Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

Basal cell carcinoma (BCC) of the skin is the most common type of cancer, and accounts for up to 40% of all cancers in the United States with a growing incidence rate in the last decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutical approaches. Furthermore, patients with BCC present an high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render of primary interest the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, it has become evident the critical role of the morphogenic Hedgehog (Hh) pathway. This pathway is found altered and activated in almost all the BCC, both sporadic or inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hedgehog components. Several Hh inhibitors have been so far identified, from the first, the natural cyclopamine to the recently FDA-approved synthetic Vismodegib, most targeting the Hh receptor Smo (either its function or its translocation to the primary cilium). Other molecules await further characterization (Bisamides compounds), while drugs currently approved for other diseases such as Itraconazole (a antimicotic agent) and Vitamin D3 have been tested on BCC with encouraging results. The outcome of the numerous ongoing clinical trials is expected to expand the field in short time. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg Gli) or to exploit combinatorial therapies (eg with PI3K inhibitors, or retinoids) in order to overcome potential drug resistance

The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia - crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 - a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling - as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains. Importantly, we show that both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. Gli proteins are negatively regulated through protein kinase A (PKA)-dependent phosphorylation. We provide evidence that USP21 recruits and stabilises Gli1 at the centrosome where it promotes its phosphorylation by PKA. By revealing an intriguing functional pairing between a spatially restricted deubiquitylase and a kinase, our study highlights the centrosome as an important hub for signal coordination

Geofysisch onderzoek binnen het \u27Nieuwerck\u27 van de kathedraal van Antwerpen (Antwerpen, provincie Antwerpen)

Van 11 tot en met 15 februari 2013 werd door ADEDE bvba in de tuin van het Nieuwerck te Antwerpen een non-destructieve geofysische prospectie uitgevoerd. Deze tuin bevindt zich ten oosten van de Onze-Lieve-Vrouwekathedraal, tussen de Groenplaats, de Melkmarkt en de Lijnwaadmarkt. De totale toegankelijke oppervlakte van het onderzoeksterrein (i. e. vrij van vegetatie) bedroeg 415m². Ondanks een verstoorde (puin)bodem en het versnipperde onderzoeksgebied (bomen, struiken en een vijver) was de inzet van geofysische detectiemethoden zinvol. De grondradar met 200MHz antenne leverde daarbij wel betere resultaten op dan de conductiviteits- en de magnetische susceptibiliteitmetingen met behulp van de EM31-MK2. Binnen het dossier van het Nieuwerck hebben de gekozen geofysische methodes aangetoond dat er een groot aantal structuren in de bodem kunnen geregistreerd worden, ook al is er een hoge graad van verstoring (door heterogene grond met puin). Na uitvoering van de detectie en terugkoppeling met bestaande boorgegevens konden met zekerheid drie en waarschijnlijk twaalf structuren herkend worden, alsook werd er een beeld gevormd van hoe de opbouw van de opvulling van het Nieuwerck in elkaar zit. Door de dikte van de opvulling konden dieperliggende structuren niet vastgesteld worden

Sonic hedgehog medulloblastoma cancer stem cells mirnome and transcriptome highlight novel functional networks

Molecular classification has improved the knowledge of medulloblastoma (MB), the most common malignant brain tumour in children, however current treatments cause severe side effects in patients. Cancer stem cells (CSCs) have been described in MB and represent a sub population characterised by self-renewal and the ability to generate tumour cells, thus representing the reservoir of the tumour. To investigate molecular pathways that characterise this sub population, we isolated CSCs from Sonic Hedgehog Medulloblastoma (SHH MB) arisen in Patched 1 (Ptch1) heterozygous mice, and performed miRNA-and mRNA-sequencing. Comparison of the miRNA-sequencing of SHH MB CSCs with that obtained from cerebellar Neural Stem Cells (NSCs), allowed us to obtain a SHH MB CSC miRNA differential signature. Pathway enrichment analysis in SHH MB CSCs mirnome and transcriptome was performed and revealed a series of enriched pathways. We focused on the putative targets of the SHH MB CSC miRNAs that were involved in the enriched pathways of interest, namely pathways in cancer, PI3k-Akt pathway and protein processing in endoplasmic reticulum pathway. In silico analysis was performed in SHH MB patients and identified several genes, whose expression was associated with worse overall survival of SHH MB patients. This study provides novel candidates whose functional role should be further investigated in SHH MB

Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients' survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a "multifunctional drug". We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species'intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR

Archeologische prospectie met ingreep in de bodem te Stekene - Kerkstraat (prov. Oost-Vlaanderen).

Dit rapport werd ingediend bij het agentschap samen met een aantal afzonderlijke digitale bijlagen. Een aantal van deze bijlagen zijn niet inbegrepen in dit pdf document en zijn niet online beschikbaar. Sommige bijlagen (grondplannen, fotos, spoorbeschrijvingen, enz.) kunnen van belang zijn voor een betere lezing en interpretatie van dit rapport. Indien u deze bijlagen wenst te raadplegen kan u daarvoor contact opnemen met: [email protected]

Archeologisch proefsleuvenonderzoek op de site Kleine Molen te Wevelgem (West-Vlaanderen)

Dit rapport werd ingediend bij het agentschap samen met een aantal afzonderlijke digitale bijlagen. Een aantal van deze bijlagen zijn niet inbegrepen in dit pdf document en zijn niet online beschikbaar. Sommige bijlagen (grondplannen, fotos, spoorbeschrijvingen, enz.) kunnen van belang zijn voor een betere lezing en interpretatie van dit rapport. Indien u deze bijlagen wenst te raadplegen kan u daarvoor contact opnemen met: [email protected]