RUNX3 transcript variants have distinct roles in ovarian carcinoma and differently influence platinum sensitivity and angiogenesis

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis

A Tunable Narrowband Source in the Sub-THz and THz Range at DELTA

At DELTA, a 1.5-GeV electron storage ring operated as a synchrotron light source by the TU Dortmund University, an interaction of ultrashort laser pulses with electron bunches is used to generate broadband as well as tunable narrowband radiation in the frequency range between 75 GHz and 5.6 THz. The performance of the source was studied using two different Fourier-transform spectrometers. It was demonstrated that the source can be used for the characterization and comparison of Schottky-diode based detectors, e.g., an on-chip spectrometer enabling single-shot applications

Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2(V617F) malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Ultrafine MnWO₄ nanoparticles and their magnetic properties

Abstract Ultrafine nanoparticles of MnWO4, a compound showing low-temperature multiferroicity in the bulk, were synthesized by the polyol method. Studies using powder X-ray diffraction, scanning and transmission electron microscopy, dynamic light scattering, differential sedimentation and sorption techniques show the formation of a single-phase material, which is composed of MnWO4 nanoparticles with a prolate ellipsoidal shape (short axis of 4–5 nm, long axis of 11–12 nm) and an unprecedented high specific surface area of 166 m2 g−1. The as-prepared MnWO4 nanoparticles are readily crystalline after the liquid-phase synthesis. Temperature and field dependent magnetization measurements indicate antiferromagnetic behavior with a single magnetic phase transition near TN ≈ 6 K. In contrast, three successive transitions below 14 K were reported for multiferroic bulk-MnWO4. Above TN, the nanoparticles show Curie–Weiss-type paramagnetic behavior. Due to the large paramagnetic moment of Mn2+ (μeff ≈ 6.2 μB), the nanoparticles can be easily manipulated by a bar magnet at ambient temperature

Continuously tunable narrowband pulses in the THz gap from laser-modulated electron bunches in a storage ring

This article reports on the generation of narrowband coherent synchrotron radiation from an electron storage ring. For the first time, this kind of radiation was now produced with continuously tunable frequencies in the so-called “THz gap” (between 1.2 and 5.6 THz), whereas previous experiments were limited to below 750 GHz. The experiment was performed at the DELTA storage ring in Dortmund, Germany, employing the interaction of external intensity-modulated laser pulses with an electron bunch, which causes a periodic longitudinal modulation of the charge density on a sub-millimeter scale. Furthermore, a strong influence of third-order dispersion in the laser pulses on the bandwidth and peak intensity of the THz radiation was observed. This effect is discussed in detail based on numerical simulations of the laser pulse generation and laser-electron interaction, and a modification of the laser system for compensating third-order dispersion is proposed