downstream signaling pathway (NLRP3, ASC, caspase-1, IL-1β and IL-18) decreased (all P <0.01). Conclusion: HBx may promote podocyte pyroptosis in HBV-GN by targeting the ROS-NLRP3 signaling pathway via the upregulation of PLA 2 R.

Paraquat (PQ) poisoning can induce acute lung injury and fibrosis and has an extremely high mortality rate. However, no effective treatments for PQ poisoning have been established. In this study, the potential efficacy of Tripterygium wilfordii Hook.f. (TwHF) in alleviating PQ-induced lung injury and fibrosis was investigated in a mouse model. Mice were randomly assigned to the control, PQ, PQ + TwHF1 (pretreatment before inducing poisoning), and PQ + TwHF2 (treatment after poisoning) groups. The mice in the PQ + TwHF1 group were pretreated with TwHF for 5 days before receiving one dose of PQ (120 mg/kg) and then received a daily oral gavage of the indicated dosages of TwHF until sacrifice. The mice in the PQ + TwHF2 group were treated with TwHF 2 h after PQ exposure until sacrifice. The pathological analysis and Fapi PET/CT showed that treatment with TwHF attenuated lung injury. And TwHF reduced pulmonary oxidative stress, as indicated by the reduction in, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels, as well as by the increase in superoxide dismutase (SOD) levels. Accordingly, the Perls DAB staining showed increased iron concentrations and western blotting revealed a decreased GPX4 expression after PQ exposure, as well as the mitigation of the overexpression of Nrf2 and HO-1 induced by PQ. In conclusion, our study demonstrated the potential of TwHF as a treatment for PQ-induced lung injury and fibrosis. The protective mechanism of this medicinal herb may involve the regulation of ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients., Methods: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients' infection developments and liver functions., Results: Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05)., Conclusions: Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants., (© 2023. The Author(s).)

Background: In the past years, only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung's disease (ADHD), most of which were individual case reports or lacked detailed clinical information. Although many studies have reported patients presenting to the emergency department (ED) with recurrent abdominal symptoms for a number of disorders, there are few data involving ADHD. However, owing to a lack of awareness of the disease, misdiagnoses and mistreatments are common. Severe complications such as perforation, bleeding, malabsorption, and even death in ADHD had been reported by many studies., Aim: To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively., Methods: We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital. Their basic information, clinical manifestations, and imaging findings were analyzed. Blood indices were compared between the ADHD and irritable bowel syndrome (IBS) groups., Results: Adult patients with ADHD had a mean age of 48.8 ± 14.3 years, and 77.4% had been treated before admission. The transverse colon was the most common dilated part (73.6%), and constipation (67.9%) was the most common symptom. ADHD patients can present with uncommon symptoms and false-negative imaging findings. Logistic regression analysis indicated that body mass index (BMI) [odds ratio (OR) = 0.786, P = 0.013], cholinesterase (per 1000 units; OR = 0.693, P = 0.008), and blood chlorine (OR = 0.816, P = 0.022) were determined to be independent related factors between the ADHD and IBS groups. The area under the receiver operating characteristics curve of these three indices combined was 0.812 ( P < 0.001)., Conclusion: Emergency physicians should be vigilant regarding patients with chronic constipation, abdominal pain, or abdominal distension, and consider the possibility of ADHD despite its rarity. Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD. BMI, cholinesterase, and blood chlorine have good discriminative abilities between ADHD and IBS. The nutritional status of adult patients with ADHD is worthy of further attention. Surgical treatment for adult patients with ADHD is important and inevitable., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Livedoid vasculopathy is a chronic, recurrent skin disorder. It seriously affects the quality of patients' life. However, the pathogenesis has not been fully identified yet. Here, this retrospective study describes the successful use of anti-TNF-α agent adalimumab in three cases of refractory livedoid vasculopathy, which has not been reported previously. In addition, we provide some clinical evidence that adalimumab therapy is efficient in improving skin lesions and relieving the pain of livedoid vasculopathy.

Freshwater shrimp are a rich species group, with a long and problematic taxonomic history attributed to their wide distribution and similar morphological characteristics. Shrimp diversity and species identification are important cornerstones for fisheries management. However, identification based on morphological characteristics is a difficult task for a nonspecialist. Abundant freshwater shrimp species are distributed in the waters of Henan Province, but investigations of freshwater shrimp are limited in this region, especially concerning molecular features. Here, we combined morphology and DNA barcodes to reveal the species diversity of freshwater shrimp in Henan province. A total of 1,200 freshwater shrimp samples were collected from 46 sampling sites, and 222 samples were chosen for further microscopic examination and molecular delimitation. We used tree-based methods (NJ, ML, and bPTP) and distance-based methods (estimation of the paired genetic distances and ABGD) to delimit species. The results showed that there were nine morphospecies based on morphological characteristics; all could effectively be defined by molecular methods, among which bPTP and ABGD defined 13 and 8 MOTUs, respectively. The estimation of the paired genetic distances of K2P and the p-distances had similar results. Mean K2P distances and p-distances within species were both equal to 1.2%. The maximum intraspecific genetic distances of all species were less than 2%, with the exception of Palaemon modestus and M. maculatum . Various analyses have shown that P. modestus and M. maculatum have a large genetic differentiation, which may indicate the existence of cryptic species. By contrast, DNA barcoding could unambiguously discriminate 13 species and detect cryptic diversity. Our results demonstrate the high efficiency of DNA barcoding to delimit freshwater shrimp diversity and detect the presence of cryptic species., Competing Interests: All authors declare that they have no competing interests., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Competing Interests: Conflicts of interest: No any benefits have been received from a commercial party related directly or indirectly to the study.

Background: The reconstruction of hepatic artery is a challenging part of the pediatric liver transplantation procedure. Hepatic artery thrombosis (HAT) and stenosis are complications which may result in ischemic biliary injury, causing early graft lost and even death., Methods: Two hundred and fifty-nine patients underwent liver transplantation in 2017 in a single liver transplantation group. Among them, 225 patients were living donor liver transplantation (LDLT) and 34 deceased donor liver transplantation (DDLT)., Results: In LDLT all reconstructions of hepatic artery were microsurgical, while in DDLT either microsurgical reconstruction or traditional continuous suture technique was done depending on different conditions. There were five (1.9%) HATs: four (4/34, 11.8%) in DDLT (all whole liver grafts) and one (1/225, 0.4%) in LDLT (P = 0.001). Four HATs were managed conservatively using anticoagulation, and 1 accepted salvage surgery with re-anastomosis. Until now, 3 HAT patients remain in good condition, whereas two developed biliary complications. One of them needed to be re-transplanted, and the other patient died due to biliary complications., Conclusions: Microsurgical technique significantly improves the reconstruction of hepatic artery in pediatric liver transplantation. The risk for arterial complications is higher in DDLT. Conservative therapy can achieve good outcome in selected HAT cases., (Copyright © 2020. Published by Elsevier B.V.)

Background: Myeloid derived suppressor cells (MDSCs) have been reported to keep elevating during sepsis. The current study was performed to investigate the immunosuppressive effect of MDSCs and their subsets with the underlying mechanisms. Methods: The immunosuppressive status was manifested by the apoptosis of splenocytes, quantity of T cells and PD-1 expression. The dynamics of quantity and PD-L1 level of MDSCs and the subsets were determined over time. The subset of MDSCs with high PD-L1 level was co-cultured with T cells to observe the suppressive effect. Results: Abdominal abscess was observed after 7 days post-sepsis. Five biomarkers related to organ functions were all significantly higher in the CLP group. The survival rate was consistent with the middle grade severity of sepsis model. Apoptosis of splenocytes increased over time during sepsis; CD4 + T cell decreased from day 1 post-sepsis; CD8+ T cells significantly reduced at day 7. The PD-1 expression in spleen was upregulated from an early stage of sepsis, and negatively related with the quantity of T cells. MDSCs were low at day 1 post-sepsis, but increased to a high level later; the dynamics of PMN-MDSC was similar to MDSCs. PD-L1 on MDSCs was highest at day 1 post-sepsis; PMN-MDSC was the main subset expressing PD-L1. The PMN-MDSC with high PD-L1 expression level extracted on day 1 after surgery from CLP mice significantly inhibited the proliferation of T cells. Conclusions: Sepsis-induced immunosuppression is initiated from a very early stage, a high expression level of PD-L1 on MDSCs and the main subset, PMN-MDSC might play a critical role suppressive role on T cells through PD-L1/PD-1 axis., (Copyright © 2020 Ruan, Feng, Xu, Xu, Song, Lin, Li and Lu.)

