Ocular Biometric Characteristics in Preoperative Diagnosis of Acute Angle Closure With and Without Zonular Laxity.

PRCIS: Biometric parameters, including binocular difference of anterior chamber depth (ACD), lens vault (LV) in affected eyes, and binocular difference of the LV, had high efficiency in diagnosing acute angle closure (AAC) with zonular laxity. PURPOSE: To investigate the ocular biometric characteristics of eyes with AAC with zonular laxity to further explore the sensitive parameters for preoperative diagnosis. METHODS: This study included 50 patients with AAC with zonular laxity and 54 patients with AAC without zonular laxity. Demographic data, ocular examination results, and biometric parameters on ultrasound biomicroscopy images were compared between the affected and fellow eyes in 2 groups. Parameters significant in the multiple linear regression model were included in a regression equation and the diagnostic efficiency was evaluated by area under the curve. RESULTS: In patients with AAC with zonular laxity, the binocular difference of central ACD, LV in affected eyes, and binocular difference of the LV were significantly larger than those in patients without zonular laxity respectively and these three parameters were all significant in multiple linear regression analysis (all P <0.001). The area under the curve of binocular difference of ACD, LV in affected eyes, and binocular difference of LV were 0.972, 0.796, and 0.855, respectively, with the cutoff values of 0.23, 1.28, and 0.19 mm. The regression equation containing these three parameters was: ln ( P /(1- P ))=-4.322 + 1.222 [LV in affected eyes (mm)] + 3.657 [binocular difference of LV (mm)] + 6.542 [binocular difference of ACD (mm)], with the accuracy of prediction reaching 94.05%. CONCLUSION: Binocular difference of ACD, LV in affected eyes, and binocular difference of LV had high efficiency in diagnosing AAC with zonular laxity.

Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1.

The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin-related protein 14-mediated autophagy.

Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14.

HLA-E inhibitor enhances the killing of neuroblastoma stem cells by co-cultured dendritic cells and cytokine-induced killer cells loaded with membrane-based microparticles.

Neuroblastoma stem cells (NSCs) can cause drug resistance and tumor recurrence. This study aimed to enhance the lytic effect of dendritic cells (DCs) co-cultured with cytokine-induced killer (CIK) cells. NSCs were obtained by suspension culture, and DC-CIK cells were loaded with extracted NSC membrane-based microparticles (MMPs) before evaluating the lytic effect of DC-CIK cells on NSCs. After inhibiting the function or expression of human leukocyte antigen-E (HLA-E) in NSCs by anti-HLA-E monoclonal antibody or siRNA, the DC-CIK cell lytic effect on NSCs was re-assessed. NSC nestin expression was high, but glial fibrillary acid protein expression and class IIIß-tubulin-1 expression were low. Moreover, NSCs exhibited strong tumorigenic ability in nude mice. Loading DCs with NSC-derived MMPs induced the differentiation of DCs and CIK cells and enhanced the killing of NSCs by DC-CIK cells. Inhibiting the function or expression of HLA-E in NSCs further enhanced the cytolytic capability of DC-CIK cells loaded with NSC-derived MMPs. HLA-E inhibitor can enhance the killing of NSC by DC-CIK cells loaded with NSC-derived MMPs.

Inhibition of Gata4 and Tbx5 by Nicotine-Mediated DNA Methylation in Myocardial Differentiation.

Maternal nicotine exposure causes alteration of gene expression and cardiovascular programming. The discovery of nicotine-medicated regulation in cardiogenesis is of major importance for the study of cardiac defects. The present study investigated the effect of nicotine on cardiac gene expression and epigenetic regulation during myocardial differentiation. Persistent nicotine exposure selectively inhibited expression of two cardiac genes, Tbx5 and Gata4, by promoter DNA hypermethylation. The nicotine-induced suppression on cardiac differentiation was restored by general nicotinic acetylcholine receptor inhibition. Consistent results of Tbx5 and Gata4 gene suppression and cardiac function impairment with decreased left ventricular ejection fraction were obtained from in vivo studies in offspring. Our results present a direct repressive effect of nicotine on myocardial differentiation by regulating cardiac gene suppression via promoter DNA hypermethylation, contributing to the etiology of smoking-associated cardiac defects.

Involvement of IL-10 and TGF-ß in HLA-E-mediated neuroblastoma migration and invasion.

Human leukocyte antigen (HLA)-E is highly expressed in a variety of tumors and, in addition to immune escape, may promote tumor growth via other mechanisms. However, the role of HLA-E in neuroblastoma (NB) migration and invasion is unknown. In the present study, HLA-E expression in human NB tumors was measured by immunohistochemistry. The effect of HLA-E on NB cell migration and invasion was studied in vitro and in vivo, as well as the effect of HLA-E on natural killer (NK)-cell cytotoxicity. HLA-E was expressed in 70.2% of the NB tumor tissues examined. HLA-E expression by NB cells inhibited NK-cell cytotoxicity and induced the release of interleukin (IL)-10 and transforming growth factor (TGF)-ß1. HLA-E and the released cytokines enhanced the ability of NB cells migration and invasion. NK cell infusion did not inhibit the growth of NB cells with high HLA-E expression but instead increased the number of metastatic cells in the bone marrow. Taken together, the results indicate that IL-10 and TGF-ß are involved in HLA-E-mediated NB migration and invasion. Thus, HLA-E may be a new treatment target in NB.

Fn14, a Downstream Target of the TGF-ß Signaling Pathway, Regulates Fibroblast Activation.

Fibrosis, the hallmark of human injuries and diseases such as serious burns, is characterized by excessive collagen synthesis and myofibroblast accumulation. Transforming growth factor-ß (TGF-ß), a potent inducer of collagen synthesis, has been implicated in fibrosis in animals. In addition to TGF-ß, fibroblast growth factor-inducible molecule 14 (Fn14) has been reported to play an important role in fibrotic diseases, such as cardiac fibrosis. However, the function and detailed regulatory mechanism of Fn14 in fibrosis are unclear. Here, we investigated the effect of Fn14 on the activation of human dermal fibroblasts. In normal dermal fibroblasts, TGF-ß signaling increased collagen production and Fn14 expression. Furthermore, Fn14 siRNA blocked extracellular matrix gene expression; even when TGF-ß signaling was activated by TGF-ß1, fibroblast activation remained blocked in the presence of Fn14 siRNA. Overexpressing Fn14 increased extracellular matrix gene expression. In determining the molecular regulatory mechanism, we discovered that SMAD4, an important TGF-ß signaling co-mediator, bound to the Fn14 promoter and activated Fn14 transcription. Taken together, these results indicate that the TGF-ß signaling pathway activates Fn14 expression through the transcription factor SMAD4 and that activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation. Therefore, Fn14 may represent a promising approach to preventing the excessive accumulation of collagen or ECM in skin fibrosis.