Targeted Photodynamic Therapy using a Vectorized Photosensitizer coupled to Folic Acid Analog induces Ovarian Tumor Cell Death and inhibits IL-6-mediated Inflammation.

Ovarian cancer (OC) is one of the most lethal cancers among women. Frequent recurrence in the peritoneum due to the presence of microscopic tumor residues justifies the development of new therapies. Indeed, our main objective is to develop a targeted photodynamic therapy (PDT) treatment of peritoneal carcinomatosis from OC to improve the life expectancy of cancer patients. Herein, we propose a targeted-PDT using a vectorized photosensitizer (PS) coupled with a newly folic acid analog (FAA), named PSFAA, in order to target folate receptor alpha (FRα) overexpressed on peritoneal metastasis. This PSFAA was the result of the coupling of pyropheophorbide-a (Pyro-a), as the PS, to a newly synthesized FAA via a polyethylene glycol (PEG) spacer. The selectivity and the PDT efficacy of PSFAA was evaluated on two human OC cell lines overexpressing FRα compared to fibrosarcoma cells underexpressing FRα. Final PSFAA, including the synthesis of a newly FAA and its conjugation to Pyro-a, was obtained after 10 synthesis steps, with an overall yield of 19%. Photophysical properties of PSFAA in EtOH were performed and showed similarity with those of free Pyro-a, such as the fluorescence and singlet oxygen quantum yields (Φf = 0.39 and ΦΔ = 0.53 for free Pyro-a, and Φf = 0.26 and ΦΔ = 0.41 for PSFAA). Any toxicity of PSFAA was noticed. After light illumination, a dose-dependent effect on PS concentration and light dose was shown. Furthermore, a PDT efficacy of PSFAA on OC cell secretome was detected inducing a decrease of a pro-inflammatory cytokine secretion (IL-6). This new PSFAA has shown promising biological properties highlighting the selectivity of the therapy opening new perspectives in the treatment of a cancer in a therapeutic impasse.

Extracellular vesicles derived from nasopharyngeal carcinoma induce the emergence of mature regulatory dendritic cells using a galectin-9 dependent mechanism.

Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.

Folate Receptor Targeted Photodynamic Therapy: A Novel Way to Stimulate Anti-Tumor Immune Response in Intraperitoneal Ovarian Cancer.

Photodynamic therapy (PDT) has shown improvements in cancer treatment and in the induction of a proper anti-tumor immune response. However, current photosensitizers (PS) lack tumor specificity, resulting in reduced efficacy and side effects in patients with intraperitoneal ovarian cancer (OC). In order to target peritoneal metastases of OC, which overexpress folate receptor (FRα) in 80% of cases, we proposed a targeted PDT using a PS coupled with folic acid. Herein, we applied this targeted PDT in an in vivo mouse model of peritoneal ovarian carcinomatosis. The efficacy of the treatment was evaluated in mice without and with human peripheral blood mononuclear cell (PBMC) reconstitution. When mice were reconstituted, using a fractionized PDT protocol led to a significantly higher decrease in the tumor growth than that obtained in the non-reconstituted mice (p = 0.0469). Simultaneously, an immune response was reflected by an increase in NK cells, and both CD4+ and CD8+ T cells were activated. A promotion in cytokines IFNγ and TNFα and an inhibition in cytokines TGFß, IL-8, and IL-10 was also noticed. Our work showed that a fractionized FRα-targeted PDT protocol is effective for the treatment of OC and goes beyond local induction of tumor cell death, with the promotion of a subsequent anti-tumor response.

A Warp-Knitted Light-Emitting Fabric-Based Device for In Vitro Photodynamic Therapy: Description, Characterization, and Application on Human Cancer Cell Lines.

Photodynamic therapy (PDT) appears to be a promising strategy in biomedical applications. However, the complexity of its parameters prevents wide acceptance. This work presents and characterizes a novel optical device based on knitted light-emitting fabrics and dedicated to in vitro PDT involving low irradiance over a long illumination period. Technical characterization of this device, called CELL-LEF, is performed. A cytotoxic study of 5-ALA-mediated PDT on human cancer cell lines is provided as a proof of concept. The target of delivering an irradiance of 1 mW/cm2 over 750 cm2 is achieved (mean: 0.99 mW/cm2; standard deviation: 0.13 mW/cm2). The device can maintain a stable temperature with the mean thermal distribution of 35.1 °C (min: 30.7 °C; max: 38.4 °C). In vitro outcomes show that 5-ALA PDT using CELL-LEF consistently and effectively induced a decrease in tumor cell viability: Almost all the HepG2 cells died after 80 min of illumination, while less than 60% of U87 cell viability remained. CELL-LEF is suitable for in vitro PDT involving low irradiance over a long illumination period.