This single-center retrospective study aims to investigate the clinical features of esophageal foreign bodies (EFBs) and determine the influence of EFB shapes on management and prognosis. A total of 427 patients aged 13 to 95 years with suspected EFB ingestion were enrolled between January 2013 and June 2018, 183 of whom were male. EFBs were divided into six shapes: pin (n = 161), sheet (n = 97), trident (n = 51), spindle (n = 66), irregular (n = 46), and sphere (n = 6). Spindle-shaped EFBs correlated with a significantly higher rate of perforation and severe complications (P < 0.001 and P = 0.021, respectively) than any other EFB shape, while sheet-shaped EFBs were linked to less severe complications (P = 0.006). The number of pressure points was provided to stratify the risk of poor prognosis for each shape. EFBs with only two pressure points (pin and spindle EFBs) required more advanced management strategies and were correlated with a higher number of patients suffering esophageal perforation (27.11%) and severe complications (12.44%) when compared with other shapes (χ 2  = 11.149 and P = 0.001; χ 2  = 5.901 and P = 0.015, respectively). Spindle shape was an independent risk factor for poor prognosis, and contributed a more clinical risk than the pin shape. In conclusion, clinical features, management, perforation rate, and severe complications differed based on EFB shape. The EFBs with two pressure points, especially the spindle-shaped EFBs, were more dangerous compared with those with more pressure points.

Background & Aims: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth., Methods: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes., Results: The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells., Conclusions: In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This retrospective and a single-center study evaluated the prognostic value of the maximum serum creatinine value (maxCr) and the maximum serum creatinine growth rate (Vmax) after paraquat (PQ) ingestion. One hundred and seventy-one patients with PQ poisoning were treated with a uniform protocol. Demographic variables, clinical manifestations, relevant laboratory data, maxCr and Vmax of all patients were recorded and calculated. The time after PQ ingestion of maxCr and Vmax were also recorded. Vmax and MaxCr exhibited statistically significant differences between the survivor (n = 53) and death (n = 118) groups. Vmax appeared earlier in the death group than the survivor group. Regard to the receiver operating characteristic (ROC) curve analysis, Vmax had an AUC of 0.861 (95% CI, 0.801-0.921) and the optimal cut-off value of 6.21 μmol/(L·h) (sensitivity, 76.3%; specificity, 81.1%). MaxCr had an area under the curve (AUC) of 0.821 (95% CI, 0.752-0.889) and the optimal cut-off value of 225.5 µmol/L (sensitivity, 82.2%; specificity, 67.9%). The comparison of the AUC in the two parameters showed no significant difference, but Vmax appeared earlier than maxCr. Based on binary logistic regression analysis, MaxCr and Vmax both showed strong predictive powers for evaluating the prognosis of acute PQ poisoning patients.

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC. Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg Cancer Res; 78(9); 2305-17. ©2018 AACR ., (©2018 American Association for Cancer Research.)

