Neutralization of Botulinum Neurotoxin Type E by a Humanized Antibody

Botulinum neurotoxins (BoNTs) cause botulism and are the deadliest naturally-occurring substances known to humans. BoNTs have been classified as one of the category A agents by the Centers for Disease Control and Prevention, indicating their potential use as bioweapons. To counter bio-threat and naturally-occurring botulism cases, well-tolerated antibodies by humans that neutralize BoNTs are relevant. In our previous work, we showed the neutralizing potential of macaque (Macaca fascicularis)-derived scFv-Fc (scFv-Fc ELC18) by in vitro endopeptidase immunoassay and ex vivo mouse phrenic nerve-hemidiaphragm assay by targeting the light chain of the botulinum neurotoxin type E (BoNT/E). In the present study, we germline-humanized scFv-Fc ELC18 into a full IgG hu8ELC18 to increase its immunotolerance by humans. We demonstrated the protection and prophylaxis capacity of hu8ELC18 against BoNT/E in a mouse model. A concentration of 2.5 ng/mouse of hu8ELC18 protected against 5 mouse lethal dose (MLD) in a mouse protection assay and complete neutralization of 1 LD50 of pure BoNT/E toxin was achieved with 8 ng of hu8ELC18 in mouse paralysis assay. Furthermore, hu8ELC18 protected mice from 5 MLD if injected up to 14 days prior to intraperitoneal BoNT/E administration. This newly-developed humanized IgG is expected to have high tolerance in humans.Peer reviewe

Static chiral Willis continuum mechanics for three-dimensional chiral mechanical metamaterials

International audienceRecent static experiments on twist effects in chiral three-dimensional mechanical metamaterials have been discussed in the context of micropolar Eringen continuum mechanics, which is a generalization of linear Cauchy elasticity. For cubic symmetry, Eringen elasticity comprises nine additional parameters with respect to linear Cauchy elasticity, of which three directly influence chiral effects. Here, we discuss the behavior of the static case of an alternative generalization of linear Cauchy elasticity, the Willis equations. We show that in the homogeneous static cubic case, only one additional parameter with respect to linear Cauchy elasticity results, which directly influences chiral effects. We show that the static Willis equations qualitatively describe the experimentally observed chiral twist effects, too. We connect the behavior to a characteristic length scale

Exterior del Lagar La Primilla en Montilla

O objetivo deste trabalho foi avaliar o efeito da suplementação com sais proteinados sobre o desempenho de novilhos em pastagem nativa diferida, no Rio Grande do Sul, Brasil. Os suplementos de sal proteinado avaliados foram: com uréia, com amiréia, com amiréia mais levedura e sal mineral. O experimento teve duração de 118 dias e foram utilizadas 8 parcelas com área de 7,5 ha, cada uma com 8 novilhos, de peso médio 264 kg, com idade de 18 meses, em delineamento completamente casualizado. A pastagem apresentou valores médios de 6,8% de proteína bruta, 73,3% de fibra em detergente neutro, e 42,5% de digestibilidade in vitro da matéria orgânica, sem que fossem detectadas diferenças significativas entre tratamentos. O ganho médio diário (0,287 kg) dos animais suplementados com o sal proteinado com amiréia e levedura, foi superior ao apresentado pelos animais que consumiram sal mineralizado (0,019 kg) mas não houve diferenças entre uréia (0,159 kg) e amiréia (0,124 kg). O consumo diário dos suplementos proteinados (0,400 kg) foi superior ao consumo do suplemento mineral (0,038 kg). A adição de levedura ativa, ao sal proteinado formulado com amiréia, melhora o desempenho de novilhos em pastagem nativa diferida.The objective of this work was to evaluate the effect of protein salts supplementation on performance of beef steers grazing differed native pasture in Rio Grande do Sul State, Brazil. Protein salts were supplemented with: urea, starea, starea plus yeast, and mineral salt. The experiment was conducted during 118 days, and utilized 8 paddocks with 7.5 ha each one, with 8 steers averaging 264 kg and 18 months old, in a completely randomized design. Average composition of pasture was 6.8% of crude protein, 73.3% of neutral detergent fiber, and 42.5% in vitro organic matter digestibility; significative differences weren’t detected among treatments. Average daily weight gain of animals fed protein salt with starea plus yeast (0.287 kg), was higher than the weight gain of animals fed mineral salt (0.019 kg); differences weren’t detected among urea (0.159 kg) and starea (0.124 kg). Daily intake of protein supplements (0.400 kg) was higher than that of mineral supplement (0.038 kg). Addition of live yeast to the protein salt formulated with starea resulted in better performance of steers grazing differed native pasture

Risk factors associated with the development of oral mucositis in pediatric oncology patients : systematic review and meta-analysis

Objectives: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the devel-opment of OM in pediatric cancer patients.Methods: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients.Results: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta- analysis showed that groups submitted to high- risk chemotherapy for OM had a 2.79- fold increased risk of OM.Conclusions: Identifying risk factors for OM is essential in order to allow individual-ized and early prevention treatment

Real-world survival outcomes of heavily pretreated patients with refractory HR+, HER2-metastatic breast cancer receiving single-agent chemotherapy-a comparison with MONARCH 1.

PurposeIn MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort.MethodsThe real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression.ResultsA real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76.ConclusionsThis study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context

Real-world survival outcomes of heavily pretreated patients with refractory HR+, HER2-metastatic breast cancer receiving single-agent chemotherapy-a comparison with MONARCH 1.

PurposeIn MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort.MethodsThe real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression.ResultsA real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76.ConclusionsThis study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context

Morphological and tissue-based molecular characterization of oral lesions in patients with COVID-19: A living systematic review

Objective: This living systematic review aims to integrate the morphological and tissue-based molecular caracterization of oral lesions occurring in individuals infected by COVID-19 (OLICs). Materials and Design: This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Web of Science, Scopus, Ovid, Embase, and LILACS were searched to identify reports on OLICs with morphological and/or tissue-based molecular data. Results: Four studies reporting five cases were included. Three patients were male, and the mean age of the individuals was 47.6 years. The most reported anatomical location was the palate (n = 4), whereas ulcers were the most frequent clinical presentation (n = 3). Histopathologically, all cases revealed cell vacuolization and exocytosis in the epithelial layer. In the mesenchymal layer, inflammatory cell infiltrate and thrombi/microvascular thrombosis were observed in three cases. Immunohistochemical reactions were performed in two cases. Both cases were negative for HHV-1, HHV-2, and CMV. One case revealed positivity for SARS-CoV-2 spike protein. No other molecular tests were found for the characterization of OLIC. Conclusions: The pathological characteristics of OLICs are still unspecific. However, with the ongoing COVID-19 pandemic and well-documented new cases, whether OLICs are due to coinfections or has a primary origin can be determined

When monoclonal antibodies are not monospecific: Hybridomas frequently express additional functional variable regions.

Monoclonal antibodies are commonly assumed to be monospecific, but anecdotal studies have reported genetic diversity in antibody heavy chain and light chain genes found within individual hybridomas. As the prevalence of such diversity has never been explored, we analyzed 185 random hybridomas, in a large multicenter dataset. The hybridomas analyzed were not biased towards those with cloning difficulties or known to have additional chains. Of the hybridomas we evaluated, 126 (68.1%) contained no additional productive chains, while the remaining 59 (31.9%) contained one or more additional productive heavy or light chains. The expression of additional chains degraded properties of the antibodies, including specificity, binding signal and/or signal-to-noise ratio, as determined by enzyme-linked immunosorbent assay and immunohistochemistry. The most abundant mRNA transcripts found in a hybridoma cell line did not necessarily encode the antibody chains providing the correct specificity. Consequently, when cloning antibody genes, functional validation of all possible VH and VL combinations is required to identify those with the highest affinity and lowest cross-reactivity. These findings, reflecting the current state of hybridomas used in research, reiterate the importance of using sequence-defined recombinant antibodies for research or diagnostic use