Controlling non-linear axial vibrations of a turbine rotor

The rotor of a 3-stage axial turbine designed for an ORC plant, supported by two axial/radial lubricated roller bearings, has some axial clearance in between the outer bearing ring and the shoulder in the casing to allow for thermal expansion. The rotor can move freely within the clearance before the bearings on both sides are able to apply a restoring force. . The axial thrust on the shaft is balanced in design conditions, but in off design conditions some unsteadiness in the operating fluid flow could generate thrust fluctuations and consequently axial shaft vibrations. In order to reduce the severity of this possible source of vibration, noise and fatigue stresses, some damping should be introduced in the system. CFD calculations have allowed to characterize the damper, which is highly non- linear. The damper has been introduced in the model of the machine and its performance has been analysed by comparing the behaviour of the damped rotor to the un-damped rotor, at the different exciting frequencies. The comparison has been performed necessarily in the time domain due to the presence of two non- linearity: unsymmetrical damper and non-linear elastic restoring force. The results of the comparison have shown the efficiency of the damper especially in conditions close to resonance

Radiosynthesis and preliminary biological evaluation of [18F]VC701, a radioligand for translocator protein. G. Di Grigoli, C. Monterisi, S. Belloli, V. Masiello, L. S. Politi, S. Valenti, M. Paolino, M. Anzini, M. Matarrese, A. Cappelli, R.M. Moresco

Positron emission tomography (PET) can be used to monitor in vivo translocator protein (TSPO) expression by using specific radioligands. Recently, several [11C]PK11195 analogues have been synthesized to improve binding stability and brain availability. [18F]VC701 was synthesized and validated in CD healthy rats by biodistribution and inhibition analysis. Imaging studies were also conducted on animals injected unilaterally in the striatum with quinolinic acid (QA) to evaluate the TSPO ligand uptake in a neuroinflammation/neurodegenerative model. [18F]VC701 was synthesized with a good chemical and radiochemical purity and specific activity higher than 37 GBq/mmol. Kinetic studies performed on healthy animals showed the highest tracer biodistribution in TSPO-rich organs, and preadministration of cold PK11195 caused an overall radioactivity reduction. Metabolism studies showed the absence of radio metabolites in the rat brain of QA lesioned rats, and biodistribution analysis revealed a progressive increase in radioactivity ratios (lesioned to nonlesioned striatum) during time, reaching an approximate value of 5 4 hours after tracer injection. These results encourage further evaluation of this TSPO radioligand in other models of central and peripheral diseases

18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis

BACKGROUND: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in combination with magnetic resonance imaging (MRI). METHODS: MOG35-55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. RESULTS: In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels

Additional file 1: Figure S1. of 18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis

PET and MRI images of EAE mice at 14 days p.i. In vivo PET and MRI representative images of three of the four EAE mice used for the in vivo imaging evaluation at 14 days post-immunization. The fourth animal is shown in Fig. 6. A) 18F-VC701 PET and MRI co-registered coronal images of Mouse 1 (clinical score at acute phase 2.5 and 0 at late stage); B) 18F-VC701 PET and MRI co-registered coronal images of Mouse 2 (clinical score 2 at 14 d.p.i. and 2.5 at 28 d.p.i.); C) 18F-VC701 PET and MRI co-registered coronal images of Mouse 3 (clinical score 1.5 in acute phase and 0 at late stage of the disease). (DOCX 41 kb

Guadecitabine plus ipilimumab in unresectable melanoma: the NIBIT-M4 clinical trial

Purpose: The immuno-modulatory activity of DNA hypomethylating agents (DHA) suggests they may improve the effectiveness of cancer immunotherapies. The phase 1b NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Experimental Design: Unresectable Stage III/IV melanoma patients received escalating doses of guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on Days 1-5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on Day 1 every 3 weeks, starting 1 week after guadecitabine, for 4 cycles. Primary endpoints were safety, tolerability and maximum tolerated dose of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, neither dose limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n=8) at Week 4 (74.5%) and Week 12 (75.5%) was significantly (p<0.05) lower than at baseline (80.3%), with a median of 2454 (Week 4) and 4131 (Week 12) differentially expressed genes. Among the 136 pathways significantly (p<0.05; Z score >2 or <-2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n=11) demonstrated up-regulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in post-treatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma, and has promising immunomodulatory and anti-tumour activity. Copyright ©2019, American Association for Cancer Research

New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia

Abstract Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation