Pharmacokinetics and Safety of a Novel Oral Liquid Formulation of 13-cis Retinoic Acid in Children with Neuroblastoma: A Randomized Crossover Clinical Trial.

(1) Background: 13-cis-retinoic acid (13-CRA) is a key component of neuroblastoma treatment protocols. This randomized crossover study compares the pharmacokinetics (PK), safety and palatability of a novel oral liquid formulation to the current method of extracting 13-CRA from capsules. (2) Methods: Pharmacokinetics was evaluated in two consecutive treatment cycles. Patients were randomized to receive either liquid or capsule formulation on cycle 1 and then crossed over to the alternative formulation on cycle 2. The daily dose was 200 mg/m2, reduced to 160 mg/m2 in patients with weight ≤ 12 kg. (3) Results: A total of 20 children, median (range) age 4.3 (1-11.6) y were recruited. Pharmacokinetic data were pooled and a population model describing the disposition of 13-CRA and 4-oxo-13-CRA was developed. Bioavailability of the liquid formulation was estimated to be 65% higher (95% CI; 51-79%) than the extracted capsule. CmaxSS and AUC(0-12)SS estimates were also significantly higher; mean (95% CI) differences were 489 (144-835) ng/mL and 3933 (2020-5846) ng/mL·h, respectively (p < 0.01). There were no significant differences in reported adverse effects. Parents found dosing considerably easier with liquid formulation. (4) Conclusions: The pharmacokinetics, safety and palatability of a new liquid formulation of 13-CRA compares favorably to 13-CRA extracted from capsules. Clinical Trial Registration: clinicaltrial.gov NCT03291080

From a consortium sequence to a unified sequence: the Bacillus subtilis 168 reference genome a decade later

Comparative genomics is the cornerstone of identification of gene functions. The immense number of living organisms precludes experimental identification of functions except in a handful of model organisms. The bacterial domain is split into large branches, among which the Firmicutes occupy a considerable space. Bacillus subtilis has been the model of Firmicutes for decades and its genome has been a reference for more than 10 years. Sequencing the genome involved more than 30 laboratories, with different expertises, in a attempt to make the most of the experimental information that could be associated with the sequence. This had the expected drawback that the sequencing expertise was quite varied among the groups involved, especially at a time when sequencing genomes was extremely hard work. The recent development of very efficient, fast and accurate sequencing techniques, in parallel with the development of high-level annotation platforms, motivated the present resequencing work. The updated sequence has been reannotated in agreement with the UniProt protein knowledge base, keeping in perspective the split between the paleome (genes necessary for sustaining and perpetuating life) and the cenome (genes required for occupation of a niche, suggesting here that B. subtilis is an epiphyte). This should permit investigators to make reliable inferences to prepare validation experiments in a variety of domains of bacterial growth and development as well as build up accurate phylogenies

As esculturas cokwe como respostas às assimetrias civilizacionais

Fundada em 1917, a Companhia de Diamantes de Angola (Diamang) ocupava uma vasta região da Lunda Norte e Lunda Sul. Além das ações voltadas para a exploração de diamantes, essa empresa concessionária constituiu em 1936 o Museu do Dundo, um espaço destinado a colecionar objetos relacionados, sobretudo, aos povos que habitavam a sua área de atuação. Os objetivos cada vez mais ambiciosos e o receio da extinção de uma arte reminiscente do “tempo tribal” levaram o Museu do Dundo a organizar não apenas expedições de recolhas de objetos, mas também a contratar e manter “protegidos” em seus domínios escultores de madeira e de marfim a fim de evitar que as transformações ocasionadas pela situação colonial influenciassem os trabalhos desses homens. Este artigo tem como objetivo apresentar algumas reflexões sobre como os anseios fictícios do Museu em relação a esses escultores foram fundamentais para compreender as constantes tensões e dificuldades em enquadrar em seu espaço não apenas esses próprios homens, mas também as suas produções.The Companhia de Diamantes de Angola (Diamang) was founded in 1917 and occupied a vast region of Lunda’s north and south areas. Aside from the activities around diamond mining this concessionary company also created a museum in 1936. The Museu do Dundo (Dundo Museum) was a space dedicated to collect objects related to the inhabitants who lived in the area exploited by the company. The increasingly ambitious objectives of the Museum and the concern regarding the disappearance of a reminiscent art from “tribal times” resulted not only in the organization of collecting expeditions but also in the recruitment and “protection” of wood and ivory sculptors inside the company’s domains to avoid that their work were influenced by changes caused by the colonialism. The main objective of this paper is to present some considerations regarding how the museum’s fictitious expectations regarding these sculptors were crucial to understand the continuous tensions and difficulties faced to accommodate not only these men but also their work in its space

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Language endangerment and language documentation in Africa

Non peer reviewe

Speech in the Royal Presence: Javanese Palace Language

Page range: 89-10

Getting Language Rights, Shifting Linguistic Traditions*

»Endangerment,« »loss,« »death,« and related terms are increasingly familiar in descriptions of sociolinguistic changes now occurring at an unprecedented scale due to forces of globalization. They can serve both as names for shared concerns of linguists and anthropologists, and as descriptions of otherwise different scenes of social encounter, because they are subject to multiple uses and interpretations. This paper focuses on tacit, enabling assumptions of three distinct strategies for framing and redressing »threats« to marginalized languages and speech communities. Recognition of their ideological grounds helps develop a sharper sense of their different uses, and the different social saliences which linguistic descriptions can have in and for marginalized communities