A new molecular paradigm in mycosis fungoides and Sézary syndrome

Mycosis Fungoides (MF) and Sézary Syndrome (SS) are clonal proliferations of mature T-cells manifesting as lymphoproliferative disorders in which the neoplastic cells show a strong propensity for skin-homing. While the predominant site of presentation in MF is the skin, the peripheral blood carries a significant tumor burden in Sézary Syndrome such that it resembles a “leukemic” disease. While the genetic basis of these diseases has been studied using different approaches in the previous years, recent genome-wide studies employing massively parallel sequencing techniques now offer new insights into the molecular pathogenesis of these diseases. In this chapter, we discuss the recent findings elucidating the genomic landscape of MF and SS. The pathways targeted by mutational alterations are discussed and a model for understanding the pathogenesis of these diseases is proposed. It is anticipated that prognostic stratification and therapeutic targeting based on mutational signatures will be achieved in the near future based on the improved understanding of the molecular pathogenesis of these diseases.     

Bacterial adaptation to the gut environment favors successful colonization

Rodent models harboring a simple yet functional human intestinal microbiota provide a valuable tool to study the relationships between mammals and their bacterial inhabitants. In this study, we aimed to develop a simplified gnotobiotic mouse model containing 10 easy-to-grow bacteria, readily available from culture repositories, and of known genome sequence, that overall reflect the dominant commensal bacterial makeup found in adult human feces. We observed that merely inoculating a mix of fresh bacterial cultures into ex-germ free mice did not guarantee a successful intestinal colonization of the entire bacterial set, as mice inoculated simultaneously with all strains only harbored 3 after 21 d. Therefore, several inoculation procedures were tested and levels of individual strains were quantified using molecular tools. Best results were obtained by inoculating single bacterial strains into individual animals followed by an interval of two weeks before allowing the animals to socialize to exchange their commensal microbes. Through this procedure, animals were colonized with almost the complete bacterial set (9/10). Differences in the intestinal composition were also reflected in the urine and plasma metabolic profiles, where changes in lipids, SCFA, and amino acids were observed. We conclude that adaptation of bacterial strains to the host’s gut environment (mono-colonization) may predict a successful establishment of a more complex microbiota in rodents.     

First description of blaNDM-1, blaOXA-48, blaOXA-181 producing Enterobacteriaceae strains in Romania

We report the first isolation and characterization of several Enterobacteriaceae strains harboring bla_NDM-1, bla_OXA-48 and/or bla_OXA-181 genes in a Romanian emergency teaching hospital. Between January 2010 and September 2012 nine carbapenemase-producing Enterobacteriaceae strains were identified. The bla_NDM-1 gene was present in two Enterobacter cloacae strains, an Escherichia coli and two Klebsiella pneumoniae strains. One of these K. pneumoniae strains also harbored the bla_OXA-181 gene. Three other K. pneumoniae strains and one Serratia marcescens carried bla_OXA-48.     

Correlation between the extent of smoking,salivary protein profiles,and dental caries in young adult smokers

Context.Proteins in the saliva are one of the defense mechanism factors that can protect the oral cavity from disease. However, smoking might affect the properties of saliva.AimTo determine the differences in salivary protein profiles and total concentrations in smokers and non-smokers and their correlation with dental caries severity as indicated by the Decayed, Missing, Filled-Teeth (DMF-T) scores.Methods and materialThis cross-sectional study included 25 smokers and 25 non-smokers. The DMF-T scores were recorded. The total salivary protein was measured by the Bradford method, and the profile proteins were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).ResultsThe average of salivary protein concentration in smokers was lower than that in non-smokers (551.486 µg/mL versus 765.361 µg/mL), but the difference was not statistically significant (P > 0.05). Further correlation analyses showed a negative correlation between the concentration of proteins based on the extent of smoking. A weak negative correlation was found between protein concentration and DMF-T scores (r = −0.239). Dominant salivary protein bands of 11.6 kDa and 54.5 kDa were found in smokers and 27 kDa, 60 kDa, and 94.5 kDa were found in non-smokers.ConclusionDifferent protein bands appeared in smokers and non-smokers. There was a weak correlation between protein concentration, DMF-T scores, and the extent of smoking.     

A rare G1P[6] super-short human rotavirus strain carrying an H2 genotype on the genetic background of a porcine rotavirus

Rotavirus strains with a rearranged 11th genome segment may show super-short RNA electropherotypes. Examples from human strains were limited to seven strains, 69M, 57M, B37, Mc345, AU19, B4106 and BE2001, which have a variety of G and P genotypes. AU19 is a rare G1P[6] human rotavirus strain detected in a Japanese infant with severe acute gastroenteritis. This study was undertaken to better understand the origin of AU19 by determining the genotype constellation of AU19. Upon nearly-full genome sequencing, AU19 had a G1-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H2 genotype constellation. Possession of I5 and A8 genotypes is indicative of its porcine rotavirus origin, whereas possession of H2 genotype is indicative of its DS-1 like human rotavirus origin. At the phylogenetic lineage level for the genome segments that share the genotype between porcine and human rotaviruses, the VP1-4, VP7, NSP3-4 genes were most closely related to those of porcine rotaviruses, but the origin of the NSP2 gene was inconclusive. As to the NSP5 gene, the lineage containing AU19 and the other three super-short human strains, 69M, 57M and B37, carrying the H2 genotype (H2b) clustered with the lineage to which DS-1- like short strains belonged (H2a) albeit with an insignificant bootstrap support. Taken all these observations together, AU19 was likely to emerge as a consequence of interspecies transmission of a porcine rotavirus to a child coupled with the acquisition of a rare H2b genotype by genetic reassortment probably from a co-circulating human strain. The addition of the AU19 NSP5 sequence to much homogeneous H2b genotypes shared by previous super-short rotavirus strains made the genetic diversity of H2b genotypes as diverse as that of the H2a genotype, lending support to the hypothesis that super-short strains carrying H2b genotype have long been circulating unnoticed in the human population.     

Clinical research in small genomically stratified patient populations

The paradigm of early drug development in cancer is shifting from ‘histology-oriented’ to ‘molecularly oriented’ clinical trials. This change can be attributed to the vast amount of tumour biology knowledge generated by large international research initiatives such as The Cancer Genome Atlas (TCGA) and the use of next generation sequencing (NGS) techniques developed in recent years. However, targeting infrequent molecular alterations entails a series of special challenges. The optimal molecular profiling method, the lack of standardised biological thresholds, inter- and intra-tumor heterogeneity, availability of enough tumour material, correct clinical trials design, attrition rate, logistics or costs are only some of the issues that need to be taken into consideration in clinical research in small genomically stratified patient populations. This article examines the most relevant challenges inherent to clinical research in these populations. Moreover, perspectives from the Academia point of view are reviewed as well as initiatives to be taken in forthcoming years.     

Genomic profiling of inflammatory breast cancer: A review

Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. Despite efforts in the past decade to delineate the molecular biology of IBC by applying high-throughput molecular profiling technologies to clinical samples, IBC remains insufficiently characterized. The reasons for that include limited sizes of the study population, heterogeneity with respect to the composition of the IBC and non-IBC control groups and technological differences across studies. In 2008, the World IBC Consortium was founded to foster collaboration between research groups focusing on IBC. One of the initial projects was to redefine the molecular profile of IBC using an unprecedented number of samples and search for gene signatures associated with survival and response to neo-adjuvant chemotherapy. Here, we provide an overview of all the molecular profiling studies that have been performed on IBC clinical samples to date.