Dynamic Scaling in the Susceptibility of the Spin-1\2 Kagome Lattice Antiferromagnet Herbertsmithite

The spin-1/2 kagome lattice antiferromagnet herbertsmithite, ZnCu$_{3}$(OH)$_{6}$Cl$_{2}$, is a candidate material for a quantum spin liquid ground state. We show that the magnetic response of this material displays an unusual scaling relation in both the bulk ac susceptibility and the low energy dynamic susceptibility as measured by inelastic neutron scattering. The quantity $\chi T^\alpha$ with $\alpha \simeq 0.66$ can be expressed as a universal function of $H/T$ or $\omega/T$. This scaling is discussed in relation to similar behavior seen in systems influenced by disorder or by the proximity to a quantum critical point.Comment: 5 pages, 3 figures v2: updated to match published version

Temozolomide is additive with cytotoxic effect of irradiation in canine glioma cell lines

Background: Similar to human glioblastoma patients, glial tumours in dogs have high treatment resistance and a guarded prognosis. In human medicine, the addition of temozolomide to radiotherapy leads to a favourable outcome in vivo as well as a higher antiproliferative effect on tumour cells in vitro. Objectives: The aim of the study was to determine the radio- and temozolomide-sensitivity of three canine glial tumour cell lines and to investigate a potential additive cytotoxic effect in combined treatment. Additionally, we wanted to detect the level of MGMT promoter methylation in these cell lines and to investigate a potential association between MGMT promoter methylation and treatment resistance. Methods: Cells were treated with various concentrations of temozolomide and/or irradiated with 4 and 8 Gy. Radiosensitization by temozolomide was evaluated using proliferation assay and clonogenic assay, and MGMT DNA methylation was investigated using bisulfite next-generation sequencing. Results: In all tested canine cell lines, clonogenicity was inhibited significantly in combined treatment compared to radiation alone. All canine glial cell lines tested in this study were found to have high methylation levels of MGMT promoter. Conclusions: Hence, an additive effect of combined treatment in MGMT negative canine glial tumour cell lines in vitro was detected. This motivates to further investigate the association between treatment resistance and MGMT, such as MGMT promoter methylation status

Spin Dynamics of the Spin-1/2 Kagome Lattice Antiferromagnet ZnCu_3(OH)_6Cl_2

We have performed thermodynamic and neutron scattering measurements on the S=1/2 kagome lattice antiferromagnet Zn Cu_3 (OH)_6 Cl_2. The susceptibility indicates a Curie-Weiss temperature of ~ -300 K; however, no magnetic order is observed down to 50 mK. Inelastic neutron scattering reveals a spectrum of low energy spin excitations with no observable gap down to 0.1 meV. The specific heat at low-T follows a power law with exponent less than or equal to 1. These results suggest that an unusual spin-liquid state with essentially gapless excitations is realized in this kagome lattice system.Comment: 4 pages, 3 figures; v2: Updates to authors list and references; v3: Updated version; v4: Published versio

Extracellular heat shock protein 70 levels in tumour-bearing dogs and cats treated with radiation therapy and hyperthermia

Hyperthermia is a form of a cancer treatment which is frequently applied in combination with radiotherapy (RT) to improve therapy responses and radiosensitivity. The mode of action of hyperthermia is multifactorial; the one hand by altering the amount of the blood circulation in the treated tissue, on the other hand by modulating molecular pathways involved in cell survival processes and immunogenic interactions. One of the most dominant proteins induced by hyperthermia is the major stress-inducible heat shock protein 70 (Hsp70). Hsp70 can be found in the blood either as a free-protein (free HSP70) derived from necrotic cells, or lipid-bound (liposomal Hsp70) when it is actively released in extracellular vesicles (EVs) by living cells. The aim of the study was to evaluate the levels of free and liposomal Hsp70 before and after treatment with RT alone or hyperthermia combined with radiotherapy (HTRT) in dogs and cats to evaluate therapy responses. Peripheral blood was collected from feline and canine patients before and at 2, 4, 6 and 24 h after treatment with RT or HTRT. Hsp70 enzyme-linked immunosorbent assays (ELISAs) were performed to determine the free and liposomal Hsp70 concentrations in the serum. The levels were analysed after the first fraction of radiation to study immediate effects and after all applied fractions to study cumulative effects. The levels of free and liposomal Hsp70 levels in the circulation were not affected by the first singular treatment and cumulative effects of RT in cats however, after finalizing all treatment cycles with HTRT free and liposomal Hsp70 levels significantly increased. In dogs, HTRT, but not treatment with RT alone, significantly affected liposomal Hsp70 levels during the first fraction. Free Hsp70 levels were significantly increased after RT, but not HTRT, during the first fraction in dogs. In dogs, on the other hand, RT alone resulted in a significant increase in liposomal Hsp70, but HTRT did not significantly affect the liposomal Hsp70 when cumulative effects were analysed. Free Hsp70 was significantly induced in dogs after both, RT and HTRT when cumulative effects were analysed. RT and HTRT treatments differentially affect the levels of free and liposomal Hsp70 in dogs and cats. Both forms of Hsp70 could potentially be further investigated as potential liquid biopsy markers to study responses to RT and HTRT treatment in companion animals

Regulated Function of the Prolyl-4-Hydroxylase Domain (PHD) Oxygen Sensor Proteins

ABSTRACT Cellular oxygen is sensed by prolyl-4-hydroxylase domain (PHD) proteins that hydroxylate hypoxia-inducible factor (HIF) α subunits. Under normoxic conditions, hydroxylated HIFα is bound by the von Hippel-Lindau (pVHL) tumor suppressor, leading to ubiquitinylation and proteasomal degradation. Under hypoxic conditions hydroxylation becomes reduced, leading to HIFα stabilization. We recently showed that changes in PHD abundance and activity can regulate HIFα stability under normoxic as well as under hypoxic conditions. Thus, the PHD oxygen sensors themselves represent effectors of cellular signalling pathways as well as potential drug targets. Here, we applied a cell-free in vitro microtiter plate-based peptide hydroxylation assay to investigate the influence of ferrous iron, Krebs cycle intermediates, transition metals, vitamin C and other antioxidants on the activity of purified PHD1 to 3. PHD activity depends not only on oxygen availability but is also regulated by iron, vitamin C and Krebs cycle intermediates, suggesting a physiological relevance of their cellular concentrations. Copper but not iron, cobalt or nickel salts catalyzed vitamin C oxidation. While vitamin C is essential for PHD activity in vitro, N-acetyl-L-cysteine had no effect, and gallic acid or n-propyl gallate efficiently inhibited the activity of all three PHDs, demonstrating different functions of these antioxidants

Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

Hypoxia-inducible factor 2α (HIF-2α) plays a pivotal role in the balancing of oxygen request throughout the body. The protein is a transcription factor that modulates the expression of a wide array of genes and, in turn, controls several key processes including energy metabolism, erythropoiesis and angiogenesis. We describe here the identification of two cases of familial erythrocytosis associated with heterozygous HIF2A missense mutations, namely Ile533Val and Gly537Arg. Ile533Val is a novel mutation and represents the genetic HIF2A change nearest to Pro-531, the primary hydroxyl acceptor residue, so far identified. Gly537Arg missense mutation has been already described in familial erythrocytosis. However, our patient is the only described case of a de novo HIF2A mutation associated with congenital polycythemia development. Functional in vivo studies, based on exogenous expression of hybrid HIF-2α transcription factors, indicated that these genetic alterations lead to the stabilization of HIF-2α protein. All the identified polycythemic subjects with HIF2A mutations show serum erythropoietin in the normal range, independently of the hematocrit values and phlebotomy frequency. The erythroid precursors obtained from the peripheral blood of patients showed an altered phenotype, including an increased rate of growth and a modified expression of some HIF-2α target genes. These results suggest the novel proposal that polycythemia observed in subjects with HIF2A mutations might be also due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels