[Clinical, endoscopic, and pathological analyses of 14 cases of gastric adenocarcinoma of the fundic gland type].

Objective: Gastric adenocarcinoma of the fundic gland type (GA-FG) is rare and often occurs in patients who are not infected with Helicobacter pylori. The current study analyzed and summarized the clinical, endoscopic, and pathological features of GA-FG, in an effort to improve its diagnosis. Methods: Patients who were diagnosed with GA-FG and treated with endoscopic submucosal dissection (ESD) resection at the Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University from January 1st 2020 to October 1st 2022 were included in the study. Their clinical manifestations, endoscopic features, pathological immunohistochemistry, and other characteristics were analyzed. Results: A total of 14 patients with GA-FG were included in the study, 5 males and 9 females, with a mean age of 59 years. Most had no substantial clinical manifestations. Twelve patients were H. pylori-negative, all patients underwent ESD resection, and all patients survived during the follow-up period of 13±9 months. Eleven patients had postoperative endoscopic follow-up records, and no recurrence was detected. Fifteen lesions were detected (2 were present in 1 patient). Twelve were located in the upper 1/3 of the stomach, 10 were ≤ 1 cm in diameter, 12 had a morphology of type 0-Ⅱa, 8 had visible discoloration changes, and 12 had visible vasodilation on the surface. Magnified endoscopy and narrow-band imaging indicated that 12 of the lesions had enlarged marginal crypt epithelium, without any obvious microvascular pattern abnormalities and no obvious borderline. After resection the pathological specimens were all without vascular infiltration, and there was no atrophy of the mucosa at the edge of the lesion. In immunohistochemistry analyses MUC-2 was negative in all cases. MUC5AC was negative in 11 cases, MUC-6 was positive in all cases, and Ki-67 was ≤ 5% in 12 cases. Conclusions: GA-FG is a newly identified type of gastric cancer with low malignancy and a good prognosis. Characteristic discoloration and surface dilated vessels are often evident endoscopically. Enlarged marginal crypt epithelium and no visible boundary lines are often apparent in magnification endoscopy and narrow band imaging.

Impaired local Vitamin D3 metabolism contributes to IL-36g overproduction in epithelial cells in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Vitamin D (VD) possesses immunomodulatory properties, but its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains poorly studied. Herein, we aim to explore the regulation and function of VD3 in CRSwNP. METHODS: 25-hydroxyvitamin D3 (25VD3) levels in serum and tissue lysates were detected by ELISA. The expression of VD receptor (VDR) and cytochrome P450 family 27 subfamily B member 1 (CYP27B1), the enzyme that converts 25VD3 to the active 1,25-hydroxyvitamin D3 (1,25VD3), and their expression regulation in human nasal epithelial cells (HNECs) were studied by RT-PCR, western blotting, immunofluorescence, and flow cytometry. RNA sequencing was performed to identify genes regulated by 1,25VD3 in HNECs. HNECs and polyp tissue explants were treated with 1,25VD3, 25VD3, and dexamethasone. RESULTS: 25VD3 levels in serum and nasal tissue lysates were decreased in patients with eosinophilic and noneosinophilic CRSwNP than control subjects. The expression of VDR and CYP27B1 were reduced in eosinophilic and noneosinophilic CRSwNP, particularly in nasal epithelial cells. VDR and CYP27B1 expression in HNECs were downregulated by interferon y and poly (I:C). Polyp-derived epithelial cells demonstrated an impaired ability to convert 25VD3 to 1,25VD3 than control tissues. 1,25VD3 and 25VD3 suppressed IL-36y production in HNECs and polyp tissues, and the effect of 25VD3 was abolished by siCYP27B1 treatment. Tissue 25VD3 levels negatively correlated with IL-36y expression and neutrophilic inflammation in CRSwNP. CONCLUSION: Reduced systemic 25VD3 level, local 1,25VD3 generation and VDR expression result in impaired VD3 signaling activation in nasal epithelial cells, thereby exaggerating IL-36y production and neutrophilic inflammation in CRSwNP.

