Search

It is unknown which posttranscriptional regulatory mechanisms are required for oncogenic competence. Here, we show that the LIN28 family of RNA-binding proteins (RBPs), which facilitate posttranscriptional RNA metabolism within ribonucleoprotein networks, is essential for the initiation of diverse oncotypes of hepatocellular carcinoma (HCC). In HCC models driven by NRASG12V/Tp53, CTNNB1/YAP/Tp53, or AKT/Tp53, mice without Lin28a and Lin28b were markedly impaired in cancer initiation. We biochemically defined an oncofetal regulon of 15 factors connected to LIN28 through direct mRNA and protein interactions. Interestingly, all were RBPs and only 1 of 15 was a Let-7 target. Polysome profiling and reporter assays showed that LIN28B directly increased the translation of 8 of these 15 RBPs. As expected, overexpression of LIN28B and IGFBP1-3 was able to genetically rescue cancer initiation. Using this platform to probe components downstream of LIN28, we found that 8 target RBPs were able to restore NRASG12V/Tp53 cancer formation in Lin28a/Lin28b-deficient mice. Furthermore, these LIN28B targets promote cancer initiation through an increase in protein synthesis. LIN28B, central to an RNP regulon that increases translation of RBPs, is important for tumor initiation in the liver.

Angiogenesis plays a key role in cancer progression, including transition to the metastatic phase via reactive oxygen species (ROS)-dependent pathways, among others. Antivascular endothelial growth factor (VEGF) antibodies have been trialed as an anti-angiogenic therapy for cancer but are associated with high cost, limited efficacy, and side effects. Cerium oxide nanoparticles (nanoceria) are promising nanomaterials for biomedical applications due to their ability to modulate intracellular ROS. Nanoceria can be produced by a range of synthesis methods, with chemical precipitation as the most widely explored. It has been reported that chemical precipitation can fine-tune primary particle size where a limited number of synthesis parameters were varied. Here, we explore the effect of temperature, precipitating agent concentration and rate of addition, stirring rate, and surfactant concentration on nanoceria primary particle size using a fractional factorial experimental design approach. We establish a robust synthesis method for faceted nanoceria with primary particle diameters of 5-6 nm. The nanoceria are not cytotoxic to a human melanoma cell line (Mel1007) at doses up to 400 μg/mL and are dose-dependently internalized by the cells. The intracellular ROS level for some cells that internalized the nanoceria is reduced, which correlates with a dose-dependent reduction in angiogenic gene expression including VEGF. These findings contribute to our knowledge of the anti-angiogenic effects of nanoceria and help to develop our understanding of potentially new anti-angiogenic agents for combination cancer therapies.

The aim of this study was to probe whether the transferrin (Tf) transport pathway can be exploited for intestinal delivery of nanoparticles. Tf was adsorbed on 100 nm model polystyrene nanoparticles (NP), followed by size characterisation of these systems. Cell uptake of Tf and Tf-adsorbed NP was investigated in intestinal epithelial Caco-2 cells cultured on multi-well plates and as differentiated polarised monolayers. Tf-NP demonstrated a remarkably higher cell uptake compared to unmodified NP in both non-polarised (5-fold) and polarised cell monolayers (16-fold difference). Application of soluble Tf significantly attenuated the uptake of Tf-NP. Notably, Tf-NP displayed remarkably higher rate (23-fold) of epithelial transport across Caco-2 monolayers compared to unmodified NP. This study therefore strongly suggests that the Tf transport pathway should be considered as a candidate biological transport route for orally-administered nanomedicines and drugs with poor oral bioavailability.

Objective: Antibiotic treatment is the standard of care for tympanostomy tube otorrhea. This meta-analysis aims to evaluate the efficacy of topical antibiotics with or without corticosteroids versus oral antibiotics in the treatment of tube otorrhea in children., Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and ProQuest., Review Methods: The above databases were searched using a search strategy for randomized controlled trials for optimal treatment of tube otorrhea in the pediatric population. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were followed. Primary outcome was cure (i.e. clearance of otorrhea) at 2-3 weeks. Secondary outcomes were microbiological eradication and complications such as dermatitis and diarrhea. The incidence of these events was defined as dichotomous variables and expressed as a risk ratio (RR) and number needed to benefit (NNTB) in a random-effects model., Results: We identified 1491 articles and selected 4 randomized controlled trials which met our inclusion criteria. Topical treatment had better cure (NNTB = 4.7, pooled RR = 1.35, p < 0.001) and microbiological eradication (NNTB = 3.5, pooled RR = 1.47, p < 0.001 among 3 of the studies) than oral antibiotics. Oral antibiotics had higher risk of diarrhea (pooled RR = 21.5, 95% CI 8.00-58.0, p < 0.001, Number needed to harm (NNTH) = 5.4) and dermatitis (pooled RR = 3.14, 95% CI 1.20-8.20, p = 0.019, NNTH = 32). The use of topical steroids in addition to topical antibiotics was associated with a higher cure rate (pooled RR = 1.59, p < 0.001 vs pooled RR = 1.57, p = 0.293)., Conclusion: Topical antibiotics should be the recommended treatment for management of tympanostomy tube otorrhea in view of its significantly improved clinical and microbiological efficacy with lower risk of systemic toxicity as compared to oral antibiotics. Further research is necessary to confirm the benefits of topical corticosteroids as an adjunct to topical antibiotics., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A very rapid method of agar gel electrophoresis on glass slides, together with a superior visualization technique employing simultaneous coupling of a hydrolysed naphthol substrate, have been developed for the identification of the tissues of origin of serum alkaline phosphatase. Combined with L-phenylalanine inhibition, specific for the intestinal enzyme, and heat inactivation, specific for the placental enzyme, the heterogeneity of serum alkaline phosphatase has been demonstrated. Normal adult serum contains predominantly liver-type alkaline phosphatase with a small but variable quantity of intestinal enzyme, and little or no bone enzyme. In childhood and in infancy there is in addition a bone isoenzyme present, the amount gradually falling to adult levels with age. In pregnancy, the rise in serum alkaline phosphatase is due to the placental enzyme.A study of nearly 2,000 sera has been undertaken and it is found that the bone enzyme is increased in osteoblastic bone diseases while in hepato-biliary disorders there is an increase in liver type enzyme. The main theories explaining the rise in serum alkaline phosphatase are examined.