A Latency-driven Availability Assessment for Multi-Tenant Service Chains

Nowadays, most telecommunication services adhere to the Service Function Chain (SFC) paradigm, where network functions are implemented via software. In particular, container virtualization is becoming a popular approach to deploy network functions and to enable resource slicing among several tenants. The resulting infrastructure is a complex system composed by a huge amount of containers implementing different SFC functionalities, along with different tenants sharing the same chain. The complexity of such a scenario lead us to evaluate two critical metrics: the steady-state availability (the probability that a system is functioning in long runs) and the latency (the time between a service request and the pertinent response). Consequently, we propose a latency-driven availability assessment for multi-tenant service chains implemented via Containerized Network Functions (CNFs). We adopt a multi-state system to model single CNFs and the queueing formalism to characterize the service latency. To efficiently compute the availability, we develop a modified version of the Multidimensional Universal Generating Function (MUGF) technique. Finally, we solve an optimization problem to minimize the SFC cost under an availability constraint. As a relevant example of SFC, we consider a containerized version of IP Multimedia Subsystem, whose parameters have been estimated through fault injection techniques and load tests

Management of Chronic Myeloid Leukemia in Advanced Phase

Management of chronic myeloid leukemia (CML) in advanced phases remains a challenge also in the era of tyrosine kinase inhibitors (TKIs) treatment. Cytogenetic clonal evolution and development of resistant mutations represent crucial events that limit the benefit of subsequent therapies in these patients. CML is diagnosed in accelerated (AP) or blast phase (BP) in <5% of patients, and the availability of effective treatments for chronic phase (CP) has dramatically reduced progressions on therapy. Due to smaller number of patients, few randomized studies are available in this setting and evidences are limited. Nevertheless, three main scenarios may be drawn: (a) patients diagnosed in AP are at higher risk of failure as compared to CP patients, but if they achieve optimal responses with frontline TKI treatment their outcome may be similarly favorable; (b) patients diagnosed in BP may be treated with TKI alone or with TKI together with conventional chemotherapy regimens, and subsequent transplant decisions should rely on kinetics of response and individual transplant risk; (c) patients in CP progressing under TKI treatment represent the most challenging population and they should be treated with alternative TKI according to the mutational profile, optional chemotherapy in BP patients, and transplant should be considered in suitable cases after return to second CP. Due to lack of validated and reliable markers to predict blast crisis and the still unsatisfactory results of treatments in this setting, prevention of progression by careful selection of frontline treatment in CP and early treatment intensification in non-optimal responders remains the main goal. Personalized evaluation of response kinetics could help in identifying patients at risk for progression

690. Permanent Epigenetic Silencing of Human Genes With Artificial Transcriptional Repressors

There are several diseases whereby the goal of gene therapy is to silence rather than replace a gene function. Paradigmatic examples are diseases caused by a dominant negative mutation or those in which silencing of a host gene confers resistance to a pathogen or compensates the function of the missing gene. Yet, gene silencing can be used to enhance efficacy of cell therapy and for biotechnological applications. Until now, two technologies have been used to silence gene expression, namely RNA interference with short harping RNAs (shRNA) and gene disruption with Artificial Nucleases (ANs). Although some promising pre-clinical and clinical data have been already obtained, the low efficiency of knock-down with shRNA and of biallelic disruption with ANs may limit efficacy of these treatments, especially when residual gene activity can exert a biological function. To overcome this issue, we have developed a novel modality of gene silencing that exploits endogenous epigenetic mechanisms to convey robust and heritable states of repression at the desired target gene. We have generated Artificial Transcriptional Repressors (ATRs), chimeric proteins containing a custom-made DNA binding domain fused to the effector domain of a chromatinmodifying enzyme involved in silencing of Endogenous RetroViruses (ERVs). By performing iterative rounds of selection in human cell lines and primary cells engineered to report for synergistic activity of candidate effector domains, we identified a combination of 3 domains that, when transiently co-assembled on the promoter of the reporter cassette, fully abrogated transgene expression in up to 90% of treated cells. Importantly, silencing was maintained for more than 250 days in cultured cell lines, was resistant to in vitro differentiation or metabolic activation of primary cells, and was confined to the reporter cassette. Silencing was associated with high levels of de novo DNA methylation at the targeted locus and was dependent on this epigenetic mark for its propagation. Finally, transient transfection of 3 ATRs targeted to the promoter region of the Beta-2-microglobulin (B2M) gene resulted in the loss of surface expression of B2M and, consequently, of the MHC-I molecules in up to 80% of treated cells. This phenotype was associated with a switch in the epigenetic and transcriptional state of the constitutively active B2M gene, which became highly decorated with DNA methylation and deprived of RNA PolII and of its transcript. Of note, silencing was resistant to IFN-γ treatment, a potent B2M inducer. Overall, these data provide the first demonstration of efficient and stable silencing of an endogenous gene upon transient delivery of ATRs. This result was made possible by repurposing the machinery involved in silencing of ERVs, which instructs self-sustaining repressive epigenetic states on the gene of interest. While silencing of B2M might be used to generate universally transplantable allogeneic cells, our hit-and-run strategy provides a powerful new alternative to conventional gene silencing for the treatment of several diseases. (LN & AL co-authorship

