110 research outputs found
Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial
AIMS/HYPOTHESIS: The aim was to evaluate the efficacy and safety of
transcutaneous frequency-modulated electromagnetic neural stimulation (frequency
rhythmic electrical modulation system, FREMS) as a treatment for symptomatic
peripheral neuropathy in patients with diabetes mellitus.
METHODS: This was a double-blind, randomised, multicentre, parallel-group study
of three series, each of ten treatment sessions of FREMS or placebo administered
within 3 weeks, 3 months apart, with an overall follow-up of about 51 weeks. The
primary endpoint was the change in nerve conduction velocity (NCV) of deep
peroneal, tibial and sural nerves. Secondary endpoints included the effects of
treatment on pain, tactile, thermal and vibration sensations. Patients eligible
to participate were aged 18-75 years with diabetes for ≥ 1 year, HbA(1c) <11.0%
(97 mmol/mol), with symptomatic diabetic polyneuropathy at the lower extremities
(i.e. abnormal amplitude, latency or NCV of either tibial, deep peroneal or sural
nerve, but with an evocable potential and measurable NCV of the sural nerve), a
Michigan Diabetes Neuropathy Score ≥ 7 and on a stable dose of medications for
diabetic neuropathy in the month prior to enrolment. Data were collected in an
outpatient setting. Participants were allocated to the FREMS or placebo arm (1:1
ratio) according to a sequence generated by a computer random number generator,
without block or stratification factors. Investigators digitised patients' date
of birth and site number into an interactive voice recording system to obtain the
assigned treatment. Participants, investigators conducting the trial, or people
assessing the outcomes were blinded to group assignment.
RESULTS: Patients (n = 110) with symptomatic neuropathy were randomised to FREMS
(n = 54) or placebo (n = 56). In the intention-to-treat population (50 FREMS, 51
placebo), changes in NCV of the three examined nerves were not different between
FREMS and placebo (deep peroneal [means ± SE]: 0.74 ± 0.71 vs 0.06 ± 1.38 m/s;
tibial: 2.08 ± 0.84 vs 0.61 ± 0.43 m/s; and sural: 0.80 ± 1.08 vs -0.91 ± 1.13
m/s; FREMS vs placebo, respectively). FREMS induced a significant reduction in
day and night pain as measured by a visual analogue scale immediately after each
treatment session, although this beneficial effect was no longer measurable 3
months after treatment. Compared with the placebo group, in the FREMS group the
cold sensation threshold was significantly improved, while non-significant
differences were observed in the vibration and warm sensation thresholds. No
relevant side effects were recorded during the study.
CONCLUSIONS/INTERPRETATION: FREMS proved to be a safe treatment for symptomatic
diabetic neuropathy, with immediate, although transient, reduction in pain, and
no effect on NCV.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01628627.
FUNDING: The clinical trial was sponsored by Lorenz Biotech (Medolla, Italy),
lately Lorenz Lifetech (Ozzano dell'Emilia, Italy)
Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-mir-17-92
The microRNA cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce RNase H-mediated degradation of MIR17HG primary transcripts and, consequently, to prevent biogenesis of miR-17-92 microRNAs (miR-17-92s). The leading LNA-ASO, named MIR17PTi, impaired proliferation of several cancer cell lines (n=48) established from both solid and hematologic tumors by on-target antisense activity, and more effectively as compared to miR-17-92s inhibitors. By focusing on multiple myeloma (MM), we found that MIR17PTi triggers apoptosis via impairment of homeostatic MYC/miR-17-92 feed-forward loops (FFLs) in patient-derived MM cells; and induced MYC-dependent synthetic lethality. We show that alteration of a BIM-centered FFL is instrumental for MIR17PTi to induce cytotoxicity in MM cells. MIR17PTi exerts strong in vivo anti-tumor activity in NOD-SCID mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetics profiles in non-human primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies
Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
Background: Genomic instability is a feature of multiple myeloma (MM), and impairment in DNA damaging response (DDR) has an established role in disease pathobiology. Indeed, a deregulation of DNA repair pathways may contribute to genomic instability, to the establishment of drug resistance to genotoxic agents, and to the escape from immune surveillance. On these bases, we evaluated the role of different DDR pathways in MM and investigated, for the first time, the direct and immune-mediated anti-MM activity of the nucleotide excision repair (NER)-dependent agent trabectedin. Methods: Gene-expression profiling (GEP) was carried out with HTA2.0 Affymetrix array. Evaluation of apoptosis, cell cycle, and changes in cytokine production and release have been performed in 2D and 3D Matrigel-spheroid models through flow cytometry on MM cell