Activity

To evaluate the safety and efficacy of transepithelial corneal cross-linking in comparison with the established epithelium-off technique for corneal ectasia.

Considerable debate exists regarding whether transepithelial and epithelium-off cross-linking are comparable in their safety and efficacy.

We searched 16 electronic databases, including Medline, Embase, Web of Science, and the grey literature, current to July 8, 2020, for randomized controlled trials comparing transepithelial and epithelium-off cross-linking for corneal ectasia. We excluded studies evaluating cross-linking for nonectatic indications, as well as non-randomized controlled trials. Our primary outcome was the change in maximal keratometry (K

) at 12 months after cross-linking, and we considered additional topographic, visual, and safety outcomes. We summarized our analyses by calculating weighted mean differences (MDs) with associated 95% confidence intervals (CIs) for continuous outcomes and relative risks (RRs) with corresponding 95th significantly fewer complications than the epithelium-off approach (RR, 0.22; 95% CI, 0.06-0.79; P= 0.020), although it was associated with an increased rate of disease progression at 12 months after treatment (RR, 4.49; 95% CI, 1.24-16.25; P= 0.022). Selleck Primaquine The required information size was met for our primary outcome and trial sequential analysis supported the conventional meta-analysis. The quality of evidence was rated as moderate using the Grading of Recommendations Assessment, Development, and Evaluation methodology.

The efficacy of transepithelial cross-linking remains inferior to the epithelium-off approach, although it is significantly safer.

The efficacy of transepithelial cross-linking remains inferior to the epithelium-off approach, although it is significantly safer.To sustain their proliferative and metastatic capacity, tumor cells increase the activity of energy-producing pathways and lysosomal compartment, resorting to autophagolysosomal degradation when nutrients are scarce. Consequently, large fragile lysosomes and enhanced energy metabolism may serve as targets for anticancer therapy. A simultaneous induction of energy stress (by caloric restriction and inhibition of glycolysis, oxidative phosphorylation, Krebs cycle, or amino acid/fatty acid metabolism) and lysosomal stress (by lysosomotropic detergents, vacuolar ATPase inhibitors, or cationic amphiphilic drugs) is an efficient anti-cancer strategy demonstrated in a number of studies. However, the mechanisms of lysosomal/energy stress co-amplification, apart from the protective autophagy inhibition, are poorly understood. We here summarize the established and suggest potential mechanisms and candidates for anticancer therapy based on the dual targeting of lysosomes and energy metabolism.

B cells play an important role in allergies through secretion of IgE. IL-4 receptor α (IL-4Rα) is key in allergic asthma and regulates type 2 cytokine production, IgE secretion, and airway hyperresponsiveness. IL-4 activation of B cells is essential for class switching and contributes to the induction of B effector 2 (Be2) cells. The role of Be2 cells and signaling via IL-4Rα in B cells is not clearly defined.

We sought to find out whether IL-4Rα-responsive B cells or Be2 function was essential in experimental allergic asthma.

Mice lacking IL-4Rα on B cells (mb1

IL-4Rα

) or littermate controls (IL-4Rα

) and mice lacking IL-4 or IL-4/IL-13 on B cells were sensitized and challenged with high-dose house dust mite (>10 μg) or with low-dose house dust mite (<3 μg). We also adoptively transferred naive IL-4Rα

or IL-4Rα

B cells into μMT

mice a day before sensitization or a day before challenge. We analyzed lung inflammation, cellular infiltrate, and airway hyperresponsiveness.

We found that IL-4Rα signaling on B cells was important for optimal T

2 allergic immune responses mainly when the load of antigen is limited. IL-4Rα signaling on B cells was essential for germinal centers and in the effector phase of allergic responses. Be2 cells were essential in airway hyperresponsiveness, but not in other parameters.

IL-4Rα signaling on B cells is deleterious in allergic asthma because it is required for optimal T

2 responses, Be2 function, germinal center formation, and Tfollicular helper cells, especially when the load of the antigen is limiting.

IL-4Rα signaling on B cells is deleterious in allergic asthma because it is required for optimal TH2 responses, Be2 function, germinal center formation, and T follicular helper cells, especially when the load of the antigen is limiting.Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance.