Intravitreal Melphalan for Vitreous Seeds: Initial Experience in China

Purpose. To evaluate the efficacy of intravitreal melphalan for vitreous seeds from retinoblastoma in Chinese patients. Methods. This is a retrospective review of 17 consecutive Chinese patients (19 eyes) with viable vitreous seeds from retinoblastoma. The patients received multiple intravitreal injections of 20 ug melphalan. Results. The International Classification of Retinoblastoma groups were B in 1 eye, C in 5 eyes, D in 11 eyes, and E in 2 eyes. On average, 6 injections (range: 1–15) were given to each eye at the interval of 2–4 weeks. Successful control of vitreous seeds was achieved in 16 of 19 eyes (84.21%). Globe retention was achieved in 73.68% (14/19) eyes. The patients were followed up for 27 months on average (median: 26; range: 17–42 months). There is a significant difference in response to intravitreal melphalan for cloud, spheres, and dust seeds with a median number of injections of 9, 6, and 3, respectively (P=0.003). Complications related to intravitreal melphalan included vitreous hemorrhage, cataract, salt-and-pepper retinopathy, and pupil posterior synechia. There was no case of epibulbar extension or systemic metastasis within the period of follow-up. Conclusion. Intravitreal melphalan achieved a high local control rate for vitreous seeds without extraocular extension and with acceptable toxicity in Chinese retinoblastoma patients

Phase-Specific Augmented Reality Guidance for Microscopic Cataract Surgery Using Long-Short Spatiotemporal Aggregation Transformer

Phacoemulsification cataract surgery (PCS) is a routine procedure conducted using a surgical microscope, heavily reliant on the skill of the ophthalmologist. While existing PCS guidance systems extract valuable information from surgical microscopic videos to enhance intraoperative proficiency, they suffer from non-phasespecific guidance, leading to redundant visual information. In this study, our major contribution is the development of a novel phase-specific augmented reality (AR) guidance system, which offers tailored AR information corresponding to the recognized surgical phase. Leveraging the inherent quasi-standardized nature of PCS procedures, we propose a two-stage surgical microscopic video recognition network. In the first stage, we implement a multi-task learning structure to segment the surgical limbus region and extract limbus region-focused spatial feature for each frame. In the second stage, we propose the long-short spatiotemporal aggregation transformer (LS-SAT) network to model local fine-grained and global temporal relationships, and combine the extracted spatial features to recognize the current surgical phase. Additionally, we collaborate closely with ophthalmologists to design AR visual cues by utilizing techniques such as limbus ellipse fitting and regional restricted normal cross-correlation rotation computation. We evaluated the network on publicly available and in-house datasets, with comparison results demonstrating its superior performance compared to related works. Ablation results further validated the effectiveness of the limbus region-focused spatial feature extractor and the combination of temporal features. Furthermore, the developed system was evaluated in a clinical setup, with results indicating remarkable accuracy and real-time performance. underscoring its potential for clinical applications