A novel prognostic nomogram predicting post-transplant pulmonary metastasis was established with a primary cohort of 308 HCC patients who received liver transplantation between 2007 and 2011 at Ren Ji Hospital. The C-indexes for predicting pulmonary metastasis was 0.85. The calibration curves fitted well between the predicted and actual outcomes. The decision curve analysis indicated that our nomogram was the optimal decision-making strategy for PM prediction compared to Milan, University of California San Franscisco, and up-to-seven criteria. These results were further validated by data from 103 patients who underwent liver transplantation between 2011 and 2012 at the same institution. In conclusion, our nomogram could be used as an effective tool to predict PM after liver transplantation., Competing Interests: CONFLICTS OF INTEREST The authors declared that they have no conflicts of interest in this work.

Carrier recombination behavior in c-plane GaN-based laser diodes (LDs) is numerically investigated by using the commercial software LASTIP. It is found that efficiency droop phenomenon does exist in GaN-based LDs before lasing, which is confirmed by experimental results. However, the current density corresponding to the peak efficiency of GaN-based LDs before lasing, J max , is nearly 40 A/cm², which is much lower than that reported by other studies. The reported J max , measured from the cavity facet side is modulated by the absorption of quantum wells, which shifts the J max to a higher value. In addition, the currents due to various recombinations are calculated. It is found that Auger recombination affects the threshold current greatly, but it only plays a small role at high current injection levels.

MicroRNA-93, derived from a paralog (miR-106b-25) of the miR-17-92 cluster, is involved in the tumorigenesis and progression of many cancers such as breast, colorectal, hepatocellular, lung, ovarian, and pancreatic cancer. However, the role of miR-93 in endometrial carcinoma and the potential molecular mechanisms involved remain unknown. Our results showed that miR-93 was overexpressed in endometrial carcinoma tissues than normal endometrial tissues. The endometrial carcinoma cell lines HEC-1B and Ishikawa were transfected with miR-93-5P, after which cell migration and invasion ability and the expression of relevant molecules were detected. MiR-93 overexpression promoted cell migration and invasion, and downregulated E-cadherin expression while increasing N-cadherin expression. Dual-luciferase reporter assay showed that miR-93 may directly bind to the 3' untranslated region of forkhead box A1 (FOXA1); furthermore, miR-93 overexpression downregulated FOXA1 expression while miR-93 inhibitor transfection upregulated FOXA1 expression at both mRNA and protein level. In addition, transfection with the most effective FOXA1 small interfering RNA promoted both endometrial cancer cell migration and invasion, and downregulated E-cadherin expression while upregulating N-cadherin expression. Therefore, we suggest that miR-93 may promote the process of epithelial-mesenchymal transition in endometrial carcinoma cells by targeting FOXA1., Competing Interests: The authors have declared that no competing interests exist.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the translation of messenger RNAs by binding their 3'-untranslated region (3' UTR). MiR-490-3p has been reported to be a suppressor in various human cancers; however, little is known about the biological functions of miR-490-3p in endometrial cancer (EC). In our study, we found that MiR-490-3p mRNA expression was significantly lower in ECs than in normal endometrial tissues. MiR-490-3p mRNA expression was also negatively associated with depth of invasion (mucosa vs. muscular and serosa) and lymph node metastasis (negative vs. positive) in EC. MiR-490-3p overexpression reduced proliferation; promoted G1 arrest and apoptosis; suppressed migration and invasion; and reduced TGFα, NF-kB, cyclin D1, survivin, matrix metalloproteinase 2 (MMP2) mRNA and protein expression, and improved Bax mRNA and protein expression. The dual-luciferase reporter assay indicated that miR-490-3p directly targeted TGFα by binding its 3' untranslated region. MiR-490-3P transfection also suppressed tumor development and TGFα expression (as determined by immunohistochemistry and western blotting) in vivo in the xenograft mouse model. This is the first demonstration that miR-490-3P might act as a suppressor in EC tumorigenesis and progression by targeting TGFα. Our results provide a theoretical basis for the further study on the molecular target for endometrial cancer.

Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients' TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.

Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients' quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.

