Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis.

BACKGROUND: The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear. AIM: To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients. METHODS: A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted. RESULTS: A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols (P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded. CONCLUSION: TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens.

Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer.

The tricarboxylic acid (TCA) cycle is an essential interface that coordinates cellular metabolism and is as a primary route determining the fate of a variety of fuel sources, including glucose, fatty acid and glutamate. The crosstalk of nutrients replenished TCA cycle regulates breast cancer (BC) progression by changing substrate levels-induced epigenetic alterations, especially the methylation, acetylation, succinylation and lactylation. Long non-coding RNAs (lncRNA) have dual roles in inhibiting or promoting energy reprogramming, and so altering the metabolic flux of fuel sources to the TCA cycle, which may regulate epigenetic modifications at the cellular level of BC. This narrative review discussed the central role of the TCA cycle in interconnecting numerous fuels and the induced epigenetic modifications, and the underlying regulatory mechanisms of lncRNAs in BC.

Chronic infectious unilateral giant thyroid cyst related to diabetes mellitus: A case report.

BACKGROUND: Patients rarely develop complicated infections in thyroid cysts. Here, we describe a patient with chronic infected unilateral giant thyroid cyst related to diabetes mellitus (DM). CASE SUMMARY: A 66-year-old male was admitted due to an evident neck lump for 5 d after approximately 40 years of gradually progressive neck mass and 7 years of DM. Doppler ultrasound and computed tomography scan showed a giant lump in the left thyroid gland lobe. He was diagnosed with a large thyroid nodule complicated by tracheal dislocation and had surgical indications. Surgical exploration revealed evident inflammatory edema and exudation between the left anterior neck muscles, the nodule and glandular tissue. Fortunately, inflammatory lesions did not affect major neck vessels. Finally, a left partial thyroidectomy was performed. Macroscopic observation showed that the cystic thyroid mass consisted of extensive cystic wall calcification and was rich in massive rough sand-like calculi content and purulent matter. Postoperative pathology confirmed benign thyroid cyst with chronic infection. CONCLUSION: The progression of this chronic infectious unilateral giant thyroid cyst may have been related to DM, and identifying blood vessels involvement can prevent serious complications during operation.

Reconstruction of Vesicle Assemblies with DNA Nanorulers for Resolving Heterogeneity of Vesicles in Live Cells.

Nanoscale vesicles such as synaptic vesicles play a pivotal role in efficient interneuronal communications in vivo. However, the coexistence of single vesicle and vesicle clusters in living cells increases the heterogeneity of vesicle populations, which largely complicates the quantitative analysis of the vesicles. The high spatiotemporal monitoring of vesicle assemblies is currently incompletely resolved. Here, this work uses synthetic vesicles and DNA nanorulers to reconstruct in vitro the vesicle assemblies that mimic vesicle clusters in living cells. DNA nanorulers program the lateral distance of vesicle assemblies from 3 to 10 nm. This work uses the carbon fiber nanoelectrode (CFNE) to amperometric monitor artificial vesicle assemblies with sub-10 nm interspaces, and obtain a larger proportion of complex events. This work resolves the heterogeneity of individual vesicle release kinetics in PC12 cells with the temporal resolution down to ≈0.1 ms. This work further analyzes the aggregation state of intracellular vesicles and the exocytosis of living cells with electrochemical vesicle cytometry. The results indicate that the exocytosis of vesicle clusters is critically dependent on the size of clusters. This technology has the potential as a tool to shed light on the heterogeneity analysis of vesicle populations.

Enhanced Sorption for the Oil Spills by SDS-Modified Rice Straw.

Frequent oil spills have caused serious consequences to the ecosystem and environment. Therefore, in order to reduce and eliminate the impact of oil spills on biology and the environment, oil spill remediation materials must be considered. As a kind of cheap and biodegradable natural organic cellulose oil-absorbing material, straw has an important practical significance in the treatment of oil spills. In order to improve the ability of rice straw to absorb crude oil, rice straw was first treated with acid and was then modified with sodium dodecyl sulfate (SDS) through a simple charge effect. Finally, the performance of oil absorption was tested and evaluated. The results illustrate that the oil absorption performance was greatly improved under the conditions of 10% H2SO4, for a 90 min reaction at 90 °C, under 2% SDS, and reacted for 120 min at 20 °C, and the rate of adsorption for rice straw to crude oil was raised by 3.33 g/g (0.83 to 4.16). Then, the rice stalks before and after the modification were characterized. Contact angle analysis shows that the modified rice stalks display better hydrophobic-lipophilic properties than unmodified rice stalks. The rice straw was characterized by XRD and TGA, and the surface structure of the rice straw was characterized by FTIR and SEM, which explain the mechanism of surface-modified rice straws with SDS to improve their oil absorption capacity.

