Comparative Pharmacokinetics of Tixagevimab/Cilgavimab (AZD7442) Administered Intravenously Versus Intramuscularly in Symptomatic SARS-CoV-2 Infection

AZD7442 (Evusheld) is a combination of two human anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID-19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (Cmax) was 38.19 μg/mL (range: 17.30–60.80) and 37.33 μg/mL (range: 14.90–58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (Tmax) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27–29 μg/mL each component) at 3 days. The area under the concentration-time curve (AUC)0–7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access

Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells

Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8(+) T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8(+) T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-gamma and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A(27-35) in three of five HLA-A*0201 melanoma patients, and of CEA(571-579) and EpCAM(263-271) in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8(+) T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients

Uso e conhecimento tradicional de plantas medicinais no Sertão do Ribeirão, Florianópolis, SC, Brasil Use and traditional knowledge of medicinal plants at Sertão do Ribeirão, Florianópolis, Santa Catarina State, Brazil

O objetivo desta pesquisa foi realizar um estudo etnobotânico sobre o uso e o conhecimento tradicional de plantas medicinais no Sertão do Ribeirão, uma comunidade de origem açoriana, inserida no domínio da Mata Atlântica e localizada dentro dos limites do Parque Municipal da Lagoa do Peri. Foram realizadas 13 entrevistas com moradores do Sertão do Ribeirão, sendo identificadas 114 espécies de plantas medicinais, distribuídas em 48 famílias botânicas. A diversidade de plantas medicinais conhecida no Sertão do Ribeirão é bastante elevada e a obtenção das plantas na própria comunidade sugere uma forte correlação entre uso e conhecimento tradicional de plantas medicinais e a possibilidade de obtê-las no local. O conhecimento etnobotânico sobre plantas medicinais não difere entre homens e mulheres e o uso de medicamentos industrializados e de plantas medicinais indica uma complementaridade entre a medicina moderna e a medicina popular. A transmissão do conhecimento feita na própria comunidade, com pais/avós e vizinhos, demonstra uma rica herança cultural local sobre plantas medicinais.<br>The aim of this research was to do an ethnobotanical study on the use and traditional knowledge of medicinal plants at Sertão do Ribeirão, an Azorean community, inserted in the Atlantic Forest domain and located within the boundaries of Lagoa do Peri Municipal Park. A total of 13 interviews were made with residents of Sertão do Ribeirão, identifying 114 species of medicinal plants, distributed in 48 botanical families. The diversity of medicinal plants known at Sertão do Ribeirão is quite high and the collection of plants by the community suggests a strong correlation between use and traditional knowledge of medicinal plants and the possibility of local gathering. Ethnobotanical knowledge of medicinal plants does not differ between women and men and the use of industrialized medicine and medicinal plants indicates a complementarity between modern and folk medicine. Knowledge transmission within the community, with parents/grandparents and neighbours, shows a rich local cultural heritage of medicinal plants

Marker-assisted conservation of European cattle breeds: an evaluation

Two methods have been developed for the assessment of conservation priorities on the basis of molecular markers. According to the Weitzman approach, contributions to genetic diversity are derived from genetic distances between populations. Alternatively, diversity within and across populations is optimized by minimizing marker-estimated kinships. We have applied, for the first time, both methods to a comprehensive data set of 69 European cattle breeds, including all cosmopolitan breeds and several local breeds, for which genotypes of 30 microsatellite markers in 25-50 animals per breed have been obtained. Both methods were used to calculate the gain in diversity if a breed was added to a set of nine non-endangered breeds. Weitzman-derived diversities were confounded by genetic drift in isolated populations, which dominates the genetic distances but does not necessarily increase the conservation value of a breed. Marker-estimated kinships across populations were less disturbed by genetic drift than the Weitzman diversities and assigned high conservation values to Mediterranean breeds, which indeed have genetic histories that differ from the non-endangered breeds. Prospects and limitations of marker-assisted decisions on conservation priorities are discussed