Gene expression and copy number profiling of follicular lymphoma biopsies from patients treated with first-line rituximab without chemotherapy.

The Nordic Lymphoma Study Group has performed two randomized clinical trials with chemotherapy-free first-line treatment (rituximab +/- interferon) in follicular lymphoma (FL), with 73% of patients alive and 38% without any need of chemotherapy after 10.6 years median follow-up. In order to identify predictive markers, that may also serve as therapeutic targets, gene expression- and copy number profiles were obtained from 97 FL patients using whole genome microarrays. Copy number alterations (CNAs) were identified, e.g. by GISTIC. Cox Lasso Regression and Lasso logistic regression were used to determine molecular features predictive of time to next therapy (TTNT). A few molecular changes were associated with TTNT (e.g. increased expression of INPP5B, gains in 12q23/q24), but were not significant after adjusting for multiple testing. Our findings suggest that there are no strong determinants of patient outcome with respect to GE data and CNAs in FL patients treated with a chemotherapy-free regimen (i.e. rituximab +/- interferon).

Differences between BCL2-break positive and negative follicular lymphoma unraveled by whole-exome sequencing.

Depending on disease stage follicular lymphoma (FL) lack the t(14;18) in ~15-~50% of cases. Nevertheless, most of these cases express BCL2. To elucidate mechanisms triggering BCL2 expression and promoting pathogenesis in t(14;18)-negative FL, exonic single-nucleotide variant (SNV) profiles of 28 t(14;18)-positive and 13 t(14;18)-negative FL were analyzed, followed by the integration of copy-number changes, copy-neutral LOH and published gene-expression data as well as the assessment of immunoglobulin N-glycosylation sites. Typical FL mutations also affected t(14;18)-negative FL. Curated gene set/pathway annotation of genes mutated in either t(14;18)-positive or t(14;18)-negative FL revealed a strong enrichment of same or similar gene sets but also a more prominent or exclusive enrichment of immune response and N-glycosylation signatures in t(14;18)-negative FL. Mutated genes showed high BCL2 association in both subgroups. Among the genes mutated in t(14;18)-negative FL 555 were affected by copy-number alterations and/or copy-neutral LOH and 96 were differently expressed between t(14;18)-positive and t(14;18)-negative FL (P<0.01). N-glycosylation sites were detected considerably less frequently in t(14;18)-negative FL. These results suggest a diverse portfolio of genetic alterations that may induce or regulate BCL2 expression or promote pathogenesis of t(14;18)-negative FL as well as a less specific but increased crosstalk with the microenvironment that may compensate for the lack of N-glycosylation.

The microstructure, local indium composition and photoluminescence in green-emitting InGaN/GaN quantum wells.

In this work, we analyse the microstructure and local chemical composition of green-emitting Inx Ga1-x N/GaN quantum well (QW) heterostructures in correlation with their emission properties. Two samples of high structural quality grown by metalorganic vapour phase epitaxy (MOVPE) with a nominal composition of x = 0.15 and 0.18 indium are discussed. The local indium composition is quantitatively evaluated by comparing scanning transmission electron microscopy (STEM) images to simulations and the local indium concentration is extracted from intensity measurements. The calculations point out that the measured indium fluctuations may be correlated to the large width and intensity decrease of the PL emission peak.

Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules.

Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.

Compositional characterization of GaAs/GaAsSb nanowires by quantitative HAADF-STEM.

The Sb concentration in axial GaAs(1-x)Sb(x) inserts of otherwise pure GaAs nanowires has been investigated with quantitative high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). The Sb concentration was quantified by comparing the experimental image intensities normalized to the incident beam intensity with intensities simulated with a frozen lattice multislice approach. Including static atomic displacements in the simulations was found to be crucial for correct compositional analysis of GaAs(1-x)Sb(x). HAADF intensities of individual nanowires were analysed both across the nanowires, exploiting their hexagonal cross-sectional shape, and along the evenly thick central part of the nanowires. From the cross-sectional intensity profiles, a decrease in the Sb concentration towards the nanowire outer surfaces was found. The longitudinal intensity profiles revealed a gradual build-up of Sb in the insert. The decrease of the Sb concentration towards the upper interface was either gradual or abrupt, depending on the growth routine chosen. The compositional analysis with quantitative HAADF-STEM was verified by energy dispersive X-ray spectroscopy.

Retrospective study of mercury in raccoons (Procyon lotor) in south Florida.

Museum and recent collections of raccoon hair were used to assess whether temporal or spatial trends existed in MMHg distributions in south Florida. The hypothesis that MMHg in raccoon hair had remained the same since 1947 could not be rejected. Some sampling regions showed increases while others did not. However, large differences existed between sites, amounting to a factor of 20 for raccoons collected during 2000 and during the period prior to 1960 (museum samples). Raccoon feeding behavior and the production of MMHg most probably accounted for the spatial differences. Large differences in MMHg concentrations existed in different tissues ranging in order of hair, liver, kidney, muscle, heart, brain, and blood in their respective ratios to blood: 96:10:6:5:4:2.5:1. Liver Hg is 7% MMHg, while hair Hg is 99% MMHg. These associations appear largely regulated by metabolic processes. Speciation of Hg is very important for gaining an understanding of ecosystem and organism Hg dynamics. Further work is needed to establish whether Se plays a role in Hg sequestration and whether hair Hg is a good surrogate for estimating Hg concentrations in other tissues in south Florida raccoon populations.

The mitogenic activity of fibroblast growth factor-1 correlates with its internalization and limited proteolytic processing.

The fibroblast growth factor-1 (FGF-1) mitogenic signal transduction pathway is not well characterized, and evidence indicates that FGF-1 binding to and activation of cell-surface receptors is not solely sufficient for a full mitogenic response. Although initiation of the phosphorylation signaling cascades are likely important in FGF-1-induced mitogenic signaling, there appear to be additional signaling requirements. In this study, we demonstrate that FGF-1 internalization and subsequent processing correlates with the mitogenic potential of the growth factor on NIH 3T3 cells. Using site-directed mutants of FGF-1 and inhibitors of the endocytic and degradative pathways, we provide evidence for growth factor internalization and exposure to an acidic environment as necessary components of FGF-1-induced mitogenesis. In addition, a protease-sensitive event(s) appears critical for a complete mitogenic response to FGF-1, whereas, this protease sensitivity was not detected under the same conditions for serum-stimulated mitogenesis. Therefore, proteolytic modification of internalized FGF-1 may result in the activation of additional, intracellular signaling events.

Primary structure of ovine fibroblast growth factor-1 deduced by protein and cDNA analysis.

The amino acid sequence of full-length ovine fibroblast growth factor-1 (FGF-1) was determined by a combination of protein and cDNA sequencing. FGF-1 cDNA analysis indicated that ovine kidney cells express mRNAs encoding both full-length FGF-1 and a truncated FGF-1 variant. An overall comparison of the ovine FGF-1 primary sequence to the eight species studied to date revealed a high degree of conservation, with ovine FGF-1 sharing 90 and 95% sequence identity with human FGF-1 and bovine FGF-1, respectively. Additionally, the FGF-1 proteins from the various species have conserved cysteine residues at positions 30 and 97 and contain acetylated amino-terminal alanine residues. Mass spectrometry analysis confirmed that the blocking group of ovine FGF-1 is also consistent with that of an acetyl-moiety. In contrast to the other FGF-1 proteins, the 154 residue primary sequence of ovine FGF-1 contains three unique amino acid differences: Arg9, Arg44, and Ile123. Ovine FGF-1, unlike human FGF-1, is a potent mitogenic factor for NIH 3T3 fibroblasts in the absence of heparin. In the presence of exogenous heparin, the mitogenic activity of ovine FGF-1 is potentiated slightly.