change produced by the treatment. However, clinicians should advise their patients to refrain from, at least to some extent, consuming coffee after the bleaching procedure to maintain the effectiveness of the treatment. The development of the cerebral cortex depends on numerous parameters, including extracellular cues and microenvironmental factors that also affect gene expression. C-Terminal Binding Proteins (CtBPs) 1 and 2 are transcriptional co-repressors which have been shown to be critically involved in embryonic development. CtBPs are oxygen sensing molecules, and we have previously demonstrated an important role for CtBP1 in integrating oxygen levels and BMP-signaling to influence neural progenitor fate choice. In turn, CtBP2 has been associated with neurodevelopment and neurological disease, and we have shown that CtBP2 acetylation and dimerization, required for proper transcriptional activity, are regulated by microenvironmental oxygen levels. Yet, the putative function of CtBP2 in mammalian cortical development and neurogenesis in vivo is still largely unknown. Here we show that CtBP2 was widely expressed by neural stem and progenitor cells (NSPCs) as well as neurons during cortical development in mice. By using in utero electroporation of siRNA to reduce the levels of CtBP2 mRNA and protein in the developing mouse brain, we found that the NSPC proliferation and migration were largely perturbed, while glial differentiation under these conditions remained unchanged. Our study provides evidence that CtBP2 is required for the maintenance and migration of the NSPCs during mouse cortical development. INTRODUCTION MET TKIs (tyrosine kinase inhibitors) have demonstrated efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than for targeted TKIs of other oncogene-addicted NSCLC. Given the known interplay between MET and PI3K, we hypothesized that in METex14 NSCLC, PI3K-pathway alterations might contribute to primary resistance to MET TKIs. METHODS We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K-pathway alterations by targeted NGS (mutations) and immunohistochemistry (loss of PTEN). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K-pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. RESULTS We found a PIK3CA mutation in 2/65 samples (3%) and loss of PTEN in 6/26 (23%). All three of the MET-TKI-treated patients with a PI3K pathway alteration had shown progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K-pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs.  https://www.selleckchem.com/products/amg510.html  CONCLUSION PI3K-pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs. Perineural infiltration (PNI) and desmoplasia are believed to be high-risk factors in the prognosis of squamous-cell-carcinoma (SCC). In the literature, dependences between PNI, de-differentiation, and desmoplasia remain unclear. The aim of this study was to analyze the respective prognostic impact of these factors in regard to local recurrence and metastasis. Between 2005 and 2015, 1399 unselected primary SCCs of 1434 patients were diagnosed. If a patient had multiple tumours, the tumour with the highest risk profile was selected. Histological sections of all tumours with a tumour thickness of ≥6mm and desmoplastic SCC (dSCC) with a tumour thickness of 2.1-5.9 mm were re-examined for PNI. Median follow-up was 36.5 months. PNI was present exclusively within tumours of the desmoplastic type (14.5%). PNI was significantly more often present in patients developing lymph node metastasis (3% all non-dSCC, 17% dSCC, 29% dSCC with PNI) and local recurrence (3%, 26%, 64%) and associated with overall tumour specific death (4%, 25%, 54%). Using a multivariate model of disease recurrence tumour-thickness ≥ 6 mm, tumour horizontal size ≥ 20 mm, immunosuppression, desmoplasia and PNI remained significant factors. In conclusion, PNI was found to be an additional marker indicative of an unfavorable prognosis and an independent high-risk factor within the desmoplastic type of SCC. Netherthon syndrome (NS) is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding Lymphoepithelial Kazal-Type-related Inhibitor (LEKTI) that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7 and KLK14. While the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to NS pathogenesis remain unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice showed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14 mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley's layer. Dsg2 staining was increased while Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves rhDSG3 and rhDSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of Il-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in NS. Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM).