Nanoparticle-filled micelles as versatile delivery vehicles for TLR4 mediated immunotherapy

303 p.Despite the tremendous potential of Toll-like receptor (TLR) 4 agonists in cancer immunotherapy, only some lipopolysaccharides (LPS) isolated from particular bacterial strains or synthetic structures like monophosphoryl lipid A (MPLA) are able to avoid toxic overactivation of the immune system while retaining adequate immunogenicity to act as vaccine adjuvants[1] . For cancer immunotherapy applications, the delivery of TLR4 agonists and their immunostimulatory activity modulation can be improved using nanoparticles. Moreover, combination of vaccines with immune checkpoint blockade (CPB) strategies could overcome the intrinsic weaknesses of vaccines and CPB monotherapies[2]. Here, we developed a nanovaccine by incorporating different LPS-related structures into nanoparticle-filled phospholipid micelles (mNPs) through a self-assembly process, exploiting the amphipathic structures of the adjuvants creating a nano-adjuvant for efficient vaccine delivery and potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc was incorporated into phospholipid micelles encapsulating oleic acid-coated 6 nm iron oxide nanoparticles (mIONPsp-Xcc LOS), producing stable pathogen-mimicking mNPs with ideal size, charge and hydrophobicity for targeting antigen presenting cells in the lymph nodes. The antigen OVA was attached to mIONPsp via a hydrazone bond (mIONPsp-HyNic-OVA) creating a NP-based antigen delivery vehicle and enabling rapid, easy-to-monitor and high yield antigen ligation at low concentrations[3] . The protective effect of mIONPsp-HyNic-OVA formulated with mIONPsp-Xcc LOS as adjuvant was investigated in mice against the highly aggressive model for murine tumor immunotherapy, B16-F10 melanoma expressing OVA. The results showed that the nanovaccines led to a higher-level tumor antigen-specific cytotoxic T lymphocyte (CTL) effector and memory responses without inducing toxicity, and that when combined with abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1), provided 100% long-term protection against repeated tumor challenge[4]. The mIONPsp and antigen conjugation strategy in combination with immune checkpoint inhibition of PD-L1 represent a promising approach to improve cancer immunotherapy of vaccines exploiting TLR4 agonists.[1]: Mastelic, B. et al., Mode of action of adjuvants: Implications for vaccine safety and design. Biologicals 38, 594¿601 (2010). [2]: Zhuting, H. et al., Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nature Reviews Immunology 18, 168¿182 (2018). [3]: Blanco-Canosa, J. B. et al., Rapid covalent ligation of fluorescent peptides to water solubilized Quantum Dots. J. Am. Chem. Soc. 132, 10027¿10033 (2010).[4] Traini, G. et al., Cancer immunotherapy of TLR4 agonist-antigen constructs enhanced with pathogen-mimicking magnetite nanoparticles and checkpoint blockade of PD-L1. Small 15, 1803993 (2015).CIC biomaGUN

Nanoparticle-filled micelles as versatile delivery vehicles for TLR4 mediated immunotherapy

303 p.Despite the tremendous potential of Toll-like receptor (TLR) 4 agonists in cancer immunotherapy, only some lipopolysaccharides (LPS) isolated from particular bacterial strains or synthetic structures like monophosphoryl lipid A (MPLA) are able to avoid toxic overactivation of the immune system while retaining adequate immunogenicity to act as vaccine adjuvants[1] . For cancer immunotherapy applications, the delivery of TLR4 agonists and their immunostimulatory activity modulation can be improved using nanoparticles. Moreover, combination of vaccines with immune checkpoint blockade (CPB) strategies could overcome the intrinsic weaknesses of vaccines and CPB monotherapies[2]. Here, we developed a nanovaccine by incorporating different LPS-related structures into nanoparticle-filled phospholipid micelles (mNPs) through a self-assembly process, exploiting the amphipathic structures of the adjuvants creating a nano-adjuvant for efficient vaccine delivery and potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc was incorporated into phospholipid micelles encapsulating oleic acid-coated 6 nm iron oxide nanoparticles (mIONPsp-Xcc LOS), producing stable pathogen-mimicking mNPs with ideal size, charge and hydrophobicity for targeting antigen presenting cells in the lymph nodes. The antigen OVA was attached to mIONPsp via a hydrazone bond (mIONPsp-HyNic-OVA) creating a NP-based antigen delivery vehicle and enabling rapid, easy-to-monitor and high yield antigen ligation at low concentrations[3] . The protective effect of mIONPsp-HyNic-OVA formulated with mIONPsp-Xcc LOS as adjuvant was investigated in mice against the highly aggressive model for murine tumor immunotherapy, B16-F10 melanoma expressing OVA. The results showed that the nanovaccines led to a higher-level tumor antigen-specific cytotoxic T lymphocyte (CTL) effector and memory responses without inducing toxicity, and that when combined with abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1), provided 100% long-term protection against repeated tumor challenge[4]. The mIONPsp and antigen conjugation strategy in combination with immune checkpoint inhibition of PD-L1 represent a promising approach to improve cancer immunotherapy of vaccines exploiting TLR4 agonists.[1]: Mastelic, B. et al., Mode of action of adjuvants: Implications for vaccine safety and design. Biologicals 38, 594¿601 (2010). [2]: Zhuting, H. et al., Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nature Reviews Immunology 18, 168¿182 (2018). [3]: Blanco-Canosa, J. B. et al., Rapid covalent ligation of fluorescent peptides to water solubilized Quantum Dots. J. Am. Chem. Soc. 132, 10027¿10033 (2010).[4] Traini, G. et al., Cancer immunotherapy of TLR4 agonist-antigen constructs enhanced with pathogen-mimicking magnetite nanoparticles and checkpoint blockade of PD-L1. Small 15, 1803993 (2015).CIC biomaGUN

Caracterización de la estructura y composición florística de dos tipos forestales del noroeste de la provincia del Chaco = Characterizing the Structure and Floristic Composition of two forest types in the northwest of the province of Chaco

Una gestión sostenible de los bosques requiere conocer aspectos ecológicos y el diseño de pautas silvícolas ajustadas a ellos. El objetivo del trabajo fue caracterizar la composición arbórea, la diversidad, la estructura horizontal y vertical de dos tipos de forestales del noroeste de la provincia del Chaco, Argentina, los cuales fueron identificados como Bosque Alto Abierto y Bosque Bajo Abierto. Los datos usados provienen de un inventario forestal de 3.665 ha boscosas efectuado en un predio de 4.978 ha. En el Bosque Alto Abierto, fueron halladas 14 especies y ocho familias botánicas; en el Bosque Bajo Abierto se encontraron ocho especies y seis familias. El coeficiente de mezcla, arrojó valores de 1:19 y 1:26 respectivamente. Con base en el índice de valor de importancia y los valores de cobertura, las especies más importantes fueron Aspidosperma quebracho-blanco, Ziziphus mistol y Schinopsis lorentzii. Ambos tipos forestales presentaron diferencias notables tanto en la continuidad de los estratos de altura como en la presencia de individuos en las clases diamétricas mayores.A sustainable forest management requires knowing ecological aspects and the design of silvicultural guidelines adjusted to them. The objective of the work was to characterize the tree composition, diversity, horizontal and vertical structure of two types of forest in the northwest of the province of Chaco, Argentina identified as High Open Forest and Low Open Forest. The data collected come from a forest inventory of 3,665 ha of woodlands covering 4,978 ha. In the High Open Forest, 14 species and 8 botanical families were found while in the Low Open Forest 8 species and 6 families. The mixing coefficient reached values of 1:19 and 1:26 respectively. On the basis of the importance value index together with the cover values, the most important species were Aspidosperma quebracho-blanco, Ziziphus mistol and Schinopsis lorentzii. Both forest types showed notable differences concerning the continuity of the height strata as well as in the presence of individuals in the largest diameter classes.EEA Sáenz PeñaFil: Kees, Sebastian Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Sáenz Peña. Campo Anexo Presidente de la Plaza; ArgentinaFil: Torres, Silvana C. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Morales, A. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Giraudo, Lucas M. Ministerio de Ambiente y Desarrollo Sostenible. Programa Bosques Nativos y Comunidad. UEL Chaco; ArgentinaFil: Ruiz Diaz, S. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Giodarno, M.A. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Galeano, V.H. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; Argentina. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Kloster, N.A. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; ArgentinaFil: Kronemberger, R.Z. Provincia de Chaco. Ministerio de la Producción. Dirección de Bosques; Argentin

