Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance

Using the Spina Bifida Life Course Model in Clinical Practice: An Interdisciplinary Approach

The Life Course Model for patients, families, caregivers, teachers, and clinicians was developed with support by the National Spina Bifida Program, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, for individuals with spina bifida. The Life Course Model facilitates a developmental approach to assessment and intervention along life's trajectory. This Life Course Model provides information about key developmental milestones for particular age groups, validated assessments that can be performed by clinicians or teachers to determine if milestones have been reached, useful suggestions for intervening in creative ways at each step, and evidence-based references. In this article, the authors introduce the viewpoints of several key clinicians who are involved in the care of individuals with spina bifida and how the Life Course Model can assist them, their patients, and their families in the process of assessment, intervention, collaboration with other clinicians, and follow-up. A case study is used to demonstrate the experience of comprehensive and collaborative management in transitioning a child and his family from infancy to adulthood. © 2010

Investigating whole‐brain metabolite abnormalities in the chronic stages of moderate or severe traumatic brain injury

Evidence suggests that neurometabolic abnormalities can persist after traumatic brain injury (TBI) and drive clinical symptoms such as fatigue and cognitive disruption. Magnetic resonance spectroscopy has been used to investigate metabolite abnormalities following TBI, but few studies have obtained data beyond the subacute stage or over large brain regions. The purpose of this study was to measure whole-brain metabolites in chronic stages of TBI. Observational study. University. Eleven men with a moderate or severe TBI more than 12 months prior, and 10 age-matched healthy controls completed whole-brain spectroscopic imaging. Ratios of N-acetylaspartate (NAA), Choline (CHO), and myo-inositol (MI) to creatine (CR) were measured in whole brain gray and white matter, as well as 64 brain regions of interest. Arterial spin labeling (ASL) data were also collected to investigate whether metabolite abnormalities were accompanied by differences in cerebral perfusion. There were no differences in metabolite ratios within whole brain gray and white matter ROIs. Linear regression showed lower NAA/CR in the white matter of the left occipital lobe but higher NAA/CR in the grey matter of the left parietal lobe. Metabolite abnormalities were observed in several brain regions in the TBI group including the corpus callosum, putamen, and posterior cingulate. However, none of findings survived correction for multiple comparison There were no differences in cerebral blood flow between patients and controls. Higher MI/CR may indicate ongoing gliosis, and it has been suggested that low CHO/CR at chronic time points may indicate cell death or lack of healthy turnover and repair. However, with the small sample size of this study, we caution against the over-interpretation of our results. None of the findings within ROIs survived correction for multiple comparison. Thus, they may be considered possible avenues for future research in this area. This article is protected by copyright. All rights reserved