LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer

[Background]: Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood.[Methods]: LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-β) signaling.[Results]: We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-β signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-β type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells.[Conclusions]: We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.This work was supported by: Marie Curie IF (H2020-MSCA-IF-2015, #703753), My First AIRC Grant (MFAG-2017, #20206), POR Campania FESR 2014/2020 (Project SATIN) to E.L.; AIRC IG grant 2018 n.21420 to A.D.L.; FIMP to D.D.C.; AECC (Proye18046BATL_002) to E.B.; My First AIRC Grant (MFAG grant #23029), WorldWide Cancer Research (Research grant #20–0188), EASI Genomics consortium (TNA project #15158) and the World Cancer Research Fund (Seed grant #2021–1769) to A.C

The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use

Ketamine was originally synthesised for use as a dissociative anaesthetic, and it remains widely used legitimately for this indication. However, there is increasing evidence of non-medical recreational use of ketamine, particularly in individuals who frequent the night-time economy. The population-level and sub-population (clubbers) prevalence of recreational use of ketamine is not known but is likely to be similar, or slightly lower than, that of other recreational drugs such as cocaine, MDMA, and amphetamine

Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia

We searched PubMed, Scopus, Web of Science, LILACS, EMBASE, and Cochrane Library databases to assess the effectiveness and safety of 5% imiquimod cream in the treatment of vulvar and vaginal. intraepithetial neoplasia. From the results of the 17 relevant articles identified (1 reported on a randomized controlled trial, 10 reported on case series, and 6 were case reports), 26% to 100% of patients had complete regression, 0% to 60% had partial regression, and 0% to 37% experienced recurrence. The most common adverse events were local burning and soreness, but not severe enough for patients to discontinue treatment. From these reports imiquimod treatment leads to complete response in a considerable percentage of patients, and those who experience partial response will require less extensive excision. Treating vulvar and vaginal intraepithelial neoplasia with 5% imiquimod cream therefore appears to be promising. (C) 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved