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Summary: Volatile short-chain fatty acids such as butyric and acetic acid have been supplemented in poultry rations as a feed ingredient and nutritive supplement. A novel Clostridium fermentation solubles broth (MiruTyton), containing short-chain fatty acids, minerals, and amino acids, was supplemented in a standard corn/soybean meal–based ration at a rate of 750, 1,500, 3,000, and 6,000 mg/kg to achieve approximately 277, 554, 1,108, and 2,216 mg/kg of ammonium butyrate in the diet. After 6 wk, supplementation at all levels did not cause significant changes in the blood parameters or any live performance metric of mixed-sex Cobb-500 broilers (N = 1,920). In addition, administering 6,000 mg/kg of MiruTyton caused no significant lesions in any of the tissue examined except for an increase (P

Abstract In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.

Abstract Background Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors. Methods Subjects were divided into three strata: stratum 1—relapsed/refractory neuroblastoma; stratum 2—relapsed/refractory CNS tumors; and stratum 3—relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. Results A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. Conclusions This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. Trial registration ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

Abstract Background Survival for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies. Aims To study the feasibility and safety of incorporating a genomic‐based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti‐GD2 immunotherapy. Methods Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor‐normal whole exome sequencing and tumor RNA‐sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3–6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression. Results Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty‐five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well‐tolerated and resulted in no unexpected adverse events related to DFMO. Conclusion This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.

Cooperative nest defense has been documented in various passerine species. Parents typically swoop and alarm-call at any predator near their nest, often attracting predominantly male conspecifics to help with nest defense. Potential reasons for males to engage in communal nest defense include direct benefits such as deterring a predator from their own nest area, by-product mutualism (paternity uncertainty in nearby nests), reciprocity, kin selection, and quality advertisement. European Starlings ( Sturnus vulgaris ) are a semicolonial and gregarious cavity-nesting passerine with biparental care. They have a mixed reproductive strategy that includes both extra-pair paternity and intraspecific brood parasitism. Therefore, both paternity and maternity uncertainty could occur in conspecific nests. Our objective was to examine whether conspecific nest defense occurred in this species, and if it did, whether both males and females participated. We exposed adult European Starlings breeding in 16 nest boxes to a taxidermy mount of an American red squirrel ( Tamiasciurus hudsonicus; experimental treatment) and a similarly sized and shaped rock (control) mid-way through the nestling period when nestlings were 11 or 12 days old. Significantly more starlings (parents and conspecifics) responded in the experimental than control trials, and they responded with a significantly higher aggregate score of defensive responses, demonstrating both the effectiveness of the taxidermy mount in eliciting defensive responses and the presence of cooperative nest defense in this species. Both males and females participated in mobbing at conspecific nests during the experimental trials. This study is the first to determine that male and female European Starlings engage in cooperative defense of conspecific nests.

Este artigo tem como tema o RPG, uma modalidade de jogo de interpretação no qual se constrói uma narrativa compartilhada entre os participantes. Os dados foram gerados entre abril e dezembro de 2018 em 7 sessões de um jogo de RPG cujos participantes se identificavam como LGBTQIs ou simpatizantes. Utilizando os conceitos de Enquadre e Alinhamento, da Sociolinguística Interacional, a pesquisa objetivava, num primeiro momento, analisar quais enquadres emergiam, como se sobrepunham e como os jogadores se alinhavam aos enquadres. Num segundo momento, procurou-se olhar para como questões de gênero e sexualidade se tornavam relevantes nas interações. Concluiu-se que, diferente de outras conversas face-a-face,o RPG possui relações de enquadre bem específicas e altamente móveis, que sãodefinidas pela própria modalidade do jogo. A forma como os participantes se alinham os enquadres varia, primeiro de enquadre a enquadre, mas também a partir de seus conhecimentos e experiências compartilhadas como grupo social minoritário. Palavras-chave: Enquadres; Alinhamento; RPG.