Predicting difficult-to-treat chronic rhinosinusitis by noninvasive biological markers.

BACKGROUND: Previous studies have been limited to the utility of clinical features and invasive nasal mucosal biomarkers in the prediction of chronic rhinosinusitis (CRS) outcomes. This study aimed to identify noninvasive biomarkers associated with difficult- to-treat CRS, enabling physicians to subgroup patients into risk groups for poor outcome before surgery. METHODS: Three hundred and nine CRS patients undergoing endoscopic sinus surgery were finally enrolled. Patients treated with oral or intranasal glucocorticoids within 3 months or 1 month before surgery, respectively, were excluded. Baseline clinical charac- teristics, nasal secretions and peripheral blood samples were collected before surgery. The protein levels of 39 biological mar- kers were detected by the Bio-Plex suspension chip method. Classification and regression tree analysis was applied to establish prediction model for difficult-to-treat CRS determined one year after surgery. A random forest algorithm was used to confirm the discriminating factors that formed the classification tree. RESULTS: In the cohort with nasal secretion sample (n = 189), 21% of CRS patients were diagnosed as difficult-to-treat after 1 year of follow-up. Nasal secretion CCL17 level, hyposmia score, allergic rhinitis comorbidity, and nasal secretion MIP-1ß level were found important predictors of difficult-to-treat CRS. A classification tree separated patients into 5 subgroups leading to an overall predictive accuracy of 94%. However, none of the plasma biological markers were associated with difficult-to-treat CRS in the cohort with blood sample (n = 128). CONCLUSIONS: Patients with difficult-to-treat-CRS were characterized by higher nasal secretion levels of CCL17 and MIP-1ß severe hyposmia and concomitant allergic rhinitis. The classification tree could be useful to identify patients with high risk of poor outcome prior to surgery and offer more personalized interventions. However, since only patients without preoperative steroid treatments were included in this study, the generalization of our predictive model in other patient populations should be conside- red with caution.

Long non-coding RNA CASC2 targeting miR-18a suppresses glioblastoma cell growth, metastasis and EMT in vitro and in vivo.

Long non-coding RNAs (lncRNAs) cancer susceptibility candidate 2 (CASC2) has been characterized as a tumor suppressor in glioma. Although CASC2 may predict the prognosis of glioma patients, the role and mechanism of CASC2 in human glioblastoma remain to be fully illuminated. Expression of CASC2 and miR- 18a was detected using RT-qPCR. Cell growth was evaluated by MTT assay, colony formation assay, and flow cytometry; metastasis and epithelial-mesenchymal transition (EMT) were determined with transwell assay and Western blot, respectively. The target binding between CASC2 and miR-18a was predicted on Starbase software, and confirmed by luciferase reporter assay and RNA immunoprecipitation. Xenograft experiment measured tumor growth. As a result, CASC2 was downregulated and miR-18a was upregulated in glioblastoma tumor tissues and cells (T98 and A172). Overexpression of CASC2 promoted apoptosis rate and E-cadherin expression, but suppressed cell viability, colony-forming ability, migration, invasion, and expression of N-cadherin and Vimentin in T98 and A172 cells, accompanied with tumor growth inhibition in vivo; whereas, silencing of CASC2 exerted the opposite effect on cell growth, metastasis and EMT of T98 and A172 cells in vitro. However, reintroduction of miR-18a could reverse CASC2 upregulation-mediated suppression on above cell behaviors in vitro. More importantly, miR-18a was a downstream target for CASC2, and was negatively regulated by CASC2. Collectively, this study demonstrated that CASC2 served as tumor suppressor in glioblastoma by inhibiting cell growth, metastasis and EMT both in vitro and in vivo partially via CASC2- miR-18a axis.

2D shear wave elastography combined with age and serum biomarkers prior to kasai surgery predicts native liver survival of biliary atresia infants.

