Diffusion and Interface Effects during Preparation of All-Solid Microstructured Fibers

All-solid microstructured optical fibers (MOF) allow the realization of very flexible optical waveguide designs. They are prepared by stacking of doped silica rods or canes in complex arrangements. Typical dopants in silica matrices are germanium and phosphorus to increase the refractive index (RI), or boron and fluorine to decrease the RI. However, the direct interface contact of stacking elements often causes interrelated chemical reactions or evaporation during thermal processing. The obtained fiber structures after the final drawing step thus tend to deviate from the targeted structure risking degrading their favored optical functionality. Dopant profiles and design parameters (e.g., the RI homogeneity of the cladding) are controlled by the combination of diffusion and equilibrium conditions of evaporation reactions. We show simulation results of diffusion and thermal dissociation in germanium and fluorine doped silica rod arrangements according to the monitored geometrical disturbances in stretched canes or drawn fibers. The paper indicates geometrical limits of dopant structures in sub-µm-level depending on the dopant concentration and the thermal conditions during the drawing process. The presented results thus enable an optimized planning of the preform parameters avoiding unwanted alterations in dopant concentration profiles or in design parameters encountered during the drawing process.     

Meso-scale turbulence in living fluids

Turbulence is ubiquitous, from oceanic currents to small-scale biological and quantum systems. Self-sustained turbulent motion in microbial suspensions presents an intriguing example of collective dynamical behavior among the simplest forms of life and is important for fluid mixing and molecular transport on the microscale. The mathematical characterization of turbulence phenomena in active nonequilibrium fluids proves even more difficult than for conventional liquids or gases. It is not known which features of turbulent phases in living matter are universal or system-specific or which generalizations of the Navier-Stokes equations are able to describe them adequately. Here, we combine experiments, particle simulations, and continuum theory to identify the statistical properties of self-sustained meso-scale turbulence in active systems. To study how dimensionality and boundary conditions affect collective bacterial dynamics, we measured energy spectra and structure functions in dense Bacillus subtilis suspensions in quasi-2D and 3D geometries. Our experimental results for the bacterial flow statistics agree well with predictions from a minimal model for self-propelled rods, suggesting that at high concentrations the collective motion of the bacteria is dominated by short-range interactions. To provide a basis for future theoretical studies, we propose a minimal continuum model for incompressible bacterial flow. A detailed numerical analysis of the 2D case shows that this theory can reproduce many of the experimentally observed features of self-sustained active turbulence.     

High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations

To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient populations. Recurrent minimally deleted regions (MDRs) were identified at 7q36.1 (7.7%), 9q21.32 (5%), 11p13 (2.3%), and 17q11.2 (2%). Approximately one-half of the 7q deletions were detectable only by single-nucleotide polymorphism-array analysis because of their limited size. Sequence analysis of MLL3, contained within the 7q36.1 MDR, in 46 diagnostic samples revealed one truncating mutation in a leukemia lacking a 7q deletion. Recurrent focal gains were identified at 8q24.21 (4.7%) and 11q25 (1.7%), both containing a single noncoding RNA. Recurrent regions of copy-neutral loss-of-heterozygosity were identified at 1p (1%), 4q (0.7%), and 19p (0.7%), with known mutated cancer genes present in the minimally altered region of 1p (NRAS) and 4q (TET2). Analysis of relapse samples identified recurrent MDRs at 3q13.31 (12.2%), 5q (4.9%), and 17p (4.9%), with the 3q13.31 region containing only LSAMP, a putative tumor suppressor. Determining the role of these lesions in leukemogenesis and drug resistance should provide important insights into core-binding factor acute myeloid leukemia.     

Mutated regions of nucleophosmin 1 elicit both CD4(+) and CD8(+) T-cell responses in patients with acute myeloid leukemia

Mutations in the nucleophosmin gene (NPM1(mut)) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1(mut). In the present study, we were able to demonstrate both CD4(+) and CD8(+) T-cell responses against NPM1(mut). Ten peptides derived from wild-type NPM1 and NPM1(mut) were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against the most interesting epitopes were performed and Cr(51)-release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4(+) T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1(mut) induced CD8(+) T-cell responses. A total of 33% of the NPM1(mut) AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4(+) T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8(+) and CD4(+) T cells. The results of the present study show that NPM1(mut) induces specific T-cell responses of CD4(+) and CD8(+) T cells and therefore is a promising target for specific immunotherapies in AML.     

Risk categories and refractory CLL in the era of chemoimmunotherapy

Standardized criteria for diagnosis and response evaluation in chronic lymphocytic leukemia (CLL) are essential to achieve comparability of results and improvement of clinical care. With the increasing range of therapeutic options, the treatment context is important when defining refractory CLL. Refractory CLL has been defined as no response or response lasting ≤ 6 months from last therapy. This subgroup has a very poor outcome, and many trials use this group as an entry point for early drug development. With the intensification of first-line regimens, the proportion of patients with refractory CLL using these criteria decreases. This has immediate consequences for recruitment of patients into trials as well as salvage strategies. Conversely, patients who are not refractory according to the traditional definition but who have suboptimal or short response to intense therapy also have a very poor outcome. In this Perspective, we discuss recent results that may lead to a reassessment of risk categories in CLL focusing on fit patients who are eligible for all treatment options. We cover aspects of the history and biologic basis for refractory CLL and will focus on how emerging data on treatment failure from large trials using chemoimmunotherapy may help to define risk groups in CLL.     

Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium

Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.