lines and patients-derived primary MM cells exposed to increasing nanomolar concentrations of trabectedin. DNA-damage response has been evaluated through Western blot, immunofluorescence, and DNA fragmentation assay. Trabectedin-induced activation of NK has been assessed by CD107a degranulation. miRNAs quantification has been done through RT-PCR. Results: By comparing GEP meta-analysis of normal and MM plasma cells (PCs), we observed an enrichment in DNA NER genes in poor prognosis MM. Trabectedin triggered apoptosis in primary MM cells and MM cell lines in both 2D and 3D in vitro assays. Moreover, trabectedin induced DDR activation, cellular stress with ROS production, and cell cycle arrest. Additionally, a significant reduction of MCP1 cytokine and VEGF-A in U266-monocytes co-cultures was observed, confirming the impairment of MM-promoting milieu. Drug-induced cell stress in MM cells led to upregulation of NK activating receptors ligands (i.e., NKG2D), which translated into increased NK activation and degranulation. Mechanistically, this effect was linked to trabectedin-induced inhibition of NKG2D-ligands negative regulators IRF4 and IKZF1, as well as to miR-17 family downregulation in MM cells. Conclusions: Taken together, our findings indicate a pleiotropic activity of NER-targeting agent trabectedin, which appears a promising candidate for novel anti-MM therapeutic strategies
Vitamin-V: Virtual Environment and Tool-boxing for Trustworthy Development of RISC-V based Cloud Services
Vitamin-V is a 2023-2025 Horizon Europe project that aims to develop a complete RISC-V open-source software stack for cloud services with comparable performance to the cloud-dominant x86 counterpart and a powerful virtual execution environment for software development, validation, verification, and test that considers the relevant RISC-V ISA extensions for cloud deployment
The neutron irradiation module at the European Spallation Source ESS
The neutron Irradiation Module at the European Spallation Source will make use of the high intensity fast neutron spectrum to study the behaviour of the materials used in the facility, set within the ESS research and development program for the target station. By studying how these materials are affected by radiation, estimates of the material degradation in irrradiated bespoke samples will allow to optimise of the design and lifetime of regularly replaced target components. The general design and a set of results from the neutronics calculations, aimed at estimating proton and neutron flux distributions, displacement damage, heat deposition and activation for the radiological hazard analysis of the Irradiation Module, set within the Italian contributions to the ESS construction phase, are reported. © Published under licence by IOP Publishing Ltd
Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren's Disease
Dupuytren's disease is a fibro-proliferative disease characterized by a disorder of the extracellular matrix (ECM) and high myofibroblast proliferation. However, studies failed to determine if the whole palm fascia is affected by the disease. The objective of this study was to analyze several components of the extracellular matrix of three types of tissues—Dupuytren's diseased contracture cords (DDC), palmar fascia clinically unaffected by Dupuytren's disease contracture (NPF), and normal forehand fascia (NFF). Histological analysis, quantification of cells recultured from each type of tissue, mRNA microarrays and immunohistochemistry for smooth muscle actin (SMA), fibrillar ECM components and non-fibrillar ECM components were carried out. The results showed that DDC samples had abundant fibrosis with reticular fibers and few elastic fibers, high cell proliferation and myofibroblasts, laminin and glycoproteins, whereas NFF did not show any of these findings. Interestingly, NPF tissues had more cells showing myofibroblasts differentiation and more collagen and reticular fibers, laminin and glycoproteins than NFF, although at lower level than DDC, with similar elastic fibers than DDC. Immunohistochemical expression of decorin was high in DDC, whereas versican was highly expressed NFF, with no differences for aggrecan. Cluster analysis revealed that the global expression profile of NPF was very similar to DDC, and reculturing methods showed that cells corresponding to DDC tissues proliferated more actively than NPF, and NPF more actively than NFF. All these results suggest that NPF tissues may be affected, and that a modification of the therapeutic approach used for the treatment of Dupuytren's disease should be considered.This work was supported by CTS-115 (Tissue Engineering Group), University of Granada/Spain
Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project
Rheological properties of magnetic biogels
We report an experimental and theoretical study of the rheological properties of magnetic biogels
consisting of fibrin polymer networks with embedded magnetite nanoparticles, swollen by aqueous solutions.
