Low expression and promoter hypermethylation of the tumour suppressor SLIT2, are associated with adverse patient outcomes in diffuse large B cell lymphoma

SLIT2 has been classified as a major tumour suppressor gene due to its frequent inactivation in different cancer types. However, alterations of SLIT2 expression and relation to patient outcomes in diffuse large B cell lymphoma (DLBCL) remain undefined. The aim of this study was to investigate the expression and the methylation status of SLIT2 gene as well as its relation to patient outcomes in DLBCL. Immunohistochemical (IHC) staining was carried out to detect the expression of SLIT2 in a series of 108 DLBCL cases. Re-analysis of previously published dataset (GSE10846) that measured gene expression in DLBCL patients who had received CHOP or R-CHOP therapy was performed to identify associations between SLIT2 and patients survival. Laser capture microdissection was performed to isolate GC B cells and DLBCL primary tumor cells. Bisulfite treatment and methylation-specific PCR (MSP) analysis were done to assess SLIT2 promotor methylation status. We report that the expression of SLIT2 protein was reduced in a subset of DLBCL cases and this was significantly correlated with advanced clinical stage (p = 0.041) and was an independent predictor of worse overall survival (OS) (p = 0.012). Re-analysis of published gene expression data showed that reduced SLIT2 mRNA expression was significantly correlated with worse OS in R-CHOP-treated ABC DLBCL patients (p = <0.01). Hypermethylation of the SLIT2 promotor was significantly correlated with low SLIT2 expression (p = 0.009). Our results provide a novel evidence of reduced expression of SLIT2 that is associated with promoter hypermethylation and adverse outcomes in patients with DLBCL

T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.

Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation. This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells. Current primary CLL xenograft models suffer from limited duration of tumour cell engraftment coupled with gradual T-cell outgrowth. Thus, a greater understanding of the interaction between CLL and T cells could improve their utility. In this study, using two distinct mouse xenograft models, we investigated whether xenografts recapitulate CLL biology, including natural environmental interactions with B-cell receptors and T cells, and whether manipulation of autologous T cells can expand the duration of CLL engraftment. We observed that primary CLL xenografts recapitulated both the tumour phenotype and T-cell repertoire observed in patients and that engraftment was significantly shorter for progressive tumours. A reduction in the number of patient T cells that were injected into the mice to 2-5% of the initial number or specific depletion of CD8+ cells extended the limited xenograft duration of progressive cases to that characteristic of indolent disease. We conclude that manipulation of T cells can enhance current CLL xenograft models and thus expand their utility for investigation of tumour biology and pre-clinical drug assessment

The Mu3e experiment: Toward the construction of an HV-MAPS vertex detector

The Mu3e experiment searches for the lepton flavor violating decay $\mu^+~\rightarrow~e^+~e^+~e^-$ with an ultimate aimed sensitivity of 1 event in $10^{16}$ decays. This goal can only be achieved by reducing the material budget per tracking layer to $X/X_0 \approx 0.1 \%$. High-Voltage Monolithic Active Pixel Sensors (HV-MAPS) which are thinned to 50 μm serve as sensors. Gaseous helium is chosen as coolant. Results of recent studies related to the sensor prototypes, the helium cooling, and module prototyping are presented. The recent chip submission MuPix10 has proven its functionality regarding efficiency and time resolution. The helium cooling system for the inner tracker could be verified using a full-scale prototype. A complete prototype equipped with MuPix10 chips will be tested inside the Mu3e magnet in summer 2021

The Mu3e experiment: Toward the construction of an HV-MAPS vertex detector

The Mu3e experiment searches for the lepton flavor violating decay $\mu^+~\rightarrow~e^+~e^+~e^-$ with an ultimate aimed sensitivity of 1 event in $10^{16}$ decays. This goal can only be achieved by reducing the material budget per tracking layer to $X/X_0 \approx 0.1 \%$. High-Voltage Monolithic Active Pixel Sensors (HV-MAPS) which are thinned to $50\ \mu m$ serve as sensors. Gaseous helium is chosen as coolant. Results of recent studies related to the sensor prototypes, the helium cooling, and module prototyping are presented. The recent chip submission MuPix10 has proven its functionality regarding efficiency and time resolution. The helium cooling system for the inner tracker could be verified using a full-scale prototype. A complete prototype equipped with MuPix10 chips will be tested inside the Mu3e magnet in summer 2021.Comment: Talk presented at the International Workshop on Future Linear Colliders (LCWS2021), 15-18 March 2021. C21-03-15.

The GRONORUN study: is a graded training program for novice runners effective in preventing running related injuries? Design of a Randomized Controlled Trial

BACKGROUND: Running is a popular form of recreational exercise. Beside the positive effects of running on health and fitness, the risk of a running related injury has to be considered. The incidence of injuries in runners is high and varies from 30–79%. However, few intervention studies on prevention of running related injuries have been performed and none of these studies involved novice runners. METHODS: GRONORUN (Groningen Novice Running) is a two armed randomized controlled trial, comparing the effects of two different training programs for novice runners on the incidence of running related injuries. Participants are novice runners, who want to train for a four mile running event. The control group will train according a standard 8 week training program. The intervention group will use a more gradual, 13 week training program which is based on "the ten percent training rule". During the thirteen week follow up participants register information on running and RRI's in an internet based running log. The primary outcome measure is RRI. An injury is defined as a musculoskeletal ailment of the lower extremity or back, causing a restriction of running for at least one week. DISCUSSION: The GRONORUN trial is the first randomized controlled trial to study a preventive intervention in novice runners. Many different training programs for novice runners are offered, but none are evidence based

Group analysis of structure equations for stars in radiative and convective equilibrium

It is proposed to use the Lie group theory of symmetries of differential equations to investigate the system of equations describing a static star in a radiative and convective equilibrium. It is shown that the action of an admissible group induces a certain algebraic structure in the set of all solutions, which can be used to find a family of new solutions. We have demonstrated that, in the most general case, the equations admit an infinite parameter group of quasi-homologous transformations. We have found invariants of the symmetries group which correspond to the fundamental relations describing a physical characteristic of the stars such as the Hertzsprung-Russell diagram or the mass-luminosity relation. In this way we can suggest that group invariants have not only purely mathematical sense, but their forms are closely associated with the basic empirical relations.Comment: LaTeX2e, 13page

MuPix and ATLASPix -- Architectures and Results

High Voltage Monolithic Active Pixel Sensors (HV-MAPS) are based on a commercial High Voltage CMOS process and collect charge by drift inside a reversely biased diode. HV-MAPS represent a promising technology for future pixel tracking detectors. Two recent developments are presented. The MuPix has a continuous readout and is being developed for the Mu3e experiment whereas the ATLASPix is being developed for LHC applications with a triggered readout. Both variants have a fully monolithic design including state machines, clock circuitries and serial drivers. Several prototypes and design variants were characterised in the lab and in testbeam campaigns to measure efficiencies, noise, time resolution and radiation tolerance. Results from recent MuPix and ATLASPix prototypes are presented and prospects for future improvements are discussed.Comment: 10 pages, proceedings, The 28th International Workshop on Vertex Detectors (VERTEX 2019), 13 - 18 Oct 2019, Lopud Island, Croati

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line

Over-expression of the adhesion molecule CD44 and its splice variants, especially CD44v6, is associated with poor prognosis and metastasis. We aimed at regulating the expression of CD44 in the highly metastatic human colon cancer cell line HM7 and thereby affecting its metastatic ability. HM7 cells show constitutive expression of CD44 standard and variants isoforms, which were significantly down-regulated by treatment with butyrate. Butyrate significantly inhibited transcription of the CD44 gene and abolished epidermal growth factor-mediated up-regulation of the reporter gene luciferase subcloned upstream to the CD44 promoter (−1.1 kb) and transfected to HM7 cells. Nuclear proteins from butyrate-treated cells bound to an epidermal growth factor receptor element motif present in the CD44 promoter. Epidermal growth factor receptor element-site directed mutations eliminated the inducibility of the luciferase reporter gene and did not allowed binding of nuclear proteins harvested from butyrate-treated cells. Butyrate induced CD44 gene repression by specifically interacting with an epidermal growth factor receptor element nuclear transcriptional factor. This interaction affects CD44 transcriptional activity vis-à-vis in vivo metastatic ability of HM7 cells. These results provide additional insight into the anticarcinogenic properties of butyrate

Solid-State Microwave Electronics

Contains reports on two research projects.National Aeronautics and Space Administration (Grant NGR-22-009-163