Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.     

Chunk‐based and fairness‐based resource allocation in multicast distributed MISO‐OFDMA systems

The resource allocation problem for the downlink of orthogonal frequency‐division multiple access (OFDMA) wireless multicast systems is investigated. It is assumed that the base station consists of multiple antennas in a distributed antenna system (DAS), whereas each user is equipped with a single antenna. The multicasting technology is able to support several groups of users with flexible quality of service (QoS) requirements. The general mathematical formulation is provided, but achieving the optimal solution has a high computational cost. In our approach, the allocation unit is not the subcarrier, as in conventional OFDMA systems, but a set of contiguous subcarriers, which is called ‘chunk’. For practical implementation, a suboptimal but efficient algorithm is proposed in order to maximize the sum of the maximum attainable data rates of multicast groups of users, subject to total available power and proportional maximum attainable data rate constraints among multicast groups of users. Simulation and complexity analyses are provided to support the benefits of chunk‐based resource allocation to multicast OFDMA DASs, supporting that the proposed algorithm can be applied to latest‐generation wireless systems that provide QoS guarantees. Copyright © 2013 John Wiley & Sons, Ltd.     

Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.