Background: A remolded microenvironment in hepatocellular carcinoma (HCC) caused by abnormally expressed matricellular proteins could promote HCC progression. The cell-matrix interactions mediated by integrins play an important role in tumor microenvironment. Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein with angiogenic and anti-inflammatory effects, is abnormally highly expressed in HCC. Here we aim to analyze its expression in liver and HCC tissues, investigate the underlined mechanisms accounted for HCC progression., Methods: EDIL3 expression level is examined in normal liver, cirrhotic liver and HCC at both mRNA and protein level. The association between EDIL3 and clinical outcomes is analyzed. The pattern of EDIL3 expression and location is examined using Immunofluorescence and ELISA. Overexpression or knock-down of EDIL3 in a panel of cell lines are subjected to assays related to proliferation, invasion, and anoikis to investigate the mechanisms of this matrix protein in HCC progression. Recombinant EDIL3 treatment is applied to confirm the results., Results: Compared with normal liver and cirrhotic liver, EDIL3 is elevated in HCC. High level of EDIL3 protein is much more commonly in patients with larger tumor or portal vein tumor thrombus (PVTT) formation, associated with poor prognosis. EDIL3 is abundantly expressed in HCC cells and secreted by cancer cells. In vitro and in vivo studies indicate that EDIL3, probably in an autocrine manner, inhibits anoikis and promotes anchorage-independent growth of HCC cells. Further mechanistic studies suggest integrin ligation by EDIL3 and thus that the sustained activation of the FAK-Src-AKT signal is responsible for the anoikis resistance and anchorage independence. Both the administration of cilengitide, a RGD-containing integrin antagonist, and silencing of integrin αV, an important RGD-binding integrin, results in the blockade of anoikis-resistance induced by EDIL3., Conclusion: Our study suggests that high levels of autocrine EDIL3 may contribute to a receptive microenvironment for the survival of detached HCC cells and may involve in cancer cell spreading. We also highlight the importance of interaction between EDIL3 and integrin αV and suggest disrupting the ligation of EDIL3 to integrins via RGD-blocking in selected patients may bear potential therapeutic value.

Dermatopontin (DPT), a tyrosine-rich, acidic matricellular protein, has been implicated in several human cancers. However, its biological functions and molecular mechanisms in cancer progression, particular hepatocellular carcinoma (HCC), remain unknown. We demonstrated that DPT was significantly down-regulated in 202 HCC clinical samples and that its expression level was closely correlated with cancer metastasis and patient prognosis. The overexpression of DPT dramatically suppressed HCC cell migration in vitro and intrahepatic metastasis in vivo. We further revealed that the down-regulation of DPT in HCC was due to epigenetic silencing by promoter DNA methylation. And the inhibitory effects of DPT on HCC cell motility were associated with dysregulated focal adhesion assembly, decreased RhoA activity and reduced focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src) phosphorylation, and all of these alterations required the involvement of integrin signaling. Furthermore, we determined that the inhibitory effects of DPT on HCC cell motility were primarily mediated through α3β1 integrin. Our study provides new evidence for epigenetic control of tumor microenvironment, and suggests matricellular protein DPT may serve as a novel prognostic marker and act as a HCC metastasis suppressor.

