Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).

Elevated ZNF704 expression is associated with poor prognosis of uveal melanoma and promotes cancer cell growth by regulating AKT/mTOR signaling.

BACKGROUND: Uveal melanoma (UM) is the most common intraocular malignancy in adults, with a poor survival prognosis. To date, limited understanding of UM's molecular mechanisms constitutes an obstacle to developing effective therapy. In this study, we examined key regulators mediating UM progression and their clinical relevance. METHODS: Transcriptomics of UM patients and cells were analyzed via RNA sequencing and bioinformatic analysis. Zinc finger protein 704 (ZNF704) was identified as prognosis-related biomarker for UM based on clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA). Gene expression was knocked down by specific shRNAs/siRNAs and overexpressed by transfection with plasmids inserted with investigated gene cDNA. Cell proliferation, viability and invasion abilities were determined by CCK8, colony formation and transwell assays, respectively. For cell cycle and apoptosis, cells were PI or PI/Annexin V-APC stained and analyzed by flow cytometry. Standard immunoblotting and quantitative RT-PCR were employed to assess the mRNA and protein abundance. To determine tumor growth in vivo, 4-week-old BALB/c-nu immune-deficient nude mice were inoculated with tumor cells. RESULTS: Analysis of differential expressed genes (DEGs) and survival analysis identified ZNF704 as a novel biomarker of UM. Prognostic analysis indicated ZNF704 as an independent predictor of UM overall survival. Expression of ZNF704 is elevated in UM tissues relative to adjacent normal choroid tissues. Knockdown of ZNF704 suppressed the growth and migration of UM cells and vice versa. In addition, expression of ZNF704 arrest UM cells at G0/G1 phase and inhibit cell apoptosis. RNA sequencing analysis indicated that SORBS3 were dysregulated after ZNF704 downregulation. Gene Set Enrichment Analysis (GSEA) revealed that upon ZNF704 knowndown, genes related with PI3K/AKT/mTOR, EMT and metastasis are enriched. Mechanistically, ZNF704 activates AKT/mTOR/glycolysis signaling pathway in UM cells. Moreover, expression of SORBS3 is downregulated by ZNF704 and knockdown of SORBS3 restored tumor cell viability in ZNF704 silenced cells. CONCLUSIONS: ZNF704 predicts poor prognosis of UM and exhibit pro-oncogenic effect in UM progression in vivo and in vitro, mediated through AKT/mTOR signaling pathway and suppression of SORBS3 expression.

Regional chemotherapy for uveal melanoma liver metastases.

Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma (UM). Compared with systemic chemotherapy, regional chemotherapy has similar efficacy and fewer systemic adverse effects. Regional chemotherapy for UM liver metastases includes hepatic artery infusion (HAI), transarterial chemoembolization (TACE), and isolated hepatic perfusion (IHP). In this review, we aim to examine the efficacy of regional chemotherapy and compare HAI, TACE, and IHP in terms of overall survival (OS). The three approaches showed no obvious difference in OS results.

High-Performance Ppb Level NO2 Gas Sensor Based on Colloidal SnO2 Quantum Wires/Ti3C2Tx MXene Composite.

Nitrogen dioxide is one origin of air pollution from fossil fuels with the potential to cause great harm to human health in low concentrations. Therefore, low-cost, low-power-consumption sensors for low-concentration NO2 detection are essential. Herein, heterojunction by SnO2 quantum wires, a traditional metal oxide NO2 sensing material, and Ti3C2Tx MXene, a novel type of 2D layered material, was synthesized using a simple solvothermal method for enhancing gas-sensing performance and reducing operating temperature. The operating temperature was reduced to 80 °C, with a best performance of 27.8 and a fast response and recovery time (11 s and 23 s, respectively). The SnO2 and Ti3C2Tx MXene composite exhibits high speed and low detection limit due to the construction of the heterojunction with high conductive Ti3C2Tx MXene. The selectivity and stability of gas sensors are carried out. This could enable the realization of fast response, high-sensitivity, and selective NO2 sensing under low operating temperatures.

Characteristics, Treatments, and Survival of Uveal Melanoma: A Comparison between Chinese and American Cohorts.

