Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) \u3e3 months (mos), testosterone \u3e150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = \u3c0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = \u3c0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213)

Photoplethysmography for the Assessment of Haemorheology

Haemorheology has been long identified as an early biomarker of a wide range of diseases, especially cardiovascular diseases. This study investigates for the first time the suitability of Photoplethysmography (PPG) as a non-invasive diagnostic method for haemorheological changes. The sensitivity of both PPG components (AC and DC) to changes in haemorheology were rigorously investigated in an in vitro experimental setup that mimics the human circulation. A custom-made reflectance PPG sensor, a pressure transducer and an ultrasonic Doppler flowmeter were used to map changes in flow dynamics and optical responses in an arterial model. The study investigated the effect of shear rates by varying fluid pumping frequencies using 4 set-points and the effect of clot formation using a chemical trigger. Both PPGAC amplitudes and PPGDC levels showed significant (p < 0.001) changes during the increase in shear rates and an immediate change after thromboplastin activation. The findings highlight that PPG has the potential to be used as a simple non-invasive method for the detection of blood characteristics, including disaggregation, radial migration and cross-linking fibrin formations. Such capability will enable the assessment of the effects of clotting-activators and anticoagulants (including non-pharmacological methods) and might aid in the early non-invasive assessment of cardiovascular pathologies

O local e o global na estrutura da política ambiental internacional: a construção social do acidente químico ampliado de Bhopal e da Convenção 174 da OIT The local and the global in the international environmental politics structure: the social construction of the Bhopal major chemical accident and the ILO Convention 174

Neste artigo, adota-se a abordagem construtivista das Relações Internacionais (RI) para analisar o impacto normativo internacional do acidente químico de Bhopal, privilegiando-se o papel constitutivo da ação humana na Política Ambiental Internacional (PAI). Emprega-se articulação de conceitos construtivistas, útil na visualização da estrutura em que está inserido o evento local e, também, do processo de construção social tanto do evento quanto da norma internacional que precipitou.O pressupostoéodeque prevalece a co-constituição entre estruturas e agentes - responsáveis pela construção social do evento-ede que, portanto, não se pode prescindir desses elementos, tampouco dos elos que os unem. Almeja-se, por um lado, compreender a maneira pela qual o evento local é construído socialmente, tendo por referência a estrutura de idéias e de normas, referidas à proteção ambiental e ao desenvolvimento sustentável; e, por outro, como a ocorrência local gera impactos políticos, sociais e normativos em nível global. Assim, evidenciam-se elementos de globalidade, pertencentes ao evento local, sobretudo quando se verifica um processo de amadurecimento ideacional e normativo que tem como marcos políticos a Conferência de Estocolmo sobre o Meio Ambiente Humano de 1972 e a Conferência das Nações Unidas sobre Desenvolvimento e Meio Ambiente, ocorrida no Rio de Janeiro, em 1992. Assim, destaca-se o contexto cultural e institucional da cena ambiental como um todo, evidenciando-se o veio condutor do processo de construção social enfocado: a relação local/global na área ambiental. Focaliza-se, também, o papel da Organização Internacional do Trabalho (OIT) como agência líder na discussão internacional da segurança química a fim de indicar por que a construção normativa enfocada se verifica no fórum daquela Organização Internacional (OI).<br>The present article utilizes the constructivist approach of International Relations (IR) to analyze the international normative impact of the Bhopal chemical accident, focusing on the constitutive role of the human action on the International Environmental Politics (IEP). It adopts an articulation of constructivist concepts, useful to visualize the structure in which the local event is embedded, as well as the social construction process of either the event and the international norm launched. The assumption is that a co-constitution relation between structure and agents, who are responsible for the social construction of the event, is preponderant and that, consequently, it is impossible to exclude these elements or their connecting links from the analysis. The article aims at understanding, on the one hand, the way in which the event is socially constructed, referring to the ideational and normative structure of environmental protection and sustainable development; and, on the other, how the local event produces political, social and normative impact at international level. As a result, the global features of local events become evident, specially considering the ideational and normative fulfillment of an environment consciousness, whose political milestones are the Stockholm 1972 United Nations Conference on the Human Environment and the 1992 United Nations Conference on Environment and Development, held in Rio de Janeiro. Therefore, the article emphasizes the cultural and institutional environmental context as whole, pointing out the local/global relationship. It also focuses on the role of the International Labour Organization (ILO) as a leader agency in the chemical safety field, in an attempt to indicate why the normative construction process has taken place on the forum of that International Organization (IO)