Notch and NF-kB: Coach and Players of Regulatory T-Cell Resposnse in Cancer

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-kB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how themultilayered crosstalk between different Notches and NF-kB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-kB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on themolecularmechanisms regulating Treg cell expansion andmigration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic Q25 approaches to improve anticancer immunity may be found

The impact of the SARS-CoV-2 pandemic on cause-specific mortality patterns: a systematic literature review

Background Understanding the effects of the COVID-19 pandemic on cause-specific mortality should be a priority, as this metric allows for a detailed analysis of the true burden of the pandemic. The aim of this systematic literature review is to estimate the impact of the pandemic on different causes of death, providing a quantitative and qualitative analysis of the phenomenon. Methods We searched MEDLINE, Scopus, and ProQuest for studies that reported cause-specific mortality during the COVID-19 pandemic, extracting relevant data. Results A total of 2413 articles were retrieved, and after screening 22 were selected for data extraction. Cause-specific mortality results were reported using different units of measurement. The most frequently analyzed cause of death was cardiovascular diseases (n = 16), followed by cancer (n = 14) and diabetes (n = 11). We reported heterogeneous patterns of cause-specific mortality, except for suicide and road accident. Conclusions Evidence on non-COVID-19 cause-specific deaths is not exhaustive. Reliable scientific evidence is needed by policymakers to make the best decisions in an unprecedented and extremely uncertain historical period. We advocate for the urgent need to find an international consensus to define reliable methodological approaches to establish the true burden of the COVID-19 pandemic on non-COVID-19 mortality

Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State

The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decreased by cyclosporin A and the thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4-dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting thioredoxin reductase by siRNA. We conclude that the mitochondrial thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release

Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9

BACKGROUND: A beneficial effect on cardiovascular risk may be obtained by improving lipid-related serum lipoprotein functions such as high-density lipoproteins (HDLs) cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) and by reducing proprotein convertase subtilisin kexin type 9 (PCSK9), independently of lipoprotein concentrations. AIM: We aimed to evaluate the effect of an innovative nutraceutical (NUT) combination containing red yeast rice (monacolin K 3.3 mg), berberine 531.25 mg and leaf extract of Morus alba 200 mg (LopiGLIK®), on HDL-CEC, serum CLC and on circulating PCSK9 levels. MATERIALS AND METHODS: Twenty three dyslipidemic subjects were treated for 4 weeks with the above NUT combination. HDL-CEC was measured using specific cell-based radioisotopic assays; serum CLC and PCSK9 concentrations were measured fluorimetrically and by enzyme-linked immunosorbent assay, respectively. RESULTS: The NUT combination significantly reduced plasma level of the total cholesterol and low-density lipoprotein cholesterol (-9.8% and -12.6%, respectively). Despite no changes in HDL-cholesterol, the NUT combination improved total HDL-CEC in 83% of the patients, by an average of 16%, as a consequence of the increase mainly of the ATP-binding cassette A1-mediated CEC (+28.5%). The NUT combination significantly reduced serum CLC (-11.4%) while it did not change PCSK9 plasma levels (312.9±69.4 ng/mL vs 334.8±103.5 mg/L, before and after treatment, respectively). CONCLUSION: The present NUT combination improves the serum lipoprotein functional profile providing complementary beneficial effects, without any detrimental increase of PCSK9 plasma levels

"Electro-clinical Syndromes" with onset in Paediatric Age. the highlights of the clinical-EEG, genetic and therapeutic advances

The genetic causes underlying epilepsy remain largely unknown, and the impact of available genetic data on the nosology of epilepsy is still limited. Thus, at present, classification of epileptic disorders should be mainly based on electroclinical features. Electro-clinical syndrome is a term used to identify a group of clinical entities showing a cluster of electro-clinical characteristics, with signs and symptoms that together define a distinctive, recognizable, clinical disorder. These often become the focus of treatment trials as well as of genetic, neuropsychological, and neuroimaging investigations. They are distinctive disorders identifiable on the basis of a typical age onset, specific EEG characteristics, seizure types, and often other features which, when taken together, permit a specific diagnosis which, in turn, often has implications for treatment, management, and prognosis. Each electro-clinical syndrome can be classified according to age at onset, cognitive and developmental antecedents and consequences, motor and sensory examinations, EEG features, provoking or triggering factors, and patterns of seizure occurrence with respect to sleep. Therefore, according to the age at onset, here we review the more frequently observed paediatric electro-clinical syndrome from their clinical-EEG, genetic and therapeutic point of views

Effect of Thermal Ageing on the Mechanical Strength of Carbon Fibre Reinforced Epoxy Composites

Applications of Carbon Fibre Reinforced Polymers (CFRP) at temperatures over 150–200 ◦C are becoming common in aerospace and automotive applications. Exposure of CFRP to these temperatures can lead to permanent changes in their mechanical properties. In this work, we investigated the effect of thermal ageing in air on the strength of carbon fabric/epoxy composites. To this end, accelerated artificial ageing at different temperatures was performed on carbon fabric/epoxy specimens. The flexural and interlaminar shear strengths of the aged specimens were assessed by three-point bending and short beam shear tests, respectively, and compared to those of unaged samples. For ageing at temperatures below the glass transition temperature of the resin, Tg, a moderate reduction of strength was found, with a maximum decrease of 25% for 2160 h at 75% Tg. On the other hand, a rapid strength decrease was observed for ageing temperatures above Tg. This was attributed to degradation of the epoxy matrix and of the fibre/epoxy interface. In particular, a 30% strength decrease was found for less than 6 h at 145% Tg. Therefore, it was concluded that even a short exposure to operating temperatures above Tg could substantially impair the load-carrying capability of CFRP components

Pyridostigmine in pediatric Intestinal pseudo-obstruction. case report of a 2-year old girl and literature review

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, longacting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility

Geological 3D model of the Po Basin

The geological 3D model of the Po Basin includes the geometry of four stratigraphic horizons (top or unconformity) bounding lithological homogeneous successions of sedimentary units, in the Triassic - Pleistocene time interval, and 179 fault geometries. Each stratigraphic horizon is supplemented by its isobaths. Where possible, the thickness of the succession above or below, respectively for basal unconformity and top, is provided with the surface depth. The lithology, event process, and age of each sedimentary succession are also provided. Each fault, with its upper tip line, is supplemented with the kinematic, mean values for strike, dip azimuth, and dip derived from the 3D surface geometry, and the age of the oldest and youngest faulted or deformed stratigraphic horizon, if obtainable from the 3D geological model. This harmonized dataset and the related data model were obtained in the framework of the GO-PEG project, co-funded by the Connecting Europe Facility (CEF) of the European Commission. More specifically, this dataset is the output of the Go-Depth use case aiming to provide a methodology and a model to conceptualize, organize and deliver easy-to-use, high-quality, interoperable subsurface information for sustainable planning and use of natural resources. To this aim the data coming from European-funded projects GeoMol (Alpine Space Programme 2012-2015) and GeoERA HotLime (Horizon 2020, 2018-2021) has been used. In view of data interoperability, the data model has been developed as an extension of the INSPIRE Geology data model. The dataset is served through APIs conforming to the OGC API - Feature standard and it is also downloadable in GeoPackage format, anticipating the application of the principles established by the Open Data Directive (Directive (EU) 2019/1024) regarding the sharing of the High-Value Datasets. We acknowledge the listed researchers who contributed seismic and geological data interpretation to the GeoMol and HotLime Project