We studied two types of magnetic biogels, differenced by the presence or absence of an applied magnetic field
during the initial steps of cross-linking. The experiments demonstrated very strong dependence of the elastic
modulus of the magnetic biogels on the concentration of the magnetic particles. We finally developed some
theoretical models that explain the observed strong concentration effects.This study was supported by projects FIS2013-41821-R (Plan Nacional de Investigación Científica, Desarrollo
e Innovación Tecnológica, MINECO, Spain, co-funded by ERDF, European Union) and FIS2017-85954-R (Ministerio de
Economía, Industria y Competitividad, MINECO, andAgencia Estatal de Investigación, AEI, Spain, co-funded by Fondo Europeo
de Desarrollo Regional, FEDER, European Union). A.Z. is grateful to the program of the Ministry of Education and Science of
the Russian Federation, projects 02.A03.21.0006, 3.1438.2017/4.6, and 3.5214.2017/6.7, as well as to the Russian Fund of Basic
Researches, project 18-08-00178
Serum coding and non-coding RNAs as biomarkers of NAFLD and fibrosis severity
BACKGROUND & AIMS:
In patients with non-alcoholic fatty liver disease (NAFLD), liver biopsy is the gold standard to detect non-alcoholic steatohepatitis (NASH) and stage liver fibrosis. We aimed to identify differentially expressed mRNAs and non-coding RNAs in serum samples of biopsy-diagnosed mild and severe NAFLD patients with respect to controls and to each other.
METHODS:
We first performed a whole transcriptome analysis through microarray (n = 12: four Control: CTRL; four mild NAFLD: NAS 64 4 F0; four severe NAFLD NAS 65 5 F3), followed by validation of selected transcripts through real-time PCRs in an independent internal cohort of 88 subjects (63 NAFLD, 25 CTRL) and in an external cohort of 50 NAFLD patients. A similar analysis was also performed on liver biopsies and HepG2 cells exposed to oleate:palmitate or only palmitate (cellular model of NAFL/NASH) at intracellular/extracellular levels. Transcript correlation with histological/clinical data was also analysed.
RESULTS:
We identified several differentially expressed coding/non-coding RNAs in each group of the study cohort. We validated the up-regulation of UBE2V1, BNIP3L mRNAs, RP11-128N14.5 lncRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with NAS 65 5 (vs NAS 64 4) and the up-regulation of HBA2 mRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with Fibrosis stages = 3-4 (vs F = 0-2). In in vitro models: UBE2V1, RP11-128N14.5 and TGFB2/TGFB2-OT1 had an increasing expression trend ranging from CTRL to oleate:palmitate or only palmitate-treated cells both at intracellular and extracellular level, while BNIP3L was up-regulated only at extracellular level. UBE2V1, RP11-128N14.5, TGFB2/TGFB2-OT1 and HBA2 up-regulation was also observed at histological level. UBE2V1, RP11-128N14.5, BNIP3L and TGFB2/TGFB2-OT1 correlated with histological/biochemical data. Combinations of TGFB2/TGFB2-OT1 + Fibrosis Index based on the four factors (FIB-4) showed an Area Under the Curve (AUC) of 0.891 (P = 3.00E-06) or TGFB2/TGFB2-OT1 + Fibroscan (AUC = 0.892, P = 2.00E-06) improved the detection of F = 3-4 with respect to F = 0-2 fibrosis stages.
CONCLUSIONS:
We identified specific serum coding/non-coding RNA profiles in severe and mild NAFLD patients that possibly mirror the molecular mechanisms underlying NAFLD progression towards NASH/fibrosis. TGFB2/TGFB2-OT1 detection improves FIB-4/Fibroscan diagnostic performance for advanced fibrosis discrimination
The instrument suite of the European Spallation Source
An overview is provided of the 15 neutron beam instruments making up the initial instrument suite of the
European Spallation Source (ESS), and being made available to the neutron user community. The ESS neutron
source consists of a high-power accelerator and target station, providing a unique long-pulse time structure
of slow neutrons. The design considerations behind the time structure, moderator geometry and instrument
layout are presented.
The 15-instrument suite consists of two small-angle instruments, two reflectometers, an imaging beamline,
two single-crystal diffractometers; one for macromolecular crystallography and one for magnetism, two powder
diffractometers, and an engineering diffractometer, as well as an array of five inelastic instruments comprising
two chopper spectrometers, an inverse-geometry single-crystal excitations spectrometer, an instrument for vibrational
spectroscopy and a high-resolution backscattering spectrometer. The conceptual design, performance
and scientific drivers of each of these instruments are described.
All of the instruments are designed to provide breakthrough new scientific capability, not currently
available at existing facilities, building on the inherent strengths of the ESS long-pulse neutron source of high
flux, flexible resolution and large bandwidth. Each of them is predicted to provide world-leading performance
at an accelerator power of 2 MW. This technical capability translates into a very broad range of scientific
capabilities. The composition of the instrument suite has been chosen to maximise the breadth and depth
of the scientific impact o
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