Pharmacogenomics insights into precision pediatric oncology

PURPOSE OF REVIEW: Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future. RECENT FINDINGS: The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while \u27poor metabolizer\u27 haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform. SUMMARY: The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future

Hunger for Culture

The 2016 world premiere of Larissa FastHorse’s play Urban Rez, which Cornerstone Theater Company produced, presented a community-based theater experience in Los Angeles County (Tongva and Tataviam homelands). In this essay, our three co-authors utilize the concept of being a guest on Tongva land as a methodology to demonstrate Two-Spirit, Queer, and Trans representation within Indigenous theater. Through the work of the playwright, cast, and crew, the Urban Rez narrative asserted self-representation in opposition to settler imaginaries through community-based participatory storytelling. Urban Rez represented a pivot in the current American Theater landscape and a continuation of Indigenous theater legacies. Our essay offers a cross-collaboration between three performers from Urban Rez that represent a wide breadth of academic experiences, performance backgrounds, and community organizing to discuss queer, Two-Spirt, and trans experiences. The co-authors discuss the legacy of counter-narratives in Native theater, demonstrate sovereignty in the play, and utilize queer theory to understand an Indigenous queer experience on stage better. We provide a reflexive co-authorship to assert relationality in the face of heteropatriarchy and contend with our hunger for culture. The co-authors recognize the Urban Rez experience as one of the first major Indigenous theater productions in Los Angeles that included queer, Two-Spirit, and transgender characters that rejected justifying representation from a deficit narrative

Nivel de Cumplimiento del Protocolo de la Amenaza de Parto Pre-término en pacientes embarazadas con edad gestacional mayor de 22 semanas y menor de 37 semanas de gestaciones ingresadas en el servicio de Alto Riesgo Obstétrico en el Hospital Bertha Calderón Roque en el primer semestre del año 2016

Objetivo: Evaluar el cumplimiento de la aplicación del protocolo de la amenaza de parto pretérmino en las pacientes atendidas en la sala del alto riesgo obstétrico del Hospital Bertha Calderón en el primer semestre del año 2016 Material y método: Estudio descriptivo de corte transversal. Se estudiaron 60 pacientes con embarazos mayores de 22 semanas menores de 37 semanas que fueron ingresadas al área de alto riesgo obstétrico del Hospital Bertha Calderón Roque en el primer semestre del año 2016, con diagnóstico de amenaza de parto pretérmino. Se utilizó la lista de chequeo de la normativa 044. Resultados: Las mujeres en estudio, 24 de ellas eran menores de 19 años (48%). 35 mujeres no poseían antecedentes patológicos personales (70%). 26 mujeres que se había realizado más de 4 controles (52%). Con el estado del cuello uterino (borramiento menor del 50% con una dilatación menor de 3 cm y comprobando la integridad de las membranas) se constató en 36 de los expedientes (72%). relación a la indicación del uso de corticoides, 38 de los expedientes (76%) cumple con la aplicación. Conclusiones: La amenaza de parto pretérmino sobresale en la población en edades menores de 19 años. Los criterios clínicos diagnósticos cumplidos fueron la edad gestacionales y la evaluación del bienestar fetal. No se cumplieron en un 100% los criterios en la implementación del tratamiento no farmacológico. No se cumplieron en un 100% los criterios en la implementación del tratamiento farmacológico. Recomendaciones: A los directores de hospital, junto a los jefes de servicio que se ponga en práctica el mandato de la revisión de expedientes clínicos de mujeres con diagnóstico de amenaza de parto pretérmino, para identificar los puntos álgidos en los que no se está cumpliendo el protocolo de la amenaza de parto prematuro para hacerlos llegar al equipo médico y así poder mejorar la calidad de atención

Broad-host range expression vectors containing manipulated meta-cleavage pathway regulatory elements of the TOL plasmid

AbstractThe construction of pERD20 and pERD21, two broad-host range expression vectors, is described. The vectors contain the Pm promoter of the meta-cleavage pathway operon of the TOL plasmid pWWO; this promoter is present within a polylinker which provides a number of downstream cloning sites close to the transcription initiation site. Transcription from the Pm promoter in these vectors is controlled not by the natural positive regulator of Pm, the Xy1S protein, but by an Xy1S mutant analogue, Xy1S2tr6, which ??hibits an altered effector specificity and can mediate a 3–8-fold higher level of transcription than can Xy1S in a wide range of temperatures. Controlled expression of cloned genes can be achieved in a broad spectrum of Gram negative bacteria grown at a wide range of temperatures

Bottom-up control of sardine and anchovy population cycles in the canary current: insights from an end-to-end model simulation