A potential role for protein palmitoylation and zDHHC16 in DNA damage response

10.1186/s12867-016-0065-9BMC Molecular Biology1711

Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

Abstract Background Acquired imatinib (IM) resistance is frequently characterized by Bcr-Abl mutations that affect IM binding and kinase inhibition in patients with chronic myelogenous leukemia (CML). Bcr-Abl-T315I mutation is the predominant mechanism of the acquired resistance to IM. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that nickel pyrithione (NiPT) potently inhibits the ubiquitin proteasome system via targeting the 19S proteasome-associated deubiquitinases (UCHL5 and USP14), without effecting on the 20S proteasome. In this present study, we investigated the effect of NiPT, a novel proteasomal deubiquitinase inhibitor, on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. Methods Cell viability was examined by MTS assay and trypan blue exclusion staining assay in KBM5, KBM5R, K562, BaF3-p210-WT, BaF3-p210-T315I cells, and CML patients’ bone marrow samples treated with NiPT. Cell apoptosis in CML cells was detected with Annexin V-FITC/PI and rhodamine-123 staining followed by fluorescence microscopy and flow cytometry and with western blot analyses for apoptosis-associated proteins. Expression levels of Bcr-Abl in CML cells were analyzed by using western blotting and real-time PCR. The 20S proteasome peptidase activity was measured using specific fluorogenic substrate. Active-site-directed labeling of proteasomal DUBs, as well as the phosphorylation of USP14 was used for evaluating the inhibition of the DUBs activity by NiPT. Mouse xenograft models of KBM5 and KBM5R cells were analyzed, and Bcr-Abl-related proteins and protein biomarkers related to proliferation, differentiation, and adhesion in tumor tissues were detected by western blots and/or immunohistological analyses. Results NiPT induced apoptosis in CML cells and inhibited the growth of IM-resistant Bcr-Abl-T315I xenografts in nude mice. Mechanistically, NiPT induced decreases in Bcr-Abl proteins, which were associated with downregulation of Bcr-Abl transcription and with the cleavage of Bcr-Abl protein by activated caspases. NiPT-induced ubiquitin proteasome system inhibition induced caspase activation in both IM-resistant and IM-sensitive CML cells, and the caspase activation was required for NiPT-induced Bcr-Abl downregulation and apoptotic cell death. Conclusions These findings support that NiPT can overcome IM resistance through both Bcr-Abl-dependent and Bcr-Abl-independent mechanisms, providing potentially a new option for CML treatment

HTRA1 variant increases risk to neovascular age-related macular degeneration in Chinese population

AbstractAge-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the world. Advanced AMD can be divided into wet AMD (choroidal neovascularization) and dry AMD (geographic atrophy, GA). Drusen is characterized by deposits in the macula without visual loss and is an early AMD sign in the Caucasian population. rs11200638 in the promoter of HTRA1 has recently been shown to increases the risk for wet AMD in both Caucasian and Hong Kong Chinese populations. In order to replicate these results in a different cohort, we genotyped rs11200638 for 164 Chinese patients (90 wet AMD and 74 drusen) and 106 normal controls in a Han Mainland Chinese cohort. The genotypes were compared using chi square analysis for an additive allelic model. rs11200638 was significantly associated with wet AMD (p=5.00×10−12). Unlike in the Caucasian population, the risk allele of rs11200638 was not associated with drusen in our Chinese population. These findings confirm the association of HTRA1 with wet AMD

Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells

Background/Aims: The ubiquitin proteasome system (UPS) is responsible for the degradation of most intracellular proteins, and proteasomal deubiquitinases (DUBs) have recently been highlighted as novel anticancer targets. It is well documented that copper complexes can inhibit UPS function through targeting both 20S proteasome and proteasomal DUBs. The antineoplastic activities of silver complexes have received much attention, but the exact mechanisms are not fully elucidated. In this study, we aim to investigate the effects of a novel silver complex [Ag(S2CN(C2H5)2)]6 (AgDT) on UPS function and its anticancer potential in non-small cell lung cancer (NSCLC). Methods: Cell viability assay (i.e., the MTS assay) and flow cytometry assay were used to analyze the cell viability and apoptosis. Proteasome inhibition was measured using 20S proteasome activity assay and 19S proteasomal DUBs activity assay. Western blot analysis and immunohistochemistry were performed to detect protein levels. The in vivo antitumor activity of AgDT was assessed with nude xenografts. Results: Silver ions, alone or in combination with disulfiram (DSF), induced UPS inhibition in NSCLC cells mainly through inhibition of proteasomal DUBs activities. Silver complex AgDT triggered intracellular accumulation of ubiquitinated proteins, and prevented the degradation of surrogate substrate GFPu. Mechanistically, AgDT potently inhibited the activities of proteasomal DUBs USP14 and UCHL5, without altering the 20S proteasome peptidases. Moreover, AgDT induced apoptosis in NSCLC cells and significantly inhibited tumor growth in xenografts. Conclusion: Our findings suggest that silver complex AgDT is a novel metal-based proteasomal DUBs inhibitor, and pharmacologic inhibition of USP14 and UCHL5 could prove to be an effective therapeutic strategy for NSCLC