Nanoparticle-filled micelles as versatile delivery vehicles for TLR4 mediated immunotherapy

303 p.Despite the tremendous potential of Toll-like receptor (TLR) 4 agonists in cancer immunotherapy, only some lipopolysaccharides (LPS) isolated from particular bacterial strains or synthetic structures like monophosphoryl lipid A (MPLA) are able to avoid toxic overactivation of the immune system while retaining adequate immunogenicity to act as vaccine adjuvants[1] . For cancer immunotherapy applications, the delivery of TLR4 agonists and their immunostimulatory activity modulation can be improved using nanoparticles. Moreover, combination of vaccines with immune checkpoint blockade (CPB) strategies could overcome the intrinsic weaknesses of vaccines and CPB monotherapies[2]. Here, we developed a nanovaccine by incorporating different LPS-related structures into nanoparticle-filled phospholipid micelles (mNPs) through a self-assembly process, exploiting the amphipathic structures of the adjuvants creating a nano-adjuvant for efficient vaccine delivery and potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc was incorporated into phospholipid micelles encapsulating oleic acid-coated 6 nm iron oxide nanoparticles (mIONPsp-Xcc LOS), producing stable pathogen-mimicking mNPs with ideal size, charge and hydrophobicity for targeting antigen presenting cells in the lymph nodes. The antigen OVA was attached to mIONPsp via a hydrazone bond (mIONPsp-HyNic-OVA) creating a NP-based antigen delivery vehicle and enabling rapid, easy-to-monitor and high yield antigen ligation at low concentrations[3] . The protective effect of mIONPsp-HyNic-OVA formulated with mIONPsp-Xcc LOS as adjuvant was investigated in mice against the highly aggressive model for murine tumor immunotherapy, B16-F10 melanoma expressing OVA. The results showed that the nanovaccines led to a higher-level tumor antigen-specific cytotoxic T lymphocyte (CTL) effector and memory responses without inducing toxicity, and that when combined with abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1), provided 100% long-term protection against repeated tumor challenge[4]. The mIONPsp and antigen conjugation strategy in combination with immune checkpoint inhibition of PD-L1 represent a promising approach to improve cancer immunotherapy of vaccines exploiting TLR4 agonists.[1]: Mastelic, B. et al., Mode of action of adjuvants: Implications for vaccine safety and design. Biologicals 38, 594¿601 (2010). [2]: Zhuting, H. et al., Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nature Reviews Immunology 18, 168¿182 (2018). [3]: Blanco-Canosa, J. B. et al., Rapid covalent ligation of fluorescent peptides to water solubilized Quantum Dots. J. Am. Chem. Soc. 132, 10027¿10033 (2010).[4] Traini, G. et al., Cancer immunotherapy of TLR4 agonist-antigen constructs enhanced with pathogen-mimicking magnetite nanoparticles and checkpoint blockade of PD-L1. Small 15, 1803993 (2015).CIC biomaGUN

Analgesia pós-operatória em gatas submetidas à ovariohisterectomia tratadas com buprenorfina por diferentes vias de administração