Sardine and anchovy can exhibit dramatic decadal-scale shifts in abundance in response to climate variability. Sharpe declines of these populations entail particularly serious commercial and ecological consequences in eastern boundary current ecosystems, where they sustain major world fisheries and provide the forage for a broad variety of predators. Understanding the mechanisms and environmental forcing that drive the observed fish variability remains a challenging problem. The modelling study presented here provides an approach that bridges a comprehensive database with an end-to-end modelling framework enabling the investigation of the sources of variability of sardine and anchovy in the Canary Current System. Different biological traits and behaviour prescribed for sardine and anchovy gave rise to different distribution and displacements of the populations, but to a rather synchronous variability in terms of abundance and biomass, in qualitative agreement with historical landing records. Analysis of years with anomalously high increase and decline of the adult population points to food availability (instead of temperature or other environmental drivers) as the main environmental factor determining recruitment for both sardine (via spawning and survival of feeding age-0 individuals) and anchovy (via survival of feeding age-0). Consistent with this, the two species thrive under enhanced upwelling-favourable winds, but only up to some threshold of the wind velocity beyond which larval drift mortality exceeds the positive effect of the extra food supply. Based on the analysis of the simulation, we found that anchovy larvae are particularly vulnerable to enhanced wind-driven advection, and as such do better with more moderate upwelling than sardines.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The RNA-binding protein, ZFP36L2, influences ovulation and oocyte maturation

ZFP36L2 protein destabilizes AU-rich element-containing transcripts and has been implicated in female fertility. In the C57BL/6NTac mouse, a mutation in Zfp36l2 that results in the decreased expression of a form of ZFP36L2 in which the 29 N-terminal amino acid residues have been deleted, ΔN-ZFP36L2, leads to fertilized eggs that arrest at the two-cell stage. Interestingly, homozygous ΔN-Zfp36l2 females in the C57BL/6NTac strain release 40% fewer eggs than the WT littermates (Ramos et al., 2004), suggesting an additional defect in ovulation and/or oocyte maturation. Curiously, the same ΔN-Zfp36l2 mutation into the SV129 strain resulted in anovulation, prompting us to investigate a potential problem in ovulation and oocyte maturation. Remarkably, only 20% of ΔN-Zfp36l2 oocytes in the 129S6/SvEvTac strain matured ex vivo, suggesting a defect on the oocyte meiotic maturation process. Treatment of ΔN-Zfp36l2 oocytes with a PKA inhibitor partially rescued the meiotic arrested oocytes. Furthermore, cAMP levels were increased in ΔN-Zfp36l2 oocytes, linking the cAMP/PKA pathway and ΔN-Zfp36l2 with meiotic arrest. Since ovulation and oocyte maturation are both triggered by LHR signaling, the downstream pathway was investigated. Adenylyl cyclase activity was increased in ΔN-Zfp36l2 ovaries only upon LH stimulation. Moreover, we discovered that ZFP36L2 interacts with the 3′UTR of LHR mRNA and that decreased expression levels of Zfp36l2 correlates with higher levels of LHR mRNA in synchronized ovaries. Furthermore, overexpression of ZFP36L2 decreases the endogenous expression of LHR mRNA in a cell line. Therefore, we propose that lack of the physiological down regulation of LHR mRNA levels by ZFP36L2 in the ovaries is associated with anovulation and oocyte meiotic arrest.Fil: Ball, Christopher B.. University of North Carolina; Estados UnidosFil: Rodriguez, Karina F.. National Institutes of Health; Estados UnidosFil: Stumpo, Deborah J.. National Institutes of Health; Estados UnidosFil: Ribeiro Neto, Fernando. National Institutes of Health; Estados UnidosFil: Korach, Kenneth S.. National Institutes of Health; Estados UnidosFil: Blackshear, Perry J.. University of Duke; Estados Unidos. National Institutes of Health; Estados UnidosFil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ramos, Silvia B. V.. University of North Carolina; Estados Unido

Robustness of the Bacterial Community in the Cabbage White Butterfly Larval Midgut

Microbial communities typically vary in composition and structure over space and time. Little is known about the inherent characteristics of communities that govern various drivers of these changes, such as random variation, changes in response to perturbation, or susceptibility to invasion. In this study, we use 16S ribosomal RNA gene sequences to describe variation among bacterial communities in the midguts of cabbage white butterfly (Pieris rapae) larvae and examine the influence of community structure on susceptibility to invasion. We compared communities in larvae experiencing the same conditions at different times (temporal variation) or fed different diets (perturbation). The most highly represented phylum was Proteobacteria, which was present in all midgut communities. The observed species richness ranged from six to 15, and the most abundant members affiliated with the genera Methylobacteria, Asaia, Acinetobacter, Enterobacter, and Pantoea. Individual larvae subjected to the same conditions at the same time harbored communities that were highly similar in structure and membership, whereas the communities observed within larval populations changed with diet and over time. In addition, structural changes due to perturbation coincided with enhanced susceptibility to invasion by Enterobacter sp. NAB3R and Pantoea stewartii CWB600, suggesting that resistance to invasion is in part governed by community structure. These findings along with the observed conservation of membership at the phylum level, variation in structure and membership at lower taxonomic levels, and its relative simplicity make the cabbage white butterfly larval community an attractive model for studying community dynamics and robustness