BACKGROUND: The prognosis of patients with biliary atresia (BA) after Kasai portoenterostomy (KPE) varies, and precisely predicting the outcomes of KPE before surgery is still challenging. METHODS: A total of 158 patients who underwent KPE in our hospital were included in this study. The patients in the training cohort were recruited from January 2012 to October 2017 (n = 118), and then, those in the validation cohort were recruited from November 2017 to April 2019 (n = 40). Combined nomogram models were developed based on two-dimensional shear wave elastography (2D SWE) values and other biomarkers. The utility of the proposed models was evaluated by C-index. RESULTS: 2D SWE played a potentially important role in predicting native liver survival (NLS) of BA patients with a C-index of 0.69 (0.63 to 0.75) in the training cohort and 0.76 (0.67 to 0.85) in the validation cohort. The nomogram A based on 2D SWE values, age, gamma-glutamyl transferase (GGT) and aspartate aminotransferase-to-platelet ratio (APRI) had a better C-index in the training cohort [0.74 (0.68-0.80) vs. 0.66 (0.60-0.73), P = 0.017] and in the validation cohort [0.78 (0.70-0.86) vs. 0.60 (0.49-0.71), P = 0.002] than the nomogram B (without 2D SWE). Using risk score developed from nomogram A, we successfully predicted 88.0% (22/25) of patients in the training cohort and 75.0% (9/12) in the validation cohort to have survival time of less than 12 months after KPE. CONCLUSION: The combined nomogram model based on 2D SWE values, age, GGT and APRI prior to KPE can effectively predict NLS in BA infants.

A retrospective study of changes of histopathology of nasal polyps in adult Chinese in central China.

BACKGROUND: The factors contributing to the eosinophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remain elusive. This study was designed to investigate the inflammatory patterns and tissue remodeling of CRSwNP in patients from central China at two time points over 14 years apart and the influence of age. METHODS: One hundred and eight CRSwNP patients enrolled in 2000 and 2001 (group A), and 134 CRSwNP patients enrolled in 2014 and 2015 (group B) were retrospectively studied. Hematoxylin-eosin stained tissue sections were used to study characteristics of inflammation and tissue remodeling. Immunohistochemistry was used to further evaluate the cells positive for eosinophil cationic protein (ECP), IL-5, IgE, tryptase or myeloperoxidase (MPO). Time- and age-related difference was analyzed. RESULTS: The number of eosinophils and proportion of eosinophilic CRSwNP were increased, whereas the numbers of total inflammatory cells and lymphocytes were decreased in group B as compared with group A. Group B had severer epithelial squamous metaplasia and basement membrane thickening, and a lower number of mucosal glands than group A. Higher numbers of ECP plus, IL-5 plus and IgE plus cells were detected in group B than those in group A. The elderly (60 yrs or older) and non-elderly (less than 60 yrs) had a comparable number of eosinophils and ratio of eosinophilic CRSwNP. CONCLUSION: Eosinophilic inflammation has been significantly augmented over time, which is associated with increased Th2 response and IgE production, and accompanied by exaggerated epithelium remodeling in CRSwNP patients from central China. Age has no significant influence on eosinophilic inflammation.

[The assessment value of peripheral blood eosinophils for treatment prognosis of chronic rhinosinusitis].

Objective:The purposes of present study were to explore the relative factors affecting treatment outcomes of chronic rhinosinusitis(CRS),and investigated the clinical manifestation changes of CRS patients after post-operative treatment of oral glucocorticoid. Method: Forty-eight CRS subjects including 14 illness un-controlled group, and 34 illness controlled group were enrolled, and peripheral blood leukocytes, eosinophils, neutrophils, mononuclear cells, lymphocytes were detected and clinical features comprised of VAS, endoscopy and CT scan scores were recorded; 20 days'oral glucocorticoid was prescribed to the patients in illness un-controlled group and the data described above were analyzed. Result:Compared to illness controlled group, illness uncontrolled subjects had higher peripheral blood eosinophils count(P=0.028), and complicated with higher rate of allergic rhinitis(P=0.035), asthma(P=0.024), atopy patients(P=0.042); the eosinophils was positively correlated with total VAS scores(R=0,410, P=0,007); the eosinophils count(P=0.007), total VAS scores(P<0.001), total endoscopy scores(P=0.001) were significant decreased after oral glucocorticoid treatment. Conclusion: Allergic rhinitis, asthma, atopy, and elevated eosinophils counts were risk factors of the prognosis of CRS, oral glucocorticoid treatment showed additional benefit to the illness un-controlled CRS subjects, and blood eosinophils count was an important predictive factor for clinical manifestation of CRS.

