A DNA target-enrichment approach to detect mutations, copy number changes and immunoglobulin translocations in multiple myeloma.

Genomic lesions are not investigated during routine diagnostic workup for multiple myeloma (MM). Cytogenetic studies are performed to assess prognosis but with limited impact on therapeutic decisions. Recently, several recurrently mutated genes have been described, but their clinical value remains to be defined. Therefore, clinical-grade strategies to investigate the genomic landscape of myeloma samples are needed to integrate new and old prognostic markers. We developed a target-enrichment strategy followed by next-generation sequencing (NGS) to streamline simultaneous analysis of gene mutations, copy number changes and immunoglobulin heavy chain (IGH) translocations in MM in a high-throughput manner, and validated it in a panel of cell lines. We identified 548 likely oncogenic mutations in 182 genes. By integrating published data sets of NGS in MM, we retrieved a list of genes with significant relevance to myeloma and found that the mutational spectrum of primary samples and MM cell lines is partially overlapping. Gains and losses of chromosomes, chromosomal segments and gene loci were identified with accuracy comparable to conventional arrays, allowing identification of lesions with known prognostic significance. Furthermore, we identified IGH translocations with high positive and negative predictive value. Our approach could allow the identification of novel biomarkers with clinical relevance in myeloma

Normal forms and internal regularization of nonlinear differential-algebraic control systems

In this article, we propose two normal forms for nonlinear differential-algebraic control systems (DACSs) under external feedback equivalence, using a notion called maximal controlled invariant submanifold. The two normal forms simplify the system structures and facilitate understanding the various roles of variables for nonlinear DACSs. Moreover, we study when a given nonlinear DACS is internally regularizable, that is, when there exists a state feedback transforming the DACS into a differential-algebraic equation (DAE) with internal regularity, the latter notion is closely related to the existence and uniqueness of solutions of DAEs. We also revise a commonly used method in DAE solution theory, called the geometric reduction method. We apply this method to DACSs and formulate it as an algorithm, which is used to construct maximal controlled invariant submanifolds and to find internal regularization feedbacks. Two examples of mechanical systems are used to illustrate the proposed normal forms and to show how to internally regularize DACSs

Scopolamine Administration Modulates Muscarinic, Nicotinic and NMDA Receptor Systems

Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1) has been reported. We hypothesized that levels of other cholinergic brain receptors as the nicotinic receptors and the N-methyl-D-aspartate (NMDA) receptor, known to be involved in memory formation, would be modified by scopolamine administration

Daratumumab Plus Lenalidomide And Dexamethasone Versus Lenalidomide And Dexamethasone In Relapsed Or Refractory Multiple Myeloma: Updated Analysis Of POLLUX

In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs. 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009

The apicomplexan plastid and its evolution

Protistan species belonging to the phylum Apicomplexa have a non-photosynthetic secondary plastid—the apicoplast. Although its tiny genome and even the entire nuclear genome has been sequenced for several organisms bearing the organelle, the reason for its existence remains largely obscure. Some of the functions of the apicoplast, including housekeeping ones, are significantly different from those of other plastids, possibly due to the organelle’s unique symbiotic origin

BMC Cancer

BACKGROUND: Although some countries have observed a stabilization in the incidence of CNS, an increasing incidence has been reported from multiple studies. Recent observations point out to the heterogeneity of incidence trends according to histological subtypes, gender and age-groups. Using a high-quality regional CNS tumor registry, this article describes the trends of CNS tumor incidence for main histological subtypes, including benign and malignant tumors, in the French department of Gironde from 2000 to 2012. METHODS: Crude and age-standardized incidence rates were calculated globally, by histological subtypes, malignant status, gender and age groups. For trends, annual percent changes (APC) were obtained from a piecewise log-linear model. RESULTS: A total of 3515 CNS tumors was registered during the period. The incidence of overall CNS tumors was 19/100000 person-years (8.3/100000 for neuroepithelial tumors and 7.3/100000 for meningeal tumors). An increased incidence of overall CNS tumors was observed from 2000 to 2012 (APC = + 2.7%; 95%-confidence interval (CI): 1.8-3.7). This trend was mainly explained by an increase in the incidence of meningiomas over the period (APC = + 5.4%, 95%-CI: 3.8-7.0). The increased incidence rate of CNS tumors was more pronounced in female and in older patients even though the incidence rate increased in all age groups. CONCLUSIONS: Part of the temporal variation may be attributed to improvement in registration, diagnosis and clinical practices but also to changes in potential risk factors. Thus, etiological studies on CNS tumors are needed to clarify this rising trend