A via de administração de um fármaco pode influenciar sobejamente na latência e duração do efeito analgésico. Objetivou-se avaliar a sedação e a analgesia de 0,01 mg/kg de buprenorfina administrada pelas vias intravenosa (IV), intramuscular (IM), transmucosa (TM) ou subcutânea (SC) em gatas submetidas à ovariohisterectomia. Cem gatas 100 de diversas raças, com idade de quatro meses a seis anos de idade foram divididas de forma aleatória em 4 grupos de acordo com as vias de administração citadas anteriormente. Os animais foram avaliados quanto a presença dor pós-operatória e sedação antes e 1, 2, 3, 4, 6, 8, 12, e 24 h após o término do procedimento cirúrgico, por meio das escalas analógica visual interativa e dinâmica (EAVID) e descritiva simples (EDS). Realizou-se analgesia resgate com 0,02 mg/kg de buprenorfina IM quando o escore de dor foi igual ou superior a 50% da EDS ou EAVID. Para um segundo resgate analgésico foi administrado 4,4 mg/kg de carprofeno SC. Os dados paramétricos foram analisados pela ANOVA, seguida do teste de Tukey e os não paramétricos pelo teste de Kruskal-Wallis, seguido do teste de Dunn. Diferenças ao longo do tempo dentro de cada grupo foram avaliadas pelo teste de Friedman, seguido do teste de Dunn. Imediatamente após cirurgia os escores de sedação da EAVID e EDS aumentaram significantemente quando comparado ao pré-operatório, reduzindo para zero 24 horas após cirurgia. Para os escores de dor da EAVID não se observou diferença significante entre GTM e GSC e entre GIM e GIV. Os valores de GTM foram significantemente maiores quando comparados à GIV à 1h e à GIM às 3,4,6,8 e 12 h. Os valores de GSC foram significantemente maiores quando comparados à GIV às 2 h e à GIM às 2,3,4,8,12 e 24 h. No total, quatro animais do GIM (16%), seis do GIV (24%), treze do GSC (52%) e dezessete do GTM (68%) necessitaram de analgesia...The route of administration of a drug may influence the onset and duration of analgesic effect. The aim of this study was to investigate the degree of sedation and analgesia of 0.01 mg/kg of buprenorphine administered by intravenous (IV), intramuscular (IM), transmucosal (TM) or subcutaneous (SC) route in cats subjected to ovariohysterectomy. One hundred cats from different breeds, aging from four months to six years of age were randomly divided into four groups according to the above routes of administration. The animals were evaluated for the presence of postoperative pain and sedation before and 1, 2, 3, 4, 6, 8, 12, and 24 h after the surgical procedure, using dynamic interactive visual analogue scale (DIVAS) and simple descriptive scale (SDS). Rescue analgesia was performed with 0.02 mg/kg of buprenorphine IM when the pain score was more than 50% of the SDS or DIVAS. A second rescue analgesia was performed with 4.4 mg/kg of carprofen SC. The parametric data were analyzed by ANOVA followed by Tukey´s test and the non-parametric data by Kruskal-Wallis, followed by Dunn´s test. Differences over time within each group were evaluated by Friedman´s test, followed by the Dunn´s test. The SDS and DIVAS sedation scores increased significantly immediately after surgery when compared to pre-operative values, reducing to zero, 24 h after surgery. There was no significant difference for the DIVAS pain scores between GTM and GSC and between GIM and GIV. The values of GTM were significantly greater when compared to the GIV at 1h and to GIM at 3, 4, 6, 8 and 12 h. The values of GSC were significantly higher when compared to GIV at 2 h and to the GIM at 2, 3, 4, 8, 12 and 24 h. In total, four animals from GIM (16%), six from GIV (24%), thirteen from GSC (52%) and seventeen from GTM (68%) needed rescue analgesia. The total number of rescue analgesic in GTM was significantly higher than... (Complete abstract click electronic access below)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Myocardial infarction in relation to colchicine poisoning: A precipitating cause of refractory toxic cardiogenic shock

International audienc