Objective: The purpose of this study was to explore the indications of radical vedio-assisted mediastinoscopic resection for esophageal cancer., Methods: The data of 109 patients with T1 esophageal cancer who underwent video-assisted mediastinoscopic resection (VAMS group) in Third Affiliated Hospital of Soochow University Hospital from December 2005 to December 2011 were collected in the study for comparison with the 58 patients with T1 esophageal cancer who underwent video-assisted thoracoscopic surgery (VATS group) in Zhongshan Hospital, Fudan University. The perioperative safety and survival were compared between the two groups., Results: All operations were successful in both groups. One perioperative death was noted in the VATS group. The incidences of post-operative complications were not significantly different between these two groups, whereas the VAMS group was favorable in terms of operative time (P<0.001) and blood loss (P<0.001), and a significantly larger number of chest lymph nodes were dissected in the VATS group compared with the VAMS group (P<0.001). Long-term follow-up showed that the overall survival was not significantly different between these two groups (P=0.876)., Conclusions: T1N0M0 esophageal cancer can be as the indication of VAMS radical resection. VAMS radical resection can be considered as the preferred option for patients with poor pulmonary and cardiac function or a history of pleural disease.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality, and is characterized by high potential for metastasis and recurrence. The outcome of it is still poor due to lacking of targeted therapeutic strategies. There is an urgent need to find new therapeutic targets for interventions against HCC metastasis and recurrence. In the present study, we found cytohesin-3, a member of the cytohesin family, was upregulated in HCC tissues, and its expression was negatively correlated with the overall survival and relapse-free survival of HCC patients. Further clinicopathological correlation analysis revealed that cytohesin-3 expression was related with tumor size and vascular invasion. And in vitro studies revealed that knock-down of cytohesin-3 suppressed HCC cells proliferation and migration. These results suggest that cytohesin-3 may act as a novel prognostic factor of HCC, and it might also be useful to exploit targeted therapeutic drugs against HCC growth and metastasis.

Chronic obstructive pulmonary disease (COPD) is characterized by the abnormal and chronic lung inflammation. We hypothesized that lung fibroblasts could contribute to the local inflammation and investigated whether low dose theophylline had a beneficial effect on fibroblasts inflammation. Subjects undergoing lobectomy for bronchial carcinoma were enrolled and divided into COPD and control groups according to spirometry. Primary human lung fibroblasts were cultured from peripheral lung tissue distant to tumor tissue. There was a significant increase in both the mRNA expressions and protein levels for IL-6 and IL-8 in fibroblasts in COPD group, and the values were negatively correlated with lung function (P < 0.05). For COPD fibroblasts, the protein levels of IL-6 and IL-8 decreased from 993.0 ± 738.9 pg/mL to 650.1 ± 421.9 pg/mL (P = 0.014) and from 703.1 ± 278.0 pg/mL to 492.0 ± 214.9 pg/mL (P = 0.001), respectively, with 5 μg/mL theophylline treatment. In addition, theophylline at the dose of 5 μg/mL reduced the increased production of IL-6 and IL-8 induced by 1 μg/mL LPS in primary human lung fibroblasts. Our data suggest that lung fibroblasts participate in the chronic inflammation in COPD by releasing IL-6 and IL-8, and low dose theophylline can alleviate the proinflammatory mediators' production by fibroblasts.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. Early diagnosis is critical for guiding the therapeutic management of ESCC. It is imperative to find more effective biomarkers of ESCC., Methods: To identify novel biomarkers for esophageal squamous cell carcinoma (ESCC), specimens from 10 patients with ESCC were subjected to a comparative proteomic analysis. The proteomic patterns of ESCC samples and normal esophageal epithelial tissues (NEETs) were compared using two-dimensional gel electrophoresis. And differentially expressed proteins were identified using MALDI-TOF-MS/MS. For further identification of protein in selected spot, western blotting and immunohistochemistry were employed., Results: Twelve proteins were up-regulated and fifteen proteins were down-regulated in the ESCC samples compared with the NEET samples. Up-regulation of galectin-7 was further confirmed by western blotting and immunohistochemistry. Furthermore, immunohistochemical staining of galectin-7 was performed on a tissue microarray containing ESCC samples (n = 50) and NEET samples (n = 10). The expression levels of galectin-7 were markedly higher in the ESCC samples than in the NEET samples (P = 0.012). In addition, tissue microarray analysis also showed that the expression level of galectin-7 was related to the differentiation of ESCC., Conclusions: The present proteomics analysis revealed that galectin-7 was highly expressed in ESCC tissues. The alteration in the expression of galectin-7 was confirmed using a tissue microarray. These findings suggest that galectin-7 could be used as a potential biomarker for ESCC.