Uveal melanoma (UM) is the most common intraocular malignant carcinoma. This study aimed to compare the clinical features, treatment modalities, and prognosis of UM patients in China with those in America over a 15-year period. In the study, 4088 American patients with primary UM from the Surveillance, Epidemiology, and End Results (SEER) database and 1508 Chinese patients from Tongren-ophthalmology Research Association of Clinical Evaluation (TRACE) were included. Univariable and multivariable analyses were performed to determine prognostic factors and propensity score matching (PSM) and sensitivity analyses were applied to adjust for confounders and identify independent prognostic factors. Chinese patients were diagnosed at a younger age (mean ± SD, 47.3 ± 12.5 years vs. 59.7 ± 14.8 years) and tumors at diagnosis were larger (diameter: 12.0 ± 3.54 mm vs. 11.3 ± 8.27 mm; thickness: 7.13 ± 3.28 mm vs. 4.91 ± 3.01 mm). Chinese patients were more likely to undergo brachytherapy than American patients. Chinese patients had better overall survival than American patients while no significant differences exhibited after adjusting for age through PSM. In conclusion, compared with American patients, Chinese patients had younger onset age, larger tumors at diagnosis and better prognosis, mainly because of their younger age.

Highly Sensitive Love Mode Acoustic Wave Platform with SiO2 Wave-Guiding Layer and Gold Nanoparticles for Detection of Carcinoembryonic Antigens.

A highly sensitive and precise Love wave mode surface acoustic wave (SAW) immunosensor based on an ST-cut 90°X quartz substrate and an SiO2 wave-guiding layer was developed to detect cancer-related biomarkers of carcinoembryonic antigens (CEAs). A delay line structure of the SAW device with a resonant frequency of 196 MHz was designed/fabricated, and its surface was functionalized through CEA antibody immobilization. The CEA antibodies were bound with gold nanoparticles and CEA antibodies to form a sandwich structure, which significantly amplified the mass loading effect and enhanced the maximum responses by 30 times. The center frequency of the Love wave immunosensor showed a linear response as a function of the CEA concentration in the range of 0.2-5 ng/mL. It showed a limit of detection of 0.2 ng/mL, and its coefficient of determination was 0.983. The sensor also showed minimal interference from nonspecific adsorptions, thus demonstrating its promise for point-of-care applications for cancer biomarkers.

Validation of the Relationship Between Iris Color and Uveal Melanoma Using Artificial Intelligence With Multiple Paths in a Large Chinese Population.

Previous studies have shown that light iris color is a predisposing factor for the development of uveal melanoma (UM) in a population of Caucasian ancestry. However, in all these studies, a remarkably low percentage of patients have brown eyes, so we applied deep learning methods to investigate the correlation between iris color and the prevalence of UM in the Chinese population. All anterior segment photos were automatically segmented with U-NET, and only the iris regions were retained. Then the iris was analyzed with machine learning methods (random forests and convolutional neural networks) to obtain the corresponding iris color spectra (classification probability). We obtained satisfactory segmentation results with high consistency with those from experts. The iris color spectrum is consistent with the raters' view, but there is no significant correlation with UM incidence.

Flexible/Bendable Acoustofluidics Based on Thin-Film Surface Acoustic Waves on Thin Aluminum Sheets.

In this paper, we explore the acoustofluidic performance of zinc oxide (ZnO) thin-film surface acoustic wave (SAW) devices fabricated on flexible and bendable thin aluminum (Al) foils/sheets with thicknesses from 50 to 1500 µm. Directional transport of fluids along these flexible/bendable surfaces offers potential applications for the next generation of microfluidic systems, wearable biosensors and soft robotic control. Theoretical calculations indicate that bending under strain levels up to 3000 µÎµ causes a small frequency shift and amplitude change (<0.3%) without degrading the acoustofluidic performance. Through systematic investigation of the effects of the Al sheet thickness on the microfluidic actuation performance for the bent devices, we identify the optimum thickness range to both maintain efficient microfluidic actuation and enable significant deformation of the substrate, providing a guide to design such devices. Finally, we demonstrate efficient liquid transportation across a wide range of substrate geometries including inclined, curved, vertical, inverted, and lateral positioned surfaces using a 200 µm thick Al sheet SAW device.

Gas sensing materials roadmap.

Gas sensor technology is widely utilized in various areas ranging from home security, environment and air pollution, to industrial production. It also hold great promise in non-invasive exhaled breath detection and an essential device in future internet of things. The past decade has witnessed giant advance in both fundamental research and industrial development of gas sensors, yet current efforts are being explored to achieve better selectivity, higher sensitivity and lower power consumption. The sensing layer in gas sensors have attracted dominant attention in the past research. In addition to the conventional metal oxide semiconductors, emerging nanocomposites and graphene-like two-dimensional materials also have drawn considerable research interest. This inspires us to organize this comprehensive 2020 gas sensing materials roadmap to discuss the current status, state-of-the-art progress, and present and future challenges in various materials that is potentially useful for gas sensors.