Characteristics of viral pneumonia in non-HIV immunocompromised and immunocompetent patients: a retrospective cohort study.

BACKGROUND: Concerning viral pneumonia, few large-scale comparative studies have been published describing non-HIV immunocompromised and immunocompetent patients, but the epidemiological characteristics of different viruses or underlying diseases in immunocompromised hosts are lacking. METHODS: We retrospectively recruited patients hospitalised with viral pneumonia from six academic hospitals in China between August 2016 and December 2019. We measured the prevalence of comorbidities, coinfections, nosocomial infections, and in-hospital mortalities. RESULTS: Of the 806 patients, 370 were immunocompromised and 436 were immunocompetent. The disease severity and in-hospital mortality of immunocompromised patients were higher than those of immunocompetent patients. During the influenza season, an increased number of cases of influenza virus (IFV) infection were found in the immunocompromised group, followed by cases of cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. During the non-influenza season, CMV was the main virus detected in the immunocompromised group, while RSV, adenovirus (AdV), parainfluenza virus (PIV), and rhinovirus (HRV) were the main viruses detected in the immunocompetent group. Pneumonia caused by Pneumocystis jirovecii (22.4%), Aspergillus spp. (14.1%), and bacteria (13.8%) were the most frequently observed coinfections in immunocompromised patients but not in immunocompetent patients (Aspergillus spp. [10.8%], bacteria [7.1%], and Mycoplasma spp. [5.3%]). CMV infection and infection with two-or-more viruses were associated with a higher in-hospital mortality rate than non-IFV infection. However, patients with IFV and non-IFV infection in immunocompromised patients had similar disease severity and prognosis. CONCLUSIONS: Immunocompromised patients have a high frequency of coinfections, and a higher mortality rate was observed among those infected with CMV and two-or-more viruses. In addition, patients with IFV and non-IFV infection in immunocompromised patients had similar same disease severity and prognosis. The type of viral infection varied with seasons.

Programming Cell-Cell Communications with Engineered Cell Origami Clusters.

Cells existing in the form of clusters often exhibit distinct physiological functions from their monodispersed forms, which have a close association with tissue and organ development, immunoresponses, and cancer metastasis. Nevertheless, the ability to construct artificial cell clusters as in vitro models for probing and manipulating intercellular communications remains limited. Here we design DNA origami nanostructure (DON)-based biomimetic membrane channels to organize cell origami clusters (COCs) with controlled geometric configuration and cell-cell communications. We demonstrate that programmable patterning of homotypic and heterotypic COCs with different configurations can result in three distinct types of intercellular communications: gap junctions, tunneling nanotubes, and immune/tumor cell interactions. In particular, the organization of T cells and cancer cells with a prescribed ratio and geometry can program in vitro immunoresponses, providing a new route to understanding and engineering cancer immunotherapy.

Effects of dexamethasone on VEGF-induced MUC5AC expression in human primary bronchial epithelial cells: Implications for asthma.

Mucins are major macromolecular components of lung mucus that are mainly responsible for the viscoelastic property of mucus. MUC5AC is a major mucin glycoprotein that is hypersecreted in asthmatic individuals. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Our previous studies indicate that VEGF upregulates MUC5AC expression by interacting with VEGF receptor 2 (VEGFR2). It has been shown that dexamethasone (Dex) downregulates MUC5AC expression; however, the underlying mechanisms have not been completely elucidated. Therefore, we sought to investigate the effect of Dex on MUC5AC expression induced by VEGF and study the underlying mechanisms. We tested the effects of Dex on VEGFR2 and RhoA activation, caveolin-1 expression, and the association of caveolin-1 and VEGFR2 in primary bronchial epithelial cells. Dex downregulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and suppressed the activation of VEGFR2 and RhoA induced by VEGF. Additionally, Dex upregulated caveolin-1 protein levels in a dose- and time-dependent manner. Furthermore, phospho-VEGFR2 expression was decreased through overexpression of caveolin-1 and increased after caveolin-1 knockdown. Dex treatment attenuated the VEGF-decreased association of caveolin-1 and VEGFR2. Collectively, our findings suggest that Dex downregulates VEGF-induced MUC5AC expression by inactivating VEGFR2 and RhoA. Furthermore, decreased MUC5AC expression by Dex was related to the increased association of caveolin-1 with VEGFR2. Further studies characterizing these mechanisms are required to facilitate the development of improved treatment strategies for asthma.

MicroRNA-425-5p Inhibits Lung Cancer Cell Growth in Vitro and in Vivo by Downregulating TFIIB-Related Factor 2.

Lung cancer is the most common cancer type with increasingly high incidence. MicroRNAs provide the potential biomarkers for lung cancer treatment. Thus, we aimed to investigate the function of microRNA-425-5p in lung cancer development and the underlying mechanisms. MicroRNA-425-5p overexpression inhibited A549 lung cancer cell proliferation in vitro and in vivo. On the other hand, microRNA-425-5p inhibition increased A549 proliferation. Mechanistically, the underlying mechanism by which microRNA-425-5p inhibits lung cancer cell growth was mediated through its ability in targeting and downregulating the TFIIB-related factor 2. Our results for the first time identified microRNA-425-5p as a tumor suppressor in lung cancer. Thus, microRNA-425-5p may serve as a potential therapeutic target for lung cancer.

Enhanced Suppression of Disulfide Cross-Linking Micelles Nanocarriers Loaded miR-145 Delivering System via Down-Regulation of MYC and FSCN1 in Colon Cancer Cells.

Colorectal carcinoma is a complex disease accounting for adenoma tumors and an aggressive phenotype, and the third leading cause of cancer death. In the past decades, miRNAs have been associated with molecular pathways of cancer and other diseases. The dysregulated miRNAs play an inhibitory or promoting role in tumorigenesis. Therefore, restoration of tumor-suppressed microRNAs (miRNA) may offer novel therapeutic approaches for cancer treatment. Nevertheless, the poor bioavailability of miRNA due to their rapid enzymatic degradation is a critical barrier in cancer gene therapy. To overcome this dilemma, we designed disulfide cross-linking micelles (DCM) nanocarrier for delivery of miR-145 to colon cancer cells and investigated its therapeutic efficacy in vitro and in vivo. Results indicated that the presence of DCM nanocarrier loaded with miR-145 enhanced selective delivery of miR-145 and facilitated cellular uptake, significantly up-regulating miR-145 expression in HCT-116 cell lines. Consequently, the cell proliferation was inhibited by arresting cell cycle at the G1 phase. Further, apoptosis of HCT-116 cells treated with miR-145 complex nanoparticles may be via downregulation of oncogenes MYC and FSCN1, predicting regulatory targets for miR-145. These results pave the way for further investigations into the potential of miR-145 complex nanocarrier for cancer gene therapy.

Upregulation of MUC5AC by VEGF in human primary bronchial epithelial cells: implications for asthma.

BACKGROUND: Airway mucus hypersecretion is an important pathophysiological feature in asthma. Mucins are glycoproteins that are mainly responsible for the viscoelastic property of mucus, and MUC5AC is a major mucin glycoprotein that is overproduced in asthma. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Therefore, we sought to investigate the effect of VEGF on MUC5AC expression and study the underlying mechanisms. METHODS: In order to elucidate the precise mechanism underlying the effect of VEGF on MUC5AC expression, we tested the effects of VEGF on RhoA activation and the association of caveolin-1 and VEGFR2 in Primary Bronchial Epithelial Cells. RESULTS: VEGF up-regulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and activated RhoA. Additionally, VEGF-induced MUC5AC expression and RhoA activation were enhanced by disrupting caveolae with cholesterol depletion and reversed by cholesterol repletion, and inhibited by a selective VEGF receptor 2 (VEGFR2) inhibitor SU1498. Furthermore, phospho-VEGFR2 expression was decreased via overexpression of caveolin-1. VEGF treatment reduced the association of caveolin-1 and VEGFR2. CONCLUSION: Collectively, our findings suggest that VEGF up-regulates MUC5AC expression and RhoA activation by interaction with VEGFR2, and this phenomenon was related with the association of caveolin-1 and VEGFR2. Further studies on these mechanisms are needed to facilitate the development of treatments for asthma.

A case report of cholangiocarcinoma combined with moderately differentiated gastric adenocarcinoma.

