Lessons Learned about Neurodegeneration from Microglia and Monocyte Depletion Studies.
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ABSTRACT:
SUBMITTER: Lund H
PROVIDER: S-EPMC5532389 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in ~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies.
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Project description:Purpose of reviewThe purpose of this review is to describe the recent knowledge gathered from the identification of seven genomic regions that have been linked to the risk of developing malignant glioma.Recent findingsThe recent novel discoveries in fine mapping and genotype-phenotype studies will be highlighted. Through imputation and next-generation sequencing a novel genetic variant, rs55705857, with a strong association at 8q24 has been discovered and validated in two studies. This locus is specifically associated with IDH1-mutated and IDH2-mutated tumors and oligodendroglial tumors, albeit the specific mechanism of tumor development is not understood. The genetic variants associated with the risk of glioma in the EGFR gene have also been associated with specific somatic aberrations, including loss at the CDKN2A/B locus and allele specific loss of EGFR in the tumors. A specific TP53 low frequency variant has also been associated with glioma risk and validated in a separate data set. The genetic risk in the telomere regulating genes TERT and RTEL appear to be associated with higher grade tumors without IDH mutations.SummaryThe link of genetic loci to specific tumor subtypes may have relevance for understanding glioma biology, and for developing new diagnostic tools and targeted therapy for glioma.
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Project description:Background and purposePediatric populations represent a vulnerable research group. Careful thought must be given to many factors when designing and implementing pediatric intervention research studies. This article discusses methodological and implementation lessons learned from two pediatric intervention pilot studies and highlights facilitators and barriers encountered.Type of methodBoth studies used a pre/post with 6-week follow-up method and were adapted versions of an evidence-based program, Creating Opportunities for Personal Empowerment (COPE).Essential featuresCOPE is a 7-session, cognitive behavioral skills building intervention. COPE for Asthma was implemented in schools with small groups for elementary-aged children with asthma and symptoms of anxiety. Mindstrong to Combat Bullying was implemented individually in the outpatient mental health setting for adolescents who had experienced bullying with concurrent symptoms of depression/anxiety.Methodological applicationBoth intervention studies were successful in achieving their research aims, but more importantly the authors learned important lessons in how to successfully work with pediatric populations in research studies. Legal considerations, such as mandated reporting, suicide risk assessment and the inclusion of parents are reviewed. Other components, such as working with children vs. adolescents, integrating research into school-based settings vs. clinic-based settings, and completing intervention research in a group setting vs. individual setting are discussed.ConclusionsThe two pilot studies highlight important factors to consider when designing and implementing pediatric intervention studies. While challenges arise in working with this vulnerable population, research is ultimately needed to provide the best evidence-based care for our future generations.Clinical trial registrationThe COPE for Asthma study is registered at www.ClinicaltrialsgovNCT03481673.
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