Comparison of Intra-Arterial Chemotherapy Efficacy Delivered Through the Ophthalmic Artery or External Carotid Artery in a Cohort of Retinoblastoma Patients

Purpose: To evaluate the efficacy of an external carotid artery (ECA) alternative route in intra-arterial chemotherapy (IAC) for treatment of retinoblastoma.Methods: In this retrospective, single-centre, case-control study, 98 retinoblastoma patients who received successful IAC were included. The drug delivery routes were the primary ophthalmic artery (OA) route and the ECA route when OA catheterization was not feasible.Results: A total of 337 successful IAC procedures were performed in our study, of which 32 (9.5%) procedures were performed through the ECA route. Eighteen eyes (18.4%) accepted at least one IAC through branches of the ECA. Statistical analysis showed that there was no significant difference in ocular clinical results (enucleation, death, recurrence and event-free) between the ECA and OA routes. No significant association was found between the route of drug delivery and the ocular survival time (p = 0.69). The use of ECA catheterization in at least one IAC cycle was not a predictor of enucleation (HR: 1.58; 95% CI: 0.56–4.46, p = 0.39). The increasing number of procedures through the ECA route did not increase the risk of enucleation (HR: 1.64; 95% CI: 0.42–6.39, p = 0.48).Conclusion: The ECA alternative route did not affect the efficacy of IAC in retinoblastoma. When the standard OA approach is not feasible, ECA system catheterization should be considered

Intrachromosomal Looping Is Required for Activation of Endogenous Pluripotency Genes during Reprogramming

SummaryGeneration of induced pluripotent stem cells (iPSCs) by defined factors is an extremely inefficient process, because there is a strong epigenetic block preventing cells from achieving pluripotency. Here we report that virally expressed factors bound to the promoters of their target genes to the same extent in both iPSCs and unreprogrammed cells (URCs). However, expression of endogenous pluripotentcy genes was observed only in iPSCs. Comparison of local chromatin structure of the OCT4 locus revealed that there was a cohesin-complex-mediated intrachromosomal loop that juxtaposes a downstream enhancer to the gene’s promoter, enabling activation of endogenous stemness genes. None of these long-range interactions were observed in URCs. Knockdown of the cohesin-complex gene SMC1 by RNAi abolished the intrachromosomal interaction and affected pluripotency. These findings highlight the importance of the SMC1-orchestrated intrachromosomal loop as a critical epigenetic barrier to the induction of pluripotency

Failure mode transition for rock cutting: theoretical, numerical and experimental modelling

Rock cutting involves removing the rock material in front of the cutter when it moves against the rock at certain penetrating depth. The responses of rocks under cutting are influenced by rock properties such as mineral constituents, strength and fracture properties, as well as the operational parameters such as the depth of cut, cutting velocity and the back rake angle. A common approach to characterise the interaction between rock and cutter is to model the cutting forces. When the depth of cut is small, cutting forces show a linear relationship against the depth of cut, indicating a ductile-dominant failure mode. As the depth of cut increases, the rock cutting failure shifts from ductile-dominant mode to brittle-dominant mode and the cutting forces gradually deviate from the linear relationship. The depth of cut at which the dominant failure mode changes is termed the critical transition depth in rock cutting. The challenge lies in developing a generalised model for cutting force prediction based on rock properties and various complex cutting conditions while incorporating both ductile and brittle failure regimes. In this thesis, the discrete element method (DEM) was employed to investigate the key rock properties that influence the failure pattern in rock cutting. It was demonstrated that rock (Brazilian) tensile strength (BTS) is as important as the uniaxial compressive strength (UCS) in the determination of the critical transition depth. The mineral grain size is also an important factor. Experiments were then carried out on two types of rock, namely Savonnières and Tuffeau limestone, to study changes in failure modes under different operational parameters of cutting velocity, back rake angle and depth of cut. Bažant’s size effect law was used for in-depth analysis of the cutting data, which performs exceptionally well in the quantification of the critical failure mode transition depth. These derived transition depths were then incorporated into the established generalised cutting force prediction model, which uses a more realistic assumption that the cutting failure is neither purely ductile nor purely brittle, but a combination of both. It was demonstrated that the generalised cutting force prediction model captures reasonably well the cutting responses and failure mechanisms for the rock under various cutting conditions. The insights presented in this study will help in the understanding of rock cutting failure mechanisms and rock cutting mechanics and will be beneficial to the optimisation of tool design and rock cutting operations.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Civil, Environmental & Mining Engineering, 2015

Novel Insights into the Role of Long Noncoding RNA in Ocular Diseases

Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a brief overview of relevant reports about lncRNAs in such ocular diseases as glaucoma, proliferative vitreoretinopathy (PVR), diabeticretinopathy (DR), and ocular tumors. We intend to highlight comprehensive studies that provide detailed data about the mechanisms of lncRNAs, their applications as diagnostic or prognostic biomarkers, and their potential therapeutic targets. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights into the methods by which lncRNAs interfere with ocular diseases

Novel insights into chromosomal conformations in cancer

Abstract Exploring gene function is critical for understanding the complexity of life. DNA sequences and the three-dimensional organization of chromatin (chromosomal interactions) are considered enigmatic factors underlying gene function, and interactions between two distant fragments can regulate transactivation activity via mediator proteins. Thus, a series of chromosome conformation capture techniques have been developed, including chromosome conformation capture (3C), circular chromosome conformation capture (4C), chromosome conformation capture carbon copy (5C), and high-resolution chromosome conformation capture (Hi-C). The application of these techniques has expanded to various fields, but cancer remains one of the major topics. Interactions mediated by proteins or long noncoding RNAs (lncRNAs) are typically found using 4C-sequencing and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Currently, Hi-C is used to identify chromatin loops between cancer risk-associated single-nucleotide polymorphisms (SNPs) found by genome-wide association studies (GWAS) and their target genes. Chromosomal conformations are responsible for altered gene regulation through several typical mechanisms and contribute to the biological behavior and malignancy of different tumors, particularly prostate cancer, breast cancer and hematologic neoplasms. Moreover, different subtypes may exhibit different 3D-chromosomal conformations. Thus, C-tech can be used to help diagnose cancer subtypes and alleviate cancer progression by destroying specific chromosomal conformations. Here, we review the fundamentals and improvements in chromosome conformation capture techniques and their clinical applications in cancer to provide insight for future research

AAV for Gene Therapy in Ocular Diseases: Progress and Prospects

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation

Therapeutic efficacy by targeting correction of Notch1-induced aberrants in uveal tumors.

There is a need for more effective treatments for uveal melanoma. The recombinant oncolytic adenovirus H101 replicates specifically in p53-depleted tumor cells, and has been approved for use by the Chinese State Food and Drug Administration. However, this treatment is associated with subsequent remission. Transfection of uveal melanoma cells with a small interfering RNA against Notch1 (siNotch1) effectively suppressed Notch1 expression, resulting in significant cell growth inhibition when combined with H101 treatment. Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA) greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone. For in vivo treatments, the combined treatment of siNotch1 and H101 showed remarkable tumor growth inhibition and prolonged mouse survival in the OCM1 xenograft model. We predict that Notch pathway deregulation could be a feature of uveal melanoma, and could be a therapeutic target, especially if p53 is concurrently targeted

A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I

Background/Aims: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy. Methods: A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays. Results: A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility. Conclusion: This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation