Pufendorf, Samuel

During the last two decades, Samuel von Pufendorf’s (1632–1694) natural law philosophy has become the subject of renewed and growing attentiveness among intellectual historians and philosophers (Seidler 2015). In the late-seventeenth century and early eighteenth century, Pufendorf was the most widely-read moral and political philosopher in Europe, whose reputation is most clearly exemplified in the impressive number of translations and editions of his works. Pufendorfian natural law theory offered a shared vocabulary and conceptual possibilities for the discussion of morality, politics and interstate relations for numerous eighteenth-century thinkers, such as Christian Thomasius, the authors of the Scottish Enlightenment and Jean-Jacques Rousseau. Pufendorf spent large parts of his career in princely courts and portrayed the history of states and their natural law foundations in his widely circulated historical works (Seidler 1997). Moreover, he also wrote on the issues of theology and church-state relations (Döring 1992, Zurbuchen 1998).Peer reviewe

Virus-like Particle (VLP) Vaccines for Cancer Immunotherapy

Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer

Transient expression of reck under hepatic ischemia/reperfusion conditions is associated with mapk signaling pathways

In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). Male Wistar rats were either subjected to 60 min partial-hepatic ischemia or sham-operated. After a 60 min or 120 min reperfusion, liver samples were collected for analysis of MMP-2 and MMP-9 by zymography and RECK, TIMP-1, and TIMP-2 content, MAPKs activation (ERK1/2, JNK1/2, and p38), as well as iNOS and eNOS by Western blot. Serum enzymes AST, ALT, and alkaline-phosphatase were quantified. A transitory decrease in hepatic RECK and TIMPs was associated with a transitory increase in both MMP-2 and MMP-9 activity and a robust activation of ERK1/2, JNK1/2, and p38 were detected at 60 min reperfusion. Hepatic expression of iNOS was maximally upregulated at 120 min reperfusion. An increase in eNOS was detected at 120 min reperfusion. I/R evoked significant hepatic injury in a time-dependent manner. These findings provide new insights into the underlying molecular mechanisms of reperfusion in inducing hepatic injury: a transitory decrease in RECK and TIMPs and increases in both MAPK and MMP activity suggest their role as triggering factors of the organ dysfunction

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.Leukemia advance online publication, 2 August 2016; doi:10.1038/leu.2016.191

Tecnologia de aplicação de agrotóxicos.

o sistema de produção de uvas praticado atualmente é altamente dependente da aplicação de agrotóxicos. Em regiões como o Norte e Noroeste do Paraná, onde não existe um período de chuvas bem definidos e com o inverno apresentando temperaturas altas e com dois ciclos de produção no ano (safra e safrinha), há um clima ideal para o desenvolvimento de doenças, exigindo dos produtores muitas aplicações de fungicidas durante o ano. Nas regiões caracterizadas por clima temperado, onde ocorre a dormência das plantas durante o inverno, o desenvolvimento vegetativo inicia nos meses de agosto e setembro, portanto, em época sujeita a temperaturas noturnas baixas. Esta condição é desfavorável ao desenvolvimento de fungos e ocorre menor necessidade de aplicações em função da menor pressão de inóculo de doenças.Programa de Desenvolvimento da Cadeia Produtiva de Vinhos, Espumantes e Suco de Uva - PAS

Tecnologia de aplicação de agrotóxicos.

O sistema de produção de uvas praticado atualmente é altamente dependente da aplicação de agrotóxicos. Em regiões como o Norte e o Noroeste do Paraná, onde não existe um período de chuvas bem definido e o inverno apresenta temperaturas altas, com dois ciclos de produção no ano (safra e safrinha), há um clima ideal para o desenvolvimento de doenças, exigindo dos produtores muitas aplicações de fungicidas durante o ano. Em regiões caracterizadas por clima temperado, onde ocorre a dormência das plantas durante o inverno, inicia o desenvolvimento vegetativo inicia nos meses de agosto e setembro, portanto, as cultivares ficam sujeitas a temperaturas noturnas baixas, condição desfavorável ao desenvolvimento de fungos. Assim, ocorre menor necessidade de aplicações em função da menor pressão de inóculo de doenças. Em regiões tropicas com clima definido de período chuvoso durante o verão e inverno seco, com necessidade de água suplementada por irrigação, as cultivares vegetam durante todo ano com sistema de produção dividido em podas de formação de ramos ou em poda curta e poda de produção ou longa, todas realizadas de forma escalonada, o que permite a colheita de uvas durantes os meses de julho a novembro. Essa prática, que viabiliza a vitivinicultura em regiões de cerrado, mantém a pressão de inóculo em níveis elevados, havendo a necessidade de tratamento fitossanitário durante todo o ano. Além do elevado uso de agrotóxicos, muitas vezes os produtores não se preocupam em conhecer os aspectos tecnológicos relacionados à aplicação de produtos para o controle de pragas, doenças e plantas daninhas. A qualidade da tecnologia de aplicação de agrotóxicos é de extrema importância, por envolver o uso de substâncias tóxicas, normalmente perigosas a saúde humana e ao ambiente.bitstream/item/153022/1/Manual-4-1-Capitulo-4.pd

Pomalidomide and dexamethasone grant rapid haematologic responses in patients with relapsed and refractory AL amyloidosis: a European retrospective series of 153 patients

Pomalidomide demonstrated activity in the treatment of AL amyloidosis in three phase II clinical trials. We evaluated the safety and efficacy of 28-day cycles of pomalidomide and dexamethasone in 153 previously treated patients with systemic AL amyloidosis. Ninety-nine (65%) were refractory to the last line of therapy and 54 (35%) had relapsed. The median number of previous lines of therapy was 3 (range: 2–7): 143 patients (93%) previously received bortezomib, 124 (81%) lenalidomide, 114 (75%) oral melphalan, and 37 (24%) underwent autologous stem cell transplant. At the completion of cycle 6, 68 (44%) patients obtained at least partial haematologic response, with 5 complete responses (CR, 3%), 35 very good partial responses (VGPR, 23%). Haematologic response resulted in improved overall survival (median survival 50 vs. 27 months, p = .033) in a 6 months landmark analysis. Obtaining at least partial response was also associated with a significant improvement of the progression-free survival (median PFS 37 vs. 18 months, p < .001). Pomalidomide is an effective treatment for heavily pre-treated patients with AL amyloidosis. Haematologic responses are associated with an overall survival advantage