RATIONALE: Multiple primary carcinoma (MPM) refers to simultaneous or successive occurrence of ≥2 types of primary malignant tumors in a single organ or in different organs of the same individual. It is rarely seen in clinical practice. Among the various types of MPM, hilar cholangiocarcinoma combined with gastric cancer is extremely rare. PATIENT CONCERNS: The patient was a 61-year-old man who was admitted to our hospital due to upper abdominal discomfort and yellow-stained skin mucosa for 9 days. DIAGNOSES: Preoperative diagnosis: Considering the typical preoperative painless jaundice as well as his clinical imaging report, the patient received the following preoperative diagnosis: obstructive jaundice, type IV hilar cholangiocarcinoma based on Bismuth-Corlette classification, and no intrahepatic distant metastasis. Intraoperative diagnosis: The results of intraoperative snap freezing and laboratory examination indicated gastric adenocarcinoma. Therefore, the patient received an intraoperative diagnosis of obstructive jaundice, hilar cholangiocarcinoma, and gastric cancer. Postoperative pathological diagnosis: Postoperative pathological examination of the gastric lesion revealed the following results: ulcerative, moderately differentiated gastric adenocarcinoma and intestinal type in the Lauren classification of stomach cancer; moderately differentiated adenocarcinoma of the bile duct. INTERVENTIONS: Surgical resection operation was carried out and the patient received chemotherapy after operation. But we could not strictly follow the relevant clinical guidelines to perform standardized operations and provide comprehensive treatment because of his economic situation, psychological factors, and the current medical environment in China. OUTCOMES: The patient did not receive standardized postoperative therapy. Although he lived and worked normally for 8 months after the operation, he died 10 months after surgery. LESSONS: This report reminds us to pay close attention to the likelihood of MPM and other low-incidence diseases. The physicians and imaging clinicians should explore all clinical possibilities to avoid misdiagnosis of this rare disease and formulate effective treatment plans to maximize the therapeutic benefits for the patient.

Analysis of the autophagy gene expression profile of pancreatic cancer based on autophagy-related protein microtubule-associated protein 1A/1B-light chain 3.

BACKGROUND: Pancreatic cancer is a highly invasive malignant tumor. Expression levels of the autophagy-related protein microtubule-associated protein 1A/1B-light chain 3 (LC3) and perineural invasion (PNI) are closely related to its occurrence and development. Our previous results showed that the high expression of LC3 was positively correlated with PNI in the patients with pancreatic cancer. In this study, we further searched for differential genes involved in autophagy of pancreatic cancer by gene expression profiling and analyzed their biological functions in pancreatic cancer, which provides a theoretical basis for elucidating the pathophysiological mechanism of autophagy in pancreatic cancer and PNI. AIM: To identify differentially expressed genes involved in pancreatic cancer autophagy and explore the pathogenesis at the molecular level. METHODS: Two sets of gene expression profiles of pancreatic cancer/normal tissue (GSE16515 and GSE15471) were collected from the Gene Expression Omnibus. Significance analysis of microarrays algorithm was used to screen differentially expressed genes related to pancreatic cancer. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze the functional enrichment of the differentially expressed genes. Protein interaction data containing only differentially expressed genes was downloaded from String database and screened. Module mining was carried out by Cytoscape software and ClusterOne plug-in. The interaction relationship between the modules was analyzed and the pivot nodes between the functional modules were determined according to the information of the functional modules and the data of reliable protein interaction network. RESULTS: Based on the above two data sets of pancreatic tissue total gene expression, 6098 and 12928 differentially expressed genes were obtained by analysis of genes with higher phenotypic correlation. After extracting the intersection of the two differential gene sets, 4870 genes were determined. GO analysis showed that 14 significant functional items including negative regulation of protein ubiquitination were closely related to autophagy. A total of 986 differentially expressed genes were enriched in these functional items. After eliminating the autophagy related genes of human cancer cells which had been defined, 347 differentially expressed genes were obtained. KEGG pathway analysis showed that the pathways hsa04144 and hsa04020 were related to autophagy. In addition, 65 clustering modules were screened after the protein interaction network was constructed based on String database, and module 32 contains the LC3 gene, which interacts with multiple autophagy-related genes. Moreover, ubiquitin C acts as a pivot node in functional modules to connect multiple modules related to pancreatic cancer and autophagy. CONCLUSION: Three hundred and forty-seven genes associated with autophagy in human pancreatic cancer were concentrated, and a key gene ubiquitin C which is closely related to the occurrence of PNI was determined, suggesting that LC3 may influence the PNI and prognosis of pancreatic cancer through ubiquitin C.

