Gaucher disease and the synucleinopathies: refining the relationship

Gaucher disease (OMIM 230800, 230900, 231000), the most common lysosomal storage disorder, is due to a deficiency in the enzyme glucocerebrosidase. Gaucher patients display a wide spectrum of clinical presentation, with hepatosplenomegaly, haematological changes, and orthopaedic complications being the predominant symptoms. Gaucher disease is classified into three broad phenotypes based upon the presence or absence of neurological involvement: Type 1 (non-neuronopathic), Type 2 (acute neuronopathic), and Type 3 (subacute neuronopathic). Nearly 300 mutations have been identified in Gaucher patients, with the majority being missense mutations. Though studies of genotype-to-phenotype correlations have revealed significant heterogeneity, some consistent patterns have emerged to inform prognostic and therapeutic decisions. Recent research has highlighted a potential role for Gaucher disease in other comorbidities such as cancer and Parkinson's Disease. In this review, we will examine the potential relationship between Gaucher disease and the synucleinopathies, a group of neurodegenerative disorders characterized by the development of intracellular aggregates of α-synuclein. Possible mechanisms of interaction will be discussed

Shining Emitter in a Stable Host: Design of Halide Perovskite Scintillators for X-ray Imaging from Commercial Concept

Halide perovskite (HP) nanocrystals (NCs) have recently shown great potential for X-ray detection and imaging. However, the practical application still has a long way to go with many technical requirements waiting to be fulfilled, including structure optimization, stability enhancement, and cost reduction. A design principle in this beginning stage is urgently needed but still lacking. Herein, with an “emitter-in-matrix” principle refined from commercial scintillators, CsPbBr3@Cs4PbBr6 with emissive CsPbBr3 NCs embedded inside a solid-state Cs4PbBr6 host is subjected to X-ray sensing and imaging. The Cs4PbBr6 matrix not only enhances the attenuation of X-rays but also dramatically improves the stability of CsPbBr3 NCs. A favorable optical design with the Cs4PbBr6 matrix being transparent to the emission from CsPbBr3 NCs enables efficient light output. As a result, stable and sensitive scintillation response to X-ray signals is demonstrated with superior linearity and ultrahigh time resolution. In order to show the huge potential for practical applications, X-ray imaging using a large-area film (360 mm × 240 mm) by the blade-coating technique is carried out to obtain a high-quality image of interior structures invisible to the human eye. In addition to the above advantages in optics, CsPbBr3@Cs4PbBr6 also enjoys facile solution synthesis with large scalability, excellent repeatability, and low cost

NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation

Imaging of Zebrafish In Vivo with Second-Harmonic Generation Reveals Shortened Sarcomeres Associated with Myopathy Induced by Statin

We employed second-harmonic generation (SHG) imaging and the zebrafish model to investigate the myopathy caused by statin in vivo with emphasis on the altered microstructures of the muscle sarcomere, the fundamental contractile element of muscles. This approach derives an advantage of SHG imaging to observe the striated skeletal muscle of living zebrafish based on signals produced mainly from the thick myosin filament of sarcomeres without employing exogenous labels, and eliminates concern about the distortion of muscle structures caused by sample preparation in conventional histological examination. The treatment with statin caused a significantly shortened sarcomere relative to an untreated control (1.73±0.09 µm vs 1.91±0.08 µm, P<0.05) while the morphological integrity of the muscle fibers remained largely intact. Mechanistic tests indicated that this microstructural disorder was associated with the biosynthetic pathway of cholesterol, or, specifically, with the impaired production of mevalonate by statins. This microstructural disorder exhibited a strong dependence on both the dosage and the duration of treatment, indicating a possibility to assess the severity of muscle injury according to the altered length of the sarcomeres. In contrast to a conventional assessment of muscle injury using clinical biomarkers in blood, such as creatine kinase that is released from only disrupted myocytes, the ability to determine microstructural modification of sarcomeres allows diagnosis of muscle injury before an onset of conventional clinical symptoms. In light of the increasing prevalence of the incidence of muscle injuries caused by new therapies, our work consolidates the combined use of the zebrafish and SHG imaging as an effective and sensitive means to evaluate the safety profile of new therapeutic targets in vivo

MicroRNA-145 Regulates Human Corneal Epithelial Differentiation

Epigenetic factors, such as microRNAs, are important regulators in the self-renewal and differentiation of stem cells and progenies. Here we investigated the microRNAs expressed in human limbal-peripheral corneal (LPC) epithelia containing corneal epithelial progenitor cells (CEPCs) and early transit amplifying cells, and their role in corneal epithelium.Human LPC epithelia was extracted for small RNAs or dissociated for CEPC culture. By Agilent Human microRNA Microarray V2 platform and GeneSpring GX11.0 analysis, we found differential expression of 18 microRNAs against central corneal (CC) epithelia, which were devoid of CEPCs. Among them, miR-184 was up-regulated in CC epithelia, similar to reported finding. Cluster miR-143/145 was expressed strongly in LPC but weakly in CC epithelia (P = 0.0004, Mann-Whitney U-test). This was validated by quantitative polymerase chain reaction (qPCR). Locked nucleic acid-based in situ hybridization on corneal rim cryosections showed miR-143/145 presence localized to the parabasal cells of limbal epithelium but negligible in basal and superficial epithelia. With holoclone forming ability, CEPCs transfected with lentiviral plasmid containing mature miR-145 sequence gave rise to defective epithelium in organotypic culture and had increased cytokeratin-3/12 and connexin-43 expressions and decreased ABCG2 and p63 compared with cells transfected with scrambled sequences. Global gene expression was analyzed using Agilent Whole Human Genome Oligo Microarray and GeneSpring GX11.0. With a 5-fold difference compared to cells with scrambled sequences, miR-145 up-regulated 324 genes (containing genes for immune response) and down-regulated 277 genes (containing genes for epithelial development and stem cell maintenance). As validated by qPCR and luciferase reporter assay, our results showed miR-145 suppressed integrin β8 (ITGB8) expression in both human corneal epithelial cells and primary CEPCs.We found expression of miR-143/145 cluster in human corneal epithelium. Our results also showed that miR-145 regulated the corneal epithelium formation and maintenance of epithelial integrity, via ITGB8 targeting

Patient-related barriers to cancer pain management – a prospective cross sectional study in a tertiary hospital.

Effective management of cancer pain is often hampered by patients’ lack of knowledge regarding cancer pain management and other barriers related to ethnicity and religious beliefs. This cross sectional study was performed to determine the patient-related barriers to effective cancer pain management. One hundred patients receiving cancer pain management were studied. Inclusion criteria were: patients over the age of 18 years, able to communicate, with known diagnosis of cancer, experiencing persistent pain for the past two weeks. A modified version of the Barriers Questionnaire II (BQ-II) was used and a modified Brief Pain Inventory was used to assess the pain profile. Barriers such as, patient’s attitude and beliefs, communication skills and fear of side effects of pain medication were determined, given a score and the summation was recorded as the total patient related barriers score. Overall, 85% of respondents achieved more than 40% pain relief and the 72 of 100 patients reported low patient related barrier scores of 6 or less. Nevertheless, the main patient related barriers were: fear of tolerance to opioids (51%), ethnicity (p=0.003) and religious beliefs (p=0.002) which constituted the major components of the patient-related barriers score. Ethnicity and religious beliefs had significant influence on patient-related barriers score suggesting the need of further investigation into this area. In order to achieve a comprehensive view, other barriers to effective cancer pain management such as those related to the health systems and healthcare providers need to be assessed together