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Vineyards in the Azores have been traditionally settled on lava field terroirs but the practical limitations of mechanization and high demand on man labor imposed by the typical micro parcel structure of these vineyards contradict the sustainability of these areas for wine production, except under government policies of heavy financial support. Besides the traditional vineyards there are significant areas in some of the islands whose soils, climate and physiographic characteristics suggest a potential for wine production that deserves to be the object of an assessment, with a view to the development of new vineyard areas offering conditions for better management and sustainability. The landscape zoning approach for the present study was based in a geographic information system (GIS) analysis incorporating factors related to climate, topography and soils. Three thermal intervals referred to climate maturity groups were defined and combined with a single slope interval of 0–15 % to exclude the landscape units above this limit. Over this resulting composite grid, the soils were then selectively cartographed through the exclusion of the soil units not fulfilling the suitability criteria. The results show that the thermal interval of warmer conditions, well represented in the traditional terroir of Pico island, has practically no expression in the other islands. However, for the intermediate and the cooler classes, we could map areas of 5611 and 18 115 ha respectively, fulfilling the defined soils and slope criteria, indicating thus the existence of some landscapes in the studied islands revealing adequate potential for future development of viticulture, although certainly demanding a good judgment on the better grape varieties to be adapted to those climatic conditions.

Vineyards in the Azores have been traditionally settled on lava field terroirs but the practical limitations of mechanization and high demand on man labor imposed by the typical micro parcel structure of these vineyards contradict the sustainability of these areas for wine production, except under government policies of heavy financial support. Besides the traditional vineyards there are significant areas in some of the islands whose soils, climate and physiographic characteristics suggest a potential for wine production that deserves to be the object of an assessment, with a view to the development of new vineyard areas offering conditions for better management and sustainability. The landscape zoning approach for the present study was based in a geographic information system (GIS) analysis incorporating factors related to climate, topography and soils. Three thermal intervals referred to climate maturity groups were defined and combined with a single slope interval of 0–15 % to exclude the landscape units above this limit. Over this resulting composite grid, the soils were then selectively cartographed through the exclusion of the soil units not fulfilling the suitability criteria. The results show that the thermal interval of warmer conditions, well represented in the traditional terroir of Pico island, has practically no expression in the other islands. However, for the intermediate and the cooler classes, we could map areas of 5611 and 18 115 ha respectively, fulfilling the defined soils and slope criteria, indicating thus the existence of some landscapes in the studied islands revealing adequate potential for future development of viticulture, although certainly demanding a good judgment on the better grape varieties to be adapted to those climatic conditions.

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCd-selective activator, the 7a-acetoxy-6ß-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCd-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCd-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCd but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCd-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCd-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases. ; We thank European Union (FEDER funds POCI/01/0145/FEDER/007728, FCOMP-01-0124-FEDER-028417 and POCI-01-0145-FEDER-007440, through Programa Operacional Factores de Competitividade—COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/ 04378/2013, UID/NEU/04539/2013, UID/DTP/04567/2016, and the project (3599-PPCDT) PTDC/DTP-FTO/1981/2014—POCI-01-0145-FEDER-016581, as well as Centro 2020 Regional Operational Programmes (CENTRO-01-0145-FEDER-000012: HealthyAging2020). FCT fellowships: SFRH/BD/87109/2012 (C. Bessa), SFRH/BD/117949/2016 (L. Raimundo), and SFRH/BD/128673/2017 (J. B. Loureiro).

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structuralmutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC. ; Funding: This work was supported by National Funds through Fundação para a Ciência e Tecnologia, I.P. via the projects UID/QUI/50006/2019 and PTDC/QUI-QOR/29664/2017. Acknowledgments: Authors acknowledge the financial support from European Union (FEDER funds POCI/01/0145/FEDER/007728 through Programa Operacional Factores de Competitividade—COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement UID/DTP/04138/2019 (iMed.ULisboa), UID/NEU/04539/2013, UID/NEU/04539/2019. CENTRO-01-0145-FEDER-000012-HealthyAging2020, UID/BIO/04469/2019, BioTecNorte operation (NORTE-01-0145-FEDER-000004), and the projects (3599-PPCDT) PTDC/DTP-FTO/1981/2014—POCI-01-0145-FEDER-016581, and POCI-01-0145-FEDER-028736. We also thank FCT for the financial support through the grant CEECIND/01772/2017 (M. M. M. Santos), and fellowships SFRH/BD/96189/2013 (S. Gomes), PD/BD/143126/2019 (V. Barcherini), SFRH/BD/117949/2016 (L. Raimundo), SFRH/BD/119144/2016 (H. Ramos), SFRH/BD/128673/2017 (J. B. Loureiro), and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences; PD/00016/2012). We also acknowledge the support from the Italian Association for Cancer Research, AIRC (IG#18985 to AI).