The Predictability of Transverse Changes in Patients Treated with Clear Aligners

: Arch expansion might be used to correct buccal corridors, improve smile aesthetics, resolve dental cross bite, and gain space to resolve crowding. In clear aligner treatment, the predictability of the expansion is still unclear. The purpose of this study was to evaluate the predictability of dentoalveolar expansion and molar inclination with clear aligners. In the study, 30 adult patients (27 ± 6.1 years old) treated with clear aligners were selected (treatment time: 8.8 ± 2.2 months). The upper and lower arch transverse diameters were measured for canines, first and second premolars, and first molars on two different sides (gingival margins and cusp tips); moreover, molar inclination was measured. A paired t-test and Wilcoxon test were used to compare prescription (planned movement) and achieved movement. In all cases, except for molar inclination, a statistically significant difference was found between achieved movement and prescription (p < 0.05). Our findings showed a total accuracy of 64% for the lower arch, 67% at the cusp level, and 59% at the gingival level, with a total accuracy of 67% for the upper arch, 71% at the cusp level, and 60% at the gingival level. The mean accuracy for molar inclination was 40%. Average expansion was greater at cusps of canines than for premolars, and it was lowest for molars. The expansion achieved with aligners is mainly due to the tipping of the crown rather than bodily movement of the tooth. The virtual plan overestimates the expansion of the teeth; thus, it is reasonable to plan an overcorrection when the arches are highly contracted

Magnetic resonance imaging 3t and total fibrotic volume in autosomal dominant polycystic kidney disease

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Several authors have attempted to identify a kidney damage marker for predicting the prognosis and the effectiveness of therapy in ADPKD. The aim of this study was to identify and quantify in ADPKD, through a novel MR protocol with 3 Tesla (MRI 3Tesla), the presence of parenchymal fibrotic tissue at early stage of disease, able to correlate the glomerular filtrate and to predict the loss of the function renal. MATERIAL AND METHODS: 15 ADPKD patients undergone to renal MRI 3Tesla at T0 and revaluated after follow up (T1) of 5 years. We have evaluated renal function, plasma aldosterone concentration (PAC), insulin resistance and surrogate markers of atherosclerosis (carotid intima media thickness (IMT), ankle/brachial index (ABI) and left ventricular mass index (LVMI). RESULTS: Our study showed a significant negative correlation between total kidney volume and estimated glomerular filtration rate (eGFR) during observational observation (p&lt;0.02). Moreover, we showed a negative correlation between eGFR with Total Fibrotic Volume (TFV) (p&lt;0.04) and Total Perfusion Volume/Total kidney Volume(&lt;0.02). Moreover TFV was correlated positively with PAC (p&lt;0.05), insulin values (p&lt;0.05), ABI (p &lt;0.05) and LVMI(p&lt;0.01). CONCLUSIONS: The MRI 3Tesla, despite the high costs, could be considered an useful and non-invasive method in the evaluation of fibrotic tissue and progression of the disease in ADPKD patients. Further clinical trials on larger group are due to confirm the results of this pilot study, suggesting that MRI 3Tesla can be useful to evaluate the effectiveness of new therapeutic strategies. This article is protected by copyright. All rights reserved

Brexpiprazole as a new approach of treatment in somatization disorder

© 2022 Published by Elsevier Ltd on behalf of International Society for the Study of Emerging Drugs. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Introduction: Somatic symptom disorder (SSD) is a mental disorder that involves one or more physical symptoms (e.g. palpitations, dizziness, diarrhoea, limb weakness, pain, and pseudo neurological symptoms) accompanied by one or more thoughts, feelings, and/or behaviours related to the somatic symptom(s) resulting in significant distress and/or dysfunction lasting for more than 6 months. At now the SSD can be refractory to psychiatric intervention including antidepressants, antiepileptics, and antipsychotics as well as the effectiveness of many of these treatments is limited. The objective of this study was to report the effectiveness of a third-generation antipsychotic drug brexpiprazole for treatment of a case of SSD together with the serotonin selective reuptake inhibitor (SSRI) fluvoxamine. Methods: A single case study of a 59-year-old female with SSD was here performed. Findings: After 4 weeks of treatment brexpiprazole, together with lamotrigine and fluvoxamine, was here effective in decreasing both depressive and anxiety symptoms, normalising previous unusual thought contents and of related behaviours. The patient reported an overall good response and started to function again in important domains of life. No adverse events occurred. Conclusion: To our knowledge, this is the first case showing Brexpiprazole effective for the treatment of a case of SSD as add-on to other drugs.Peer reviewedFinal Published versio

The Yin and Yang of Current Antifungal Therapeutic Strategies: How Can We Harness Our Natural Defenses?

Fungal infections have aroused much interest over the last years because of their involvement in several human diseases. Immunocompromission due to transplant-related therapies and malignant cancer treatments are risk factors for invasive fungal infections, but also aggressive surgery, broad-spectrum antibiotics and prosthetic devices are frequently associated with infectious diseases. Current therapy is based on the administration of antifungal drugs, but the occurrence of resistant strains to the most common molecules has become a serious health-care problem. New antifungal agents are urgently needed and it is essential to identify fungal molecular targets that could offer alternatives for development of treatments. The fungal cell wall and plasma membrane are the most important structures that offer putative new targets which can be modulated in order to fight microbial infections. The development of monoclonal antibodies against new targets is a valid therapeutic strategy, both to solve resistance problems and to support the immune response, especially in immunocompromised hosts. In this review, we summarize currently used antifungal agents and propose novel therapeutic approaches, including new fungal molecular targets to be considered for drug development