The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole using 5160 photomultipliers to detect Cherenkov light from relativistic, charged particles. ...Most IceCube science goals rely on precise understanding and modelling of the optical properties of the instrumented ice. A peculiar light propagation effect observed by IceCube is an anisotropic attenuation, which is aligned with the local flow of the ice. Recent efforts have shown this effect is most likely due to curved photon trajectories resulting from the asymmetric light diffusion in the birefringent polycrystalline microstructure of the ice. This new model can be optimized by adjusting the average orientation, size and shape of the ice crystals. We present the parametrization of the birefringence effect in our photon propagation simulation, the fitting procedures and results. The anticipated potential of calibration instrumentation in the upcoming IceCube Upgrade to improve on known shortcomings of the current ice modelling is also discussed.
To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using ...Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.
Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy ...established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).
Clinical Pharmacology & Therapeutics (2011) 89 5, 662–673. doi:10.1038/clpt.2011.34
Many experimental setups, such as for the calibration of photosensors, require light sources with sub-nanosecond timing precision. We present the design and evaluation of a brightness controlled, ...picosecond light pulser based on an avalanche transistor pulse driving circuit. It can be used with a large variety of LEDs and VCSELs, enabling usage over a wide wavelength range, with light curves as short as ∼100 ps standard deviation.
To determine the pattern of genetic alterations in primary central nervous system lymphomas (PCNSL), 19 PCNSL were studied by high-density single-nucleotide polymorphism arrays. Recurrent losses ...involved 6p21.32, 6q21, 8q12-12.2, 9p21.3, 3p14.2, 4q35.2, 10q23.21 and 12p13.2, whereas gains involved 18q21-23, 19q13.31, 19q13.43 and the entire chromosomes X and 12. Partial uniparental disomies (pUPDs) were identified in 6p and 9p21.3. These genomic alterations affected the HLA locus, the CDKN2A/p16, CDKN2B/p15 and MTAP, as well as the PRDM1, FAS, MALT1, and BCL2 genes. Increased methylation values of the CDKN2A/p16 promoter region were detected in 75% (6/8) PCNSL. Gene expression profiling showed 4/21 (20%) minimal common regions of imbalances to be associated with a differential mRNA expression affecting the FAS, STAT6, CD27, ARHGEF6 and SEPT6 genes. Collectively, this study unraveled novel genomic imbalances and pUPD with a high resolution in PCNSL and identified target genes of potential relevance in the pathogenesis of this lymphoma entity.
To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. ...Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.
Here, primary effusion lymphoma (PEL) is a rare large B-cell neoplasm particularly affecting immunodeficient hosts with an increased incidence in young or middle-aged males infected with the HIV.1 ...The clinical outcome of patients with PEL is unfavorable with a median survival of <6 months.1 PEL has been closely associated with human herpes virus 8 (HHV8, previously called Kaposi sarcoma herpesvirus) infection.1 In some cases a coinfection of HHV8 with the Epstein–Barr Virus (EBV) has been described.1 HHV8 encodes various genes homologous to cellular genes that have proliferative and anti-apoptotic functions.2 Although HHV8 is supposed to be a major driver of PEL, it alone is not sufficient for a full-blown lymphomagenesis.2 PEL usually shows complex karyotypes with many chromosomal aberrations.3 This chromosomal complexity might be driven by the viral infection and lead to genetic alterations cooperating with HHV8 in PEL lymphomagenesis.4
Aim
The role of chemokines and their receptors, which regulate trafficking and homing of leucocytes to inflamed organs in human or murine autoimmune neuritis, has not yet been elucidated in detail, ...Therefore, the role of the chemokine receptors CXCR4 and CXCR7 and their ligand CXCL12 was studied in autoimmune‐mediated inflammation of the peripheral nervous system.
Methods
CXCL12/CXCR4 and/or CXCL12/CXCR7 interactions were specifically inhibited by the compounds AMD3100 or CCX771, respectively, in experimental autoimmune neuritis (EAN) of C57BL/6J mice immunized with P0106–125 peptide.
Results
Disease activity was significantly suppressed by blocking CXCR7 while antagonization of CXCR4 enhanced disease activity. Enhanced disease activity was accompanied by significantly increased transcription of IFN‐γ, IL‐12 and TNF‐α mRNA in regional lymph nodes and spleen as well as by increased serum levels of IFN‐γ. Furthermore, by blocking CXCR4, expression of the cell adhesion molecules ICAM‐1 and VCAM‐1 was upregulated on vascular endothelial cells of the sciatic nerve, which coincided with significantly increased infiltration of the sciatic nerve by CD4+ T cells and macrophages. Remarkably, combined antagonization of both CXCR4 and CXCR7 significantly suppressed disease activity. This was accompanied by increased frequencies of activated and highly IFN‐γ‐expressing, P0106–125‐specific T cells in regional lymph nodes and spleen; however, these cells were unable to infiltrate the sciatic nerve.
Conclusion
These data suggest differential and hierarchically ordered roles for CXCR4/CXCL12‐ vs. CXCR7/CXCL12‐dependent effects during EAN: CXCR7/CXCL12 interaction is a gatekeeper for pathogenic cells, regardless of their CXCR4/CXCL12‐dependent state of activation.
Purpose
The Outcome measures for vascular malformation (OVAMA) group reached consensus on the core outcome domains for the core outcome set (COS) for peripheral vascular malformations (venous, ...lymphatic and arteriovenous malformations). However, it is unclear which instruments should be used to measure these domains. Therefore, our aims were to identify all outcome measurement instruments available for vascular malformations, and to evaluate their measurement properties.
Methods
With the first literature search, we identified outcomes and instruments previously used in prospective studies on vascular malformations. A second search yielded studies on measurement properties of patient- and physician-reported instruments that were either developed for vascular malformations, or used in prospective studies. If the latter instruments were not specifically validated for vascular malformations, we performed a third search for studies on measurement properties in clinically similar diseases (vascular or lymphatic diseases and benign tumors). We assessed the methodological quality of these studies following the Consensus-based Standards for the selection of health Measurement Instruments methodology, and evaluated the quality of the measurement properties.
Results
The first search yielded 27 studies, none using disease-specific instruments. The second and third search included 22 development and/or validation studies, concerning six instruments. Only the Lymphatic Malformation Function Instrument was developed specifically for vascular malformations. Other instruments were generic QoL instruments developed and/or partly validated for clinically similar diseases.
Conclusions
Additional research on measurement properties is needed to assess which instruments may be included in the COS. This review informs the instrument selection and/or the development of new instruments.
Systematic review registration
PROSPERO, 42017056242.
Long-term adaptation of soft tissues is realized through growth and remodeling (G&R). Mathematical models are powerful tools in testing hypotheses on G&R and supporting the design and interpretation ...of experiments. Most theoretical G&R studies concentrate on description of either growth or remodeling. Our model combines concepts of remodeling of collagen recruitment stretch and orientation suggested by other authors with a novel model of general 3D growth. We translate a growth-induced volume change into a change in shape due to the interaction of the growing tissue with its environment. Our G&R model is implemented in a finite element package in 3D, but applied to two rotationally symmetric cases, i.e., the adaptation towards the homeostatic state of the human aorta and the development of a fusiform aneurysm. Starting from a guessed non-homeostatic state, the model is able to reproduce a homeostatic state of an artery with realistic parameters. We investigate the sensitivity of this state to settings of initial parameters. In addition, we simulate G&R of a fusiform aneurysm, initiated by a localized degradation of the matrix of the healthy artery. The aneurysm stabilizes in size soon after the degradation stops.
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