Prognosis Prediction of Uveal Melanoma After Plaque Brachytherapy Based on Ultrasound With Machine Learning.

INTRODUCTION: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Plaque brachytherapy remains the dominant eyeball-conserving therapy for UM. Tumor regression in UM after plaque brachytherapy has been reported as a valuable prognostic factor. The present study aimed to develop an accurate machine-learning model to predict the 4-year risk of metastasis and death in UM based on ocular ultrasound data. MATERIAL AND METHODS: A total of 454 patients with UM were enrolled in this retrospective, single-center study. All patients were followed up for at least 4 years after plaque brachytherapy and underwent ophthalmologic evaluations before the therapy. B-scan ultrasonography was used to measure the basal diameters and thickness of tumors preoperatively and postoperatively. Random Forest (RF) algorithm was used to construct two prediction models: whether a patient will survive for more than 4 years and whether the tumor will develop metastasis within 4 years after treatment. RESULTS: Our predictive model achieved an area under the receiver operating characteristic curve (AUC) of 0.708 for predicting death using only a one-time follow-up record. Including the data from two additional follow-ups increased the AUC of the model to 0.883. We attained AUCs of 0.730 and 0.846 with data from one and three-time follow-up, respectively, for predicting metastasis. The model found that the amount of postoperative follow-up data significantly improved death and metastasis prediction accuracy. Furthermore, we divided tumor treatment response into four patterns. The D(decrease)/S(stable) patterns are associated with a significantly better prognosis than the I(increase)/O(other) patterns. CONCLUSIONS: The present study developed an RF model to predict the risk of metastasis and death from UM within 4 years based on ultrasound follow-up records following plaque brachytherapy. We intend to further validate our model in prospective datasets, enabling us to implement timely and efficient treatments.

miRNA-145/miRNA-205 inhibits proliferation and invasion of uveal melanoma cells by targeting NPR1/CDC42.

AIM: To investigate the role of microRNA-145 (miRNA-145) and microRNA-205 (miRNA-205) in proliferation and invasion of uveal melanoma (UM) cells. METHODS: The expression level of miRNA-145 and miRNA-205 from samples of UM patients were determined by real-time polymerase chain reaction (RT-PCR). The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205. Several epithelial-to-mesenchymal transition (EMT)-related proteins were screened by Western blotting. UM clinical samples from The Cancer Genome Atlas (TCGA) were applied to search for potential protein interaction. Pearson's correlation analysis was applied to estimate co-expression between genes. Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205. RESULTS: The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples. Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miRNA-205 overexpression. The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42 (CDC42). After database searching and sequence alignment, we identified that Neuropilin 1 (NRP1) had binding sites for both miRNA-145 and miRNA-205. CONCLUSION: The miRNA-145 and miRNA-205 can reduce the proliferation, migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.

Graphene oxide-Au nano particle coated quartz crystal microbalance biosensor for the real time analysis of carcinoembryonic antigen.

A label-free quartz crystal microbalance (QCM) biosensor was developed for the selective and real-time estimation of carcinoembryonic antigen (CEA) through the present study. Graphene oxide-Au nanoparticles (GO-AuNPs) was in situ synthesised on the surface of the QCM electrode and the antibody of CEA (monoclonal anti-CEA from mouse) was covalently immobilized on this layer as the bioreceptor for CEA. Mercaptoacetic acid-EDC-NHS reaction mechanism was used for anti-CEA immobilization. The effect of oxygen plasma treatment of the QCM electrode surface before bioreceptor preparation on the performance of the biosensor was tested and was found promising. CEA solutions with various concentrations were analysed using the bioreceptors to estimate the sensitivity and detection limit of the biosensor. The biosensors selectively recognized and captured CEA biomolecules with a detection limit of 0.06 and 0.09 ng mL-1 of CEA for oxygen plasma-treated (E2) and untreated (E1) bioreceptors, respectively. The sensitivity was estimated at 102 and 79 Hz, respectively, for E2 and E1. Clinical serum samples were analysed and the results were found in good agreement with the ELISA analysis. Long term stability was also found to be excellent. Langmuir adsorption isotherm was also conducted using the experimental results.