Rapid Transmembrane Transport of DNA Nanostructures by Chemically Anchoring Artificial Receptors on Cell Membranes.

Highly efficient transmembrane transport of exogenous reagents into cells is of vital importance for developing drug-delivery systems. Conventionally, transmembrane transport of exogenous reagents was accomplished with the assistance of transfection agents or other artificial means. However, the high toxicity and low transport efficiency of current delivery techniques still remain to be solved. In this work, by anchoring artificial receptors onto cell membranes with a mild chemical reaction, we demonstrated that the exogenous reagent framework nucleic acids, namely tetrahedral DNA nanostructures (TDN) can bind onto cell membranes effectively by the hybridization between single-stranded DNA (ssDNA) and pendant ssDNA of TDN. The transport rate was greatly enhanced, with the endocytosis time could be as fast as 0.5 h. Furthermore, the transport quantity was prominently improved, with around 30 % of TDN endocytosed within 4 h. Owing to its rapid transmembrane transport speed and improved endocytosis quantity, this artificial-receptor-mediated transmembrane transport is a promising tool for achieving rapid and highly efficient transmembrane transport of exogenous reagents.

Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer.

AIM: To investigate the relationship between autophagy and perineural invasion (PNI), clinical features, and prognosis in patients with pancreatic cancer. METHODS: Clinical and pathological data were retrospectively collected from 109 patients with pancreatic ductal adenocarcinoma who underwent radical resection at the First Affiliated Hospital of Zhengzhou University from January 2011 to August 2016. Expression levels of the autophagy-related protein microtubule-associated protein 1A/1B-light chain 3 (LC3) and PNI marker ubiquitin carboxy-terminal hydrolase (UCH) in pancreatic cancer tissues were detected by immunohistochemistry. The correlations among LC3 expression, PNI, and clinical pathological features in pancreatic cancer were analyzed. The patients were followed for further survival analysis. RESULTS: In 109 cases of pancreatic cancer, 68.8% (75/109) had evidence of PNI and 61.5% (67/109) had high LC3 expression. PNI was associated with lymph node metastasis, pancreatitis, and CA19-9 levels (P < 0.05). LC3 expression was related to lymph node metastasis (P < 0.05) and was positively correlated with neural invasion (P < 0.05, r = 0.227). Multivariate logistic regression analysis indicated that LC3 expression, lymph node metastasis, pancreatitis, and CA19-9 level were factors that influenced neural invasion, whereas only neural invasion itself was an independent factor for high LC3 expression. Univariate analysis showed that LC3 expression, neural invasion, and CA19-9 level were related to the overall survival of pancreatic cancer patients (P < 0.05). Multivariate COX regression analysis indicated that PNI and LC3 expression were independent risk factors for poor prognosis in pancreatic cancer (P < 0.05). CONCLUSION: PNI in patients with pancreatic cancer is positively related to autophagy. Neural invasion and LC3 expression are independent risk factors for pancreatic cancer with a poor prognosis.

E-cadherin expression phenotypes associated with molecular subtypes in invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis.

BACKGROUND: This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). METHODS: A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. RESULTS: E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P < 0.050); moreover, the molecular subtypes were an independent factor influencing E-cad expression in early-stage IDCs. A total of 12 observational studies (including our study) were included in the meta-analysis. The meta-analytical results show a significantly greater risk of E-cad expression loss in triple-negative breast cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). CONCLUSIONS: Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.

Role of licochalcone A in VEGF-induced proliferation of human airway smooth muscle cells: implications for asthma.

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Licochalcone A is the predominant characteristic chalcone in licorice root. We found that licochalcone A inhibited vascular endothelial growth factor (VEGF)-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed via inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, but not that of Akt. Furthermore, licochalcone A treatment inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and ERK and blocked the downregulation of caveolin-1 in a concentration-dependent manner. Collectively, our findings suggested that licochalcone A inhibited VEGF-induced ASM cell proliferation by suppressing VEGFR2 and ERK1/2 activation and downregulating caveolin-1. Further studies of these mechanisms are needed to facilitate the development of treatments for smooth muscle hyperplasia-associated diseases of the airway, such as asthma.

Sinomenine Protects PC12 Neuronal Cells against H2O2-induced Cytotoxicity and Oxidative Stress via a ROS-dependent Up-regulation of Endogenous Antioxidant System.

Sinomenine (SN), a purified alkaloid from Chinese herb Sinomenium acutum that was used preferentially in the treatment of rheumatoid diseases, has exerted neuroprotective effects and anti-inflammatory properties in many previous studies. Some studies have revealed that the antioxidant property of SN, acting mainly through inhibiting NADPH oxidase activation, was involved in the beneficial effects of SN. However, SN belongs to the family of dextrorotatory morphinan analogues, which may initiate elevation of reactive oxygen species (ROS) levels. Thus in the present report, we conducted studies to examine its impact and mechanism on the resistance of PC12 neuronal cells to oxidative stress. Precondition with SN (0.1-5 µM) for 12 h significantly decreased H2O2-induced cytotoxicity and remarkably alleviated oxidative injury. However, SN exhibited little direct free radical scavenging property in vitro and induced "appropriate" production of ROS in PC12 cell. Interestingly, the SN-triggering ROS production served as a signal to activate the Nrf2 antioxidant system including Nrf2, HO-1, and NQO-1, which was inhibited by the antioxidant trolox. Furthermore, Nrf2 knockdown largely attenuated the beneficial effects of SN precondition on oxidative stress. In conclusion, our findings suggested that SN increased the resistance to oxidative stress in neuronal cells via a ROS-dependent up-regulation of endogenous antioxidant system, and this mechanism may be involved in the neuroprotection of SN.

Effect of active vitamin D3 on VEGF-induced ADAM33 expression and proliferation in human airway smooth muscle cells: implications for asthma treatment.

BACKGROUND: Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthma. Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) may influence asthma pathogenesis. A disintegrin and metalloproteinase (ADAM)33 has been identified as playing a role in the pathophysiology of asthma. ADAM33, which is expressed in ASM cells, is suggested to play a role in the function of these cells. Recent studies show that 1,25-(OH)2D3 exerts direct inhibitory effects on passively sensitized human ASM cells in vitro, including inhibition of ADAM33 expression and cell proliferation; however, the mechanism has not been fully understood. METHODS: In order to elucidate the precise mechanism underlying the effect of 1,25(OH)2D3 on VEGF-induced ADAM33 expression and ASM cell proliferation, we tested the effects of 1,25(OH)2D3 on cell cycle progression and evaluated the levels of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-Akt in VEGF-stimulated ASM cells. RESULTS: We found that 1,25(OH)2D3 inhibited VEGF-induced ADAM33 expression and ASM cell proliferation, as well as cell cycle arrest. Additionally, VEGF-induced ADAM33 expression and ASM cell proliferation was suppressed via inhibition of ERK1/2 activity, but not that of Akt. Furthermore, 1,25(OH)2D3 treatment inhibited VEGF-induced activation of VEGFR2 as well as that of ERK and Akt in a concentration-dependent manner. 1,25(OH)2D3 also inhibited transforming growth factor (TGF)-ß-induced VEGF secretion by ASM cells. CONCLUSIONS: Collectively, our findings suggest that 1,25(OH)2D3 inhibits VEGF-induced ASM cell proliferation by suppressing VEGFR2 and ERK1/2 activation and downregulating ADAM33. Further studies of these mechanisms are needed to facilitate the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma.

Preoperative aspartate aminotransferase-to-platelet ratio index (APRI) is a predictor on postoperative outcomes of hepatocellular carcinoma.

Preoperative aspartate aminotransferase-to-platelet ratio index (APRI) has been identified as a biochemical marker for histological fibrogenesis and fibrosis in cirrhosis and prognosis of hepatocellular carcinoma (HCC). Whether preoperative APRI can predict postoperative short-term outcomes has not been studied. The purpose of this study was to investigate the ability of preoperative APRI to predict short-term outcomes following liver resection for HCC. APRI was evaluated in 360 patients undergoing liver resection for HCC. The receiver operating characteristic curve analysis was conducted to determine the cutoff value of the APRI in predicting postoperative morbidity. Univariate and multivariate analysis was performed to identify the risk factors for postoperative outcomes. The correlation of the preoperative APRI value with clinicopathological parameters was also examined. We found that the optimal cutoff value of the APRI was set at 9.5 for postoperative complications. APRI was an independent risk factor for overall complications by univariate and multivariate analyses. HCC patients with elevated APRI (>9.5) had a worse liver function and significantly higher postoperative complication rate. In conclusion, preoperative APRI is a useful biochemical marker to predict postoperative outcomes in HCC patients.