Highlights d Knockdown of Ptbp1 converts Mu ¨ller glia into retinal ganglion cells in mature retinas d Central projections of converted retinal ganglion cells restore visual responses d Induction of neurons with dopaminergic features in PD model mice

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.

Isoliquiritigenin, which is possibly a principal anti-tumor constituent of licorice, a traditional Chinese herb, was examined for apoptosis-inducing activity in human gastric cancer MGC-803 cells. Typical morphological and biochemical features of apoptosis including cell shrinkage, chromatin condensation, DNA ladder formation, and appearance of apoptotic peaks (subG(1)) were observed in MGC-803 cells with isoliquiritigenin treatment. Using Fluo-3 and Rh123 as fluorescent probes, respectively, it was found that the intracellular free calcium concentration increased and the mitochondrial transmembrane potential (Deltapsi(m)) decreased in a dose-dependent manner in apoptotic cells. These results suggest that isoliquiritigenin induced apoptosis of MGC-803 cells through calcium- and Deltapsi(m)-dependent pathways, indicating that it is potentially useful as a natural anti-cancer agent.

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties.RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine α-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen.

Purpose: The study aim was to investigate the risk factors for the progression of oral leukoplakia (OLK) to malignancy.Patients and Methods: The data from 2,628 patients with OLK were retrospectively reviewed. Of these 2,628 patients, 192 had undergone sequential biopsies and were separated into 4 groups according to their final diagnosis. The risk factors were analyzed using Kaplan-Meier univariate survival analysis and Cox multivariate analysis.Results: In 41 of the 2,628 patients (1.7%), the OLK had progressed to cancer, with a mean interval to malignancy of 26.7 months. Of the 192 patients with sequential biopsies, OLK was maintained or had progressed to mild, moderate, or severe dysplasia or carcinoma in 50, 66, 35, and 41 patients, respectively. The 3-and 5-year oral cancer-free survival (OCFS) was 78.9 and 72.5%, respectively. The factors associated with worse overall survival were lesions located in the ventral tongue (P = .04), alcohol use (P = .025), nonhomogeneous lesions (P < .01), and high-risk dysplasia (P < .01). Cox regression analyses indicated that nonhomogeneous lesions (P = .03) and high-risk dysplasia (P < .01) were independent prognostic factors for the progression of OLK to malignancy.Conclusions: High-risk dysplasia and nonhomogeneous lesions were shown to be important factors for progression to malignancy in patients with OLK. Thus, such patients should receive close follow-up and undergo sequential biopsies in the first 2 to 3 years for early screening of OLK evolving into a malignancy.