Comparison of efficacy of fluticasone propionate versus clarithromycin for postoperative treatment of different phenotypic chronic rhinosinusitis: a randomized controlled trial.

BACKGROUND: Chronic rhinosinusitis (CRS) can be divided to CRS without nasal polyps (CRSsNP) and eosinophilic and non-eosinophilic CRS with nasal polyps (CRSwNP). There is little evidence on the efficacy of glucocorticoids and macrolides in different phenotypic patients. The aim of this study was to compare the benefit of glucocorticoids and macrolides following endoscopic sinus surgery (ESS) in different phenotypic CRS. METHODS: This study was a prospective single-blind comparative effectiveness trial. A total of 187 Chinese patients with CRS were stratified to CRSsNP and eosinophilic and non-eosinophilic CRSwNP group and then randomized to receive fluticasone propionate nasal spray at 200 microgram or clarithromycin tablet at 250 mg once daily for 3 months after ESS. Oral prednisone was given as a rescue therapy after the stop of study medication. Patients were assessed before ESS and 1, 3, 6 and 12 months after dosing. Symptom severity was scored by patients using visual analog scale method and endoscopic findings were scored by the senior physician blinded to treatment according to European Position Paper on Rhinosinusitis and Nasal polyps 2012. RESULTS: The total and individual symptom scores, and total and individual endoscopic domain scores were reduced significantly after ESS in both medication groups, whereas no significant difference was observed for two medications at most follow-up visits in each subtype of CRS. No difference in the frequency of subjects with rescue therapy or refractory CRS was found between two medication groups either. CONCLUSIONS: We could not show significant difference of effect between fluticasone propionate and clarithromycin in the post-operative treatment for CRSsNP and eosinophilic and non-eosinophilic CRSwNP patients.

[The mechanism of nicotine on human bronchial smooth muscle cell contraction].

Objective: To investigate the molecular mechanism of contractility dysfunction of human bronchial smooth muscle cells induced by nicotine. Methods: Primary human bronchial smooth muscle cells were cultured in vitro. The cells were divided into a control group and a nicotine group which was treated with 10(-5) mol/L nicotine for 48 h and transfected with or without α7nAChR-siRNA (The siNC group, siNC + nicotine group and siα7nAChR + nicotine group). The effects of nicotine on the cell contractile function were examined by collagen gel shrinkage assay. The expressions of α7nAChR and TRPC6 protein in nicotine-treated human bronchial smooth muscle cells were detected by Western blotting. The change of intracellular calcium concentration by nicotine was detected by calcium ion imaging system.Data were analyzed by t test or single factor analysis of variance. Results: The area of collagen gel in the nicotine group (24±8)% was significantly lower than that in the control group (59±14)% (t=3.78, P<0.05). Compared with the control group, the expression of α7nAChR protein in nicotine-induced group (173±16)% was significantly higher than that of controls 100±0)%, t=-6.848, P<0.05. Compared with the siNC group [(72±10)%, (0.79±0.07), (0.41±0.04) and (0.17±0.02) respectively], the collagen gel area of siNC + nicotine group was significantly reduced by (37±10)%. However, the basal calcium level (1.04±0.02), store operated calcium entry level (SOCE, 0.68±0.03) and receptor operated calcium entry level (ROCE, 0.36±0.02) were remarkably elevated in the nicotine treated group (all P<0.05). Furthermore, compared with siNC + nicotine group, the area of collagen gel in siα7nAChR + nicotine group was significantly increased (62±10)%, and the basal calcium level (0.78±0.06), SOCE level (0.39±0.05) and ROCE level (0.15±0.02) were significantly reduced (all P<0.05). Conclusions: Nicotine can increase the expression of TRPC6 protein, SOCE and ROCE level, and increase the intracellular calcium concentration by upregulating the expression of α7nAChR protein, thereby promoting smooth muscle cell contraction.

Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes.

BACKGROUND: The expression of chronic rhinosinusitis (CRS) is multidimensional. Disease heterogeneity in patients with CRS remains poorly understood. This study aimed to identify endotypes of CRS using cluster analysis by integrating multidimensional characteristics and to explore their association with treatment outcomes. METHODS: A total of 28 clinical variables and 39 mucosal cellular and molecular variables were analyzed using principal component analysis. Cluster analysis was performed on 246 prospectively recruited Chinese CRS patients with at least 1-year postoperative follow-up. Difficult-to-treat CRS was characterized in each generated cluster. RESULTS: Seven subject clusters were identified. Cluster 1 (13.01%) was comparable to the classic well-defined eosinophilic CRS with polyps, having severe disease and the highest proportion of difficult-to-treat CRS. Patients in cluster 2 (16.26%) and cluster 4 (13.82%) had relatively lower proportions of presence of polyps and presented mild inflammation with moderate proportions of difficult-to-treat cases. Subjects in cluster 2 were highly atopic. Cluster 3 (7.31%) and cluster 6 (21.14%) were characterized by severe or moderate neutrophilic inflammation, respectively, and with elevated levels of IL-8 and high proportions of difficult-to-treat CRS. Cluster 5 (4.07%) was a unique group characterized by the highest levels of IL-10 and lacked difficult-to-treat cases. Cluster 7 (24.39%) demonstrated the lowest symptom severity, a low proportion of difficult-to-treat CRS, and low inflammation load. Finally, we found that difficult-to-treat CRS was associated with distinct clinical features and biomarkers in the different clusters. CONCLUSIONS: Distinct clinicopathobiologic clusters of CRS display differences in clinical response to treatments and characteristics of difficult-to-treat CRS.

Association between single nucleotide polymorphisms in AKT1 and the risk of prostate cancer in the Chinese Han population.

AKT1, also known as v-akt murine thymoma viral oncogene homolog 1, is involved in the regulation of cell-survival and anti-apoptotic activities, which may affect the pathogenesis of various cancers. However, the association between genetic variants of AKT1 and the risk of developing prostate cancer has not been investigated before. This study investigated the associations between three polymorphisms (rs1130214, rs3730358, and rs2494732) in AKT1 and the risk of development of prostate cancer in the Chinese Han population. Sequenom MassARRAY & iPLEX technology were used to genotype these polymorphisms in 493 Chinese Han patients with prostate cancer and 309 age-matched healthy individuals. Compared to the CC genotype of the rs3730358 polymorphism, the CT genotype of the same polymorphism was strongly associated with a decreased risk of prostate cancer (OR = 0.617, 95%CI = 0.390-0.976, P = 0.037). However, there was no significant difference between the allele frequency of the rs3730358 polymorphism and those of the other two polymorphisms (P > 0.05). Moreover, no significant difference was found in the haplotype analysis (P > 0.05). Our study found that the variant genotype CT of rs3730358 of AKT1 was associated with a decreased risk of prostate cancer, which suggested that this polymorphism could play an important role in the development of the disease.

Interferon-γ-induced insufficient autophagy contributes to p62-dependent apoptosis of epithelial cells in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Autophagy is a lysosomal degradation pathway that is essential for cell survival, differentiation, and homeostasis. This study aimed to investigate the contribution of autophagy to the pathogenesis of CRS with nasal polyps (CRSwNP). METHODS: The expression of autophagic proteins [microtubule-associated protein 1 light chain 3B (LC3B)-II, autophagy-related proteins (Atg), and Beclin 1], substrate proteins (p62 and ubiquitinated proteins), and apoptotic signaling molecules [cysteine-aspartic protease-3 and cysteine-aspartic protease-8, and poly-ADP-ribose polymerase] in the sinonasal mucosa and nasal epithelial cells (NECs) was detected by immunohistochemistry and Western blotting. Autophagic vacuoles were observed with transmission electron microscopy. BEAS-2B cells and NECs were treated with rapamycin, bafilomycin A1, or various cytokines. In some experiments, cultured NECs were transfected with small interfering RNA targeting p62 (sip62) or Atg5 (siAtg5). Cultured cells were analyzed with Western blotting and flow cytometry. RESULTS: Although autophagic protein expression and autophagic vacuole formation were increased in both eosinophilic and noneosinophilic CRSwNP, particularly in NECs, there was also an up-regulation of substrate proteins and apoptotic signaling molecules. IFN-γ, but not IL-4, IL-13, or IL-17A, simultaneously enhanced LC3B-II and p62 levels as well as cell apoptosis in BEAS-2B cells and/or normal NECs. Bafilomycin A1 up-regulated the levels of LC3B-II and p62 in polyp NECs and IFN-γ-treated normal NECs. IFN-γ-induced apoptosis of normal NECs was exaggerated by bafilomycin A1 and siAtg5. Sip62 suppressed apoptosis of polyp NECs and IFN-γ-treated NECs. IFN-γ protein levels were increased in both eosinophilic and noneosinophilic CRSwNP. CONCLUSIONS: IFN-γ induces activated but insufficient autophagy and thus contributes to a degree to p62-dependent apoptosis of NECs in CRSwNP.

Pathways of Acetyl-CoA Metabolism Involved in the Reversal of Palmitate-Induced Glucose Production by Metformin and Salicylate.

The pathways through which fatty acids induce insulin resistance have been the subject of much research. We hypothesise that by focussing on the reversal of insulin resistance, novel insights can be made regarding the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered during the prevention of palmitate-induced glucose production in hepatocytes using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075 mM, 48 h) with or without metformin (0.25 mM) and sodium salicylate (2 mM) in the final 24 h of palmitate treatment, and effects on glucose production were determined. RNA microarray measurements followed by gene set enrichment analysis were performed to investigate pathway regulation. Lipidomic analysis and measurement of secreted bile acids and cholesterol were also performed. Reversal of palmitate-induced glucose production by metformin and sodium salicylate was characterised by co-ordinated down-regulated expression of pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. All 20 enzymes that regulate the conversion of acetyl-CoA to cholesterol were reduced following metformin and sodium salicylate. Selected findings were confirmed using primary mouse hepatocytes. Although total intracellular levels of diacylglycerol, triacylglycerol and cholesterol esters increased with palmitate, these were not, however, further altered by metformin and sodium salicylate. 6 individual diacylglycerol, triacylglycerol and cholesterol ester species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. These results implicate acetyl-CoA metabolism and C18 lipid species as modulators of hepatic glucose production that could be targeted to improve glucose homeostasis.

Interaction of thymic stromal lymphopoietin, IL-33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 system contribute to the initiation and development of Th2 responses. This study aimed to explore the involvement of TSLP, IL-25, IL-33, and their receptors in type 2 T-helper (Th) responses in chronic rhinosinusitis with nasal polyps (CRSwNPs) and their cross-regulation in human nasal epithelial cells (HNECs). METHODS: Immunohistochemistry, quantitative RT-PCR, ELISA, Bio-Plex assay, and flow cytometry were used to detect the expression of TSLP/common γ-like TSLP receptor (TSLPR)/IL-7 receptor α (IL-7Rα), IL-25/IL-17B receptor (IL-17RB), and IL-33/membrane-bound ST2 (ST2L)/soluble ST2 (sST2) in sinonasal mucosa and HNECs. HNECs cultured at an air-liquid interface were used to explore the expression in regulation of these cytokine systems. RESULTS: Compared with controls and noneosinophilic CRSwNP, the expression of TSLP/TSLPR/IL-7Rα and ST2L/sST2 was significantly increased in eosinophilic CRSwNP, predominantly in epithelial cells. In contrast, the expression of IL-33 and IL-25/IL-17RB was enhanced in epithelial cells in both eosinophilic and noneosinophilic CRSwNP compared to controls. The expression of TSLP, TSLPR, and ST2L was positively correlated with symptom and computer tomography scan scores in eosinophilic CRSwNP and with Th2 cytokine expression in sinonasal mucosa. The expression of ST2L was correlated with TSLP and its receptor expression. TSLP could induce ST2L expression that promoted IL-33-induced TSLP expression in HNECs. In addition, TSLP/TSLPR/IL-7Rα and ST2L could be induced by Th2 cytokines, while IL-25/IL-17RB and IL-33 could be upregulated by Th1/Th17 cytokines, in HNECs. CONCLUSIONS: The positive feedback loop between TSLP, IL-33 and their receptors, and Th2 cytokines may facilitate Th2-skewed inflammation in eosinophilic CRSwNP.

Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps.

BACKGROUND: Eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) display distinct patterns of inflammation. However, the pathogenic mechanisms underlying the heterogeneity of CRSwNP need further investigation. OBJECTIVE: To investigate local immunoglobulin E (IgE) production and phenotype of mast cells in eosinophilic and non-eosinophilic CRSwNP in Chinese. METHODS: Total and specific IgE levels were analysed by means of the ImmunoCAP system. The molecular steps involved in class-switch recombination to IgE were investigated using RT-PCR assays. Mast cell phenotypes, IgE- and high-affinity IgE receptor (FcεRI)-positive cells, and allergen binding to specific IgE in sinonasal mucosa were determined by means of immunohistochemistry. RESULTS: Compared with controls and non-eosinophilic CRSwNP, local total IgE levels were increased, and local specific IgE to common aeroallergens was more frequently found, in Chinese eosinophilic CRSwNP independent of atopy and without significant association with Staphylococcus aureus enterotoxins. The ε germline gene transcript was also more frequently detected in eosinophilic CRSwNP. The number of IgE- and FcεRI-positive cells was increased in eosinophilic CRSwNP. Most IgE- and FcεRI-positive cells were mast cells. Dust mite antigens could bind to IgE on mast cells in situ. The number of mast cells positive for both tryptase and chymase and activated mast cells was increased in eosinophilic CRSwNP and the number of activated mast cells positively correlated with local IgE level, eotaxin-1 level, and eosinophil count in CRSwNP. CONCLUSIONS AND CLINICAL RELEVANCE: The local IgE induced by common aeroallergens may mediate mast cell activation and contribute to subsequent eosinophilic inflammation in Chinese CRSwNP. This study offers a rationale for considering intervention strategies designed to target 'local allergy' in eosinophilic CRSwNP.

EIF5A2 predicts outcome in localised invasive bladder cancer and promotes bladder cancer cell aggressiveness in vitro and in vivo.

BACKGROUND: EIF5A2, eukaryotic translation initiation factor 5A2, is associated with several human cancers. In this study, we investigated the role of EIF5A2 in the metastatic potential of localised invasive bladder cancer (BC) and its underlying molecular mechanisms were explored. METHODS: The expression pattern of EIF5A2 in localised invasive BC was determined by immunohistochemistry. In addition, the function of EIF5A2 in BC and its underlying mechanisms were elucidated with a series of in vitro and in vivo assays. RESULTS: Overexpression of EIF5A2 was an independent predictor for poor metastasis-free survival of localised invasive BC patients treated with radical cystectomy. Knockdown of EIF5A2 inhibited BC cell migratory and invasive capacities in vitro and metastatic potential in vivo and reversed epithelial-mesenchymal transition (EMT), whereas overexpression of EIF5A2 promoted BC cells motility and invasiveness in vitro and metastatic potential in vivo and induced EMT. In addition, we found that EIF5A2 might activate TGF-ß1 expression to induce EMT and drive aggressiveness in BC cells. EIF5A2 stabilized STAT3 and stimulated nuclear localisation of STAT3, which resulted in increasing enrichment of STAT3 onto TGF-ß1 promoter to enhance the transcription of TGF-ß1. CONCLUSIONS: EIF5A2 overexpression predicts tumour metastatic potential in patients with localised invasive BC treated with radical cystectomy. Furthermore, EIF5A2 elevated TGF-ß1 expression through STAT3 to induce EMT and promotes aggressiveness in BC.