Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy.

Significance: Hypoxia is emerging as a crucial regulator of the tumor microenvironment; it governs the metastatic potential of multiple primary cancers. It is also potentially involved in the regulation of tumorigenesis, tumor metabolism, and proangiogenic activity. Recent Advances: A wealth of clinical data across a wide range of cancer types has revealed strong correlations between hypoxia or the overexpression of hypoxia-inducible transcription factors and the rates of distant metastases and poor prognoses. Hypoxia-inducible factor (HIF)-1α, one of the key regulatory molecules of the HIF-1 signaling pathways, is involved in multiple crucial steps in the metastatic cascade. Critical Issues: Here, we present recent findings on the roles of the HIF-1 complex in tumor metastasis and highlight the potential of HIF-1α as a target for abrogating tumor metastasis. Moreover, we systematically describe the regulatory role of HIF-1 at each step of the metastatic cascade. Finally, we present the most recent advances in potential pharmacological interventions and the development of specific HIF-1 inhibitors for blocking tumor metastasis. Future Directions: Well-designed clinical trials are urgently needed to validate the anti-metastatic activity of HIF-1 inhibitors discovered in preclinical models. Antioxid. Redox Signal. 34, 1484-1497.

The penetration and distribution of topical atropine in animal ocular tissues.

PURPOSE: To conduct a multi-tissue investigation on the penetration and distribution of topical atropine in myopia treatment, and determine if atropine is detectable in the untreated contralateral eye after uniocular instillation. METHODS: Nine mature New Zealand white rabbits were evenly divided into three groups. Each group was killed at 5, 24 and 72 hr, respectively, following uniocular instillation of 0.05 ml of 1% atropine. Tissues were sampled after enucleation: conjunctiva, sclera, cornea, iris, ciliary body, lens, retina, aqueous, and vitreous humors. The assay for atropine was performed using liquid chromatography-mass spectrometry (LC-MS), and molecular tissue distribution was illustrated using matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) via an independent experiment on murine eyes. RESULTS: At 5 hr, the highest (mean ± SEM) concentration of atropine was detected in the conjunctiva (19.05 ± 5.57 ng/mg, p < 0.05) with a concentration gradient established anteriorly to posteriorly, as supported by MALDI-IMS. At 24 hr, preferential binding of atropine to posterior ocular tissues occurred, demonstrating a reversal of the initial concentration gradient. Atropine has good ocular bioavailability with concentrations of two magnitudes higher than its binding affinity in most tissues at 3 days. Crossing-over of atropine to the untreated eye occurred within 5 hr post-administration. CONCLUSION: Both transcorneal and transconjunctival-scleral routes are key in atropine absorption. Posterior ocular tissues could be important sites of action by atropine in myopic reduction. In uniocular atropine trials, cross-over effects on the placebo eye should be adjusted to enhance results reliability. Combining the use of LC-MS and MALDI-IMS can be a viable approach in the study of the ocular pharmacokinetics of atropine.

Recent advances in the applications of metabolomics in eye research.

Metabolomics, the identification and quantitation of metabolites in a system, have been applied to identify new biomarkers or elucidate disease mechanism. In this review, we discussed the application of metabolomics in several ocular diseases and recent developments in metabolomics regarding tear fluids analysis, data acquisition and processing.

Availability and variability in guidelines on diabetic retinopathy screening in Asian countries.

BACKGROUND: Diabetic retinopathy (DR) is a blinding yet treatable complication of diabetes. DR screening is highly cost-effective at reducing blindness. Amidst the rapidly growing diabetic population in Asia, the prevalence of DR in the region is relatively less well known. AIMS: To review existing national DR screening guidelines of 50 countries in Asia, compare them against the International Council of Ophthalmology (ICO) guideline, and summarise the prevalence rates of DR and sight-threatening DR (STDR) in these countries. METHODS: We systematically searched for published guidelines from the National Guideline Clearinghouse and other databases, and contacted local diabetic and ophthalmological associations of all 50 Asian countries. RESULTS: Eleven Asian countries have published relevant guidelines, nine of which pertain to general diabetes care and two are DR-specific, covering less than half of Asia's population. The median DR prevalence among patients with diabetes is 30.5% (IQR: 23.2%-36.8%), similar to the USA and the UK. However, rates of STDR are consistently higher. All guidelines from the 11 Asian countries fulfil the ICO standard on when to start and repeat screening, except for screening interval for pregnant patients. However, only 2 of the 11 guidelines fulfil the ICO referral criteria and 6 partially fulfil. A third of the recommendations on screening process, equipment and personnel is either unavailable or incomplete. CONCLUSIONS: Countries in Asia need to establish more comprehensive and evidence-based DR screening guidelines to facilitate the execution of robust screening programmes that could help reduce DR-related blindness, improve patient outcomes and reduce healthcare costs.