La Psychologie de la forme / The Psychology of Form

A teoria da Forma (Gestalttheorie)4 é, ao mesmo tempo, uma filosofia e uma psicologia. Por um lado, ela introduz as noções de forma ou de estrutura, tanto na interpretação do mundo físico quanto do mundo biológico e mental; ela estabelece a conexão de fatos que as concepções tradicionais separam e funda, sobre essas aproximações, uma filosofia monista da natureza. Por outro lado, aplica essas mesmas noções, no domínio especial da psicologia, a problemas determinados e concretos. Quer libertar essa ciência de certos quadros tradicionais, que limitaram os seus horizontes e afastaram-se da realidade e da vida. Mas sua orientação permanece científica; seus fundamentos são, antes de tudo, experimentadores habituados a pedir, a observações exatas e minuciosas, o controle de suas hipóteses mais ousadas. Seria, pois, fazer a mais falsa idéia dessa teoria &­ e esse erro foi cometido, por vezes &­ nela ver uma pura especulação filosófica, e crer que seu interesse se limita à exploração, por meio de uma nova linguagem, de certas analogias, muito gerais, entre diversas classes de fatos. Para compreendê-la e julgá-la, ser-nos-á necessário &­ dentro dos limites que se impõem pelas dimensões desse livro &­ seguir os autores no seu laboratório e assistir a alguns de seus experimentos. Aliás, qualquer que seja a sorte futura da teoria, os fatos novos que terá divulgado permanecerão, as idéias experimentais conservarão seu interesse. O papel de uma teoria não provém unicamente da inteligibilidade que introduz nos fatos conhecidos, mas também do seu valor heurístico e da sua fecundidade na pesquisa. A teoria da Forma surgiu na Alemanha, nos princípios do século XX. Veremos, mais adiante, a que crise havia conduzido, naquela época, a evolução de uma psicologia orientada, desde meio século, para a análise. Por toda parte sentia-se a necessidade de novos princípios. A reconhecida insuficiência da teoria dos elementos fazia reclamar uma psicologia dos conjuntos, das estruturas, das formas; esse programa era comum a várias escolas. Mas nosso objetivo não é fazer a história desse movimento. Limitaremos nossa exposição a uma dessas escolas, a que nos pareceu a mais interessante, tanto pela homogeneidade de sua doutrina, como pela importância de sua contribuição experimental, aquela que na Alemanha se chama escola de Berlim, ilustrada pelos nomes de Wertheimer, de Köhler, de Koffka, de Lewin. Deixaremos para indicar, se houver ocasião, os pontos em que assentam as diferenças entre as escolas.

International comparison of orthotic brace prices.

This study compared market prices (i.e. third-party reimbursement and patient co-payment) of prefabricated neck, wrist and knee braces in Belgium, France, the Netherlands, Ontario (Canada) and the UK. Data were collected through contacts with health authorities, health insurance funds, manufacturers and distributors. Market prices varied substantially between countries, indicating that manufacturers adapt their price setting strategy to the policy environment and the structure of the brace market of a country. Belgian prices tended to exceed prices in other countries for the selected neck, wrist and knee braces. There seems to be scope for reducing Belgian prices of selected braces.

Reforming the Belgian market for orthotic braces: what can we learn from the international experience?

OBJECTIVES: This article aims to review regulation governing outpatient orthotic braces (neck, wrist and knee braces) in France, the Netherlands and Sweden with a view to reforming the Belgian market. METHODS: Information about the regulatory framework was derived from an analysis of legal texts and a survey completed by national experts. RESULTS: Strategies to keep down prices include public procurement in Sweden, maximum prices in France, and exclusion of expensive braces from reimbursement in the Netherlands. Reimbursement is linked to a medical indication or a chronic condition in France, the Netherlands and Sweden. To gain reimbursement, the cost-effectiveness of orthotic braces needs to be demonstrated in France and the Netherlands. Orthotic braces tend to be initially prescribed by a specialist physician and distributed by orthotists, medical equipment shops and/or community pharmacies. CONCLUSIONS: Extensive government intervention exists in the outpatient orthotic brace market in the countries studied. Our recommendations to reform the Belgian market for prefabricated orthotic braces are to separate reimbursement for service provision from reimbursement for braces; to set prices by means of a tendering process or an international price comparison; and to make reimbursement conditional on effectiveness and cost-effectiveness of braces.

Do tariffs and prices correspond with costs? A case study of orthotic braces.

OBJECTIVES: The Belgian third-party payer wishes to set reimbursement tariffs at a level that reflects the costs of orthotic braces. This article aims to calculate production and distribution costs of a prefabricated hard neck and knee brace and to explore whether Belgian tariffs and actual retail prices correspond with estimated costs of these two braces. METHODS: The cost model considered manufacturing costs, general overheads, research and development costs, warehousing costs, profit and distribution margins. Data were gathered from manufacturers, a production site visit, desk research, a decomposition of finished products and stakeholder interviews. The price year was 2007. RESULTS: The cost model estimated a retail price of euro55-euro150 for the neck brace, depending on assumptions. The estimated retail price for the neck brace was lower than the reimbursement tariff of euro194 and the actual retail price of euro241. The estimated retail price of euro331-euro694 for the knee brace was lower than the actual retail price of euro948. CONCLUSIONS: Actual retail prices and reimbursement tariffs for a neck brace and a knee brace exceeded prices based on estimated costs. Therefore, there appears to be scope for reducing tariffs.

Manual de psicología

Este libro, equilibrado, puede considerarse como un espejo recomendable de la psicología general. El autor toma partido frente a las exageraciones de ciertos conductistas (sin dejar de compartir con ellos muchos puntos de vista) y se coloca en la vereda de enfrente de la fenomenología, en particular la francesa, que según él no aporta al desarrollo de la psicología, otra cosa que arriesgadas dialécticas