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Introduction: Ageing population is a great challenge for modern societies which have to adapt themselves to this new reality. Increasing longevity and low birth rates also contribute to an aged population, with implications both socially and economically. With increased longevity, people live more years after retirement and should be more prepared to deal with the difficulties that can arise from this transition. Retirement is one of the major transitions in adult life and it can originate different kind of vulnerabilities. If it difficult to retire alone, it can be even more difficult when it happens as a couple. Objective: The project REATIVA is a Portuguese project funded by the European Union and the Portuguese government which has as goal to promote health during the transition to retirement. We aimed to know the perceptions of couples who experience adaptation to the retirement process and the strategies adopted to address them. Methodology: The research team conducted a descriptive study of a qualitative nature. The target population was couples in which at least one of their spouses was retired for less than five years, registered in health care providers in Primary Health Care of the Regional Health Administration Center. The selected participants were subjected to an approach for semi-structured interview, after signing informed consent, and the information was gathered by digital audio recording and subjected to thematic analysis using the NVivo10® program. Results: The following themes were revealed: Before retirement, Moment of retirement, Today's experience, Expectations for the future and Recommendations for future intervention with couples. The theme before retirement presented two subthemes: expectations and idealizations and marital dynamics. Regarding the moment of retirement, the three sub-themes that emerged were: perceived changes, resources used and vulnerabilities. The theme of today's experience consisted of portraits of conjugality, resources and vulnerabilities of this moment of ...

Bovine Serum Albumin (BSA) nanoemulsions were produced by high pressure homogenization with a tri-block copolymer (Poloxamer 407), which presents a central hydrophobic chain of polyoxypropylene (PPO) and two identical lateral hydrophilic chains of polyethylene glycol (PEG). We observed a linear correlation between tri-block copolymer concentration and size - the use of 5 mg/mL of Poloxamer 407 yields nanoemulsions smaller than 100 nm. Molecular dynamics and fluorescent tagging of the tri-block copolymer highlight their mechanistic role on the size of emulsions. This novel method enables the fabrication of highly stable albumin emulsions in the nano-size range, highly desirable for controlled drug delivery. Folic Acid (FA)-tagged protein nanoemulsions were shown to promote specific Folate Receptor (FR)-mediated targeting in FR positive cells. The novel strategy presented here enables the construction of size controlled, functionalized protein-based nanoemulsions with excellent characteristics for active targeting in cancer therapy. ; European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement NMP4-LA-2009-228827 NANOFOL. This work was supported by FEDER through POFC – COMPETE and by Portuguese funds from FCT through the project PEst-OE/BIA/UI4050/2014. The authors also thank the FCT Strategic Project of UID/BIO/04469/2013 ...

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).

Frontmatter -- Contents -- List of Figures and Tables -- Contributors -- Foreword- Critical Theory, Globalization, and Higher Education: Political Economy and the Cul-de-Sac of the Postmodernist Cultural Turn -- PART ONE Theoretical and Conceptual Underpinnings -- I. Introduction: Globalization and Higher Education in the Americas -- 2. A World Without War -- 3. The University in the 21st Century: Toward a Democratic and Emancipatory University Reform -- PART TWO Findings from Particular Countries and Regions in the Americas -- 4. Academic Capitalism and the New Economy: Privatization as Shifting the Target of Public Subsidy in Higher Education -- 5. Reforming the Reforms: Transformation and Crisis in Latin American and Caribbean Universities -- 6. Globalization and the Challenge to National Universities in Argentina and Mexico -- 7. Latin American Identities in Transition: A Diagnosis of Argentine and Brazilian Universities -- 8. Brazil's Local Solutions to Global Problems -- 9. Mexico's Estimulos: Faculty Compensation Based on Piecework -- 10. Graduate Student Unionization as a Postindustrial Social Movement: Identity, Ideology, and the Contested US Academy -- PART THREE Concluding Analyses -- 11. The Political Economy of Higher Education in the Time of Global Markets: Whither the Social Responsibility of the University? -- 12. The Global Economy, the State, Social Movements, and the University: Concluding Remarks and an Agenda for Action -- Index

Background Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status. ; European Union (FEDER funds through Programa Operacional Factores de Competitividade – COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) through the projects UID/QUI/50006/2019, COMPETE 2020 (POCI-01-0145-FEDER-006684/POCI-01-0145-FEDER-007440) and the BioTecNorte operation (NORTE-01-0145-FEDER-000004), (3599-PPCDT) PTDC/DTP-FTO/1981/2014 – POCI-01-0145-FEDER-016581 and UID/QUI/0081/2013; the Italian Association for Cancer Research, AIRC (IG#5506 to G.F.), Compagnia S. Paolo, Turin, Italy (Project 2017.0526 to G.F.) and Ministry of Health, (Project 5 × 1000, 2013 and 2015; ...

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 structural mutp53. 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. ; 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 ...

Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor . These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance. ; Eugenia Nogueira (SFRH/BD/81269/2011), Ana Loureiro (SFRH/BD/81479/2011) and Catarina Almeida (SFRH/BPD/48533/2008) hold scholarships from Fundacao para a Ciencia e a Tecnologia (FCT). Goncalo J. L. Bernardes is a Royal Society University Research Fellow at the Department of Chemistry, University of Cambridge and an Investigador FCT at the Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa. This study was funded by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement NMP4-LA-2009-228827 NANOFOL. This study was also supported by FEDER through POFC-COMPETE, by national funds from FCT through the ...

Specific folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. Directed folate receptor targeting using liposomes is usually achieved using folate linked to a phospholipid or cholesterol anchor. This link is formed using a large spacer like polyethylene glycol. Here, we report an innovative strategy for targeted liposome delivery that uses a hydrophobic fragment of surfactant protein D linked to folate. Our proposed spacer is a small 4 amino acid residue linker. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity, with high stability and specificity. To compare the drug delivery potential of both liposomal targeting systems, we encapsulated the nuclear dye Hoechst 34580. The eventual increase in blue fluorescence would only be detectable upon liposome disruption, leading to specific binding of this dye to DNA. Our delivery system was proven to be more efficient (2-fold) in Caco-2 cells than classic systems where the folate moiety is linked to liposomes by polyethylene glycol. ; Eugenia Nogueira (SFRH/BD/81269/2011) and Ana Loureiro (SFRH/BD/81479/2011) hold scholarships from Fundacao para a Ciencia e a Tecnologia (FCT). Goncalo J. L. Bernardes is a Royal Society University Research Fellow at the Department of Chemistry, University of Cambridge and an Investigador FCT at the Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa. This study was funded by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement NMP4-LA-2009-228827 NANOFOL. The authors thank the FCT Strategic Project of UID/BIO/04469/2013 unit, the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and the Project "BioHealth - Biotechnology and Bioengineering approaches to improve health quality", Ref. NORTE-07-0124-FEDER-000027, co-funded by the Programa Operacional Regional do Norte (ON.2 - O Novo Norte), QREN, FEDER. This work was also supported by FCT I.P. through the strategic ...