Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a self-replicating isoform (prion) that ...accumulates in the central nervous system of affected individuals. The structure of PrP(Sc) is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP(C) may provide an opportunity to overcome these problems. PrP(C) ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole Fe(III)-TMPyP, which was previously shown to bind PrP(C), and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP(C)-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP(C)-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer's Disease. These results demonstrate that molecules binding to PrP(C) may produce a dual effect of blocking prion replication and inhibiting PrP(C)-mediated toxicity.
Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into ...PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self‐replicating, misfolded isoform (PrPSc) of the cellular prion protein (PrPC). No ...therapies are available for these pathologies. We capitalized on previously described cell‐based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.
Today the use of Construction and Demolition Materials (CDM) can be considered as a suitable solution for the construction or the rehabilitation of road pavements. In this context, it is central to ...minimizing waste production, favoring the reuse through new production cycles to replace virgin natural raw materials. As illustrated in this study, steel slag has mechanical properties that justify its use as aggregate in the manufacture of bituminous mixes. In road construction, their use is focused on the substitution of fine aggregate and filler in bituminous mixtures. Mechanical characterizations, Marshall stability and indirect tensile resilient modulus (ITSM) tests were used to evaluate the laboratory performance of the mixtures. The research aims are to provide the use of these materials for the construction of the entire road pavement structure; in this study authors used these materials both in the characterization of cementitious layers and in those with bituminous conglomerate. In both cases, the use of steel slag has favored an increase of stiffness in the mixtures.
Breast Cancer (BC) is the most common cancer among women worldwide and is characterized by intra- and inter-tumor heterogeneity that strongly contributes towards its poor prognosis. The Estrogen ...Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67 antigen are the most examined markers depicting BC heterogeneity and have been shown to have a strong impact on BC prognosis. Radiomics can noninvasively predict BC heterogeneity through the quantitative evaluation of medical images, such as Magnetic Resonance Imaging (MRI), which has become increasingly important in the detection and characterization of BC. However, the lack of comprehensive BC datasets in terms of molecular outcomes and MRI modalities, and the absence of a general methodology to build and compare feature selection approaches and predictive models, limit the routine use of radiomics in the BC clinical practice. In this work, a new radiomic approach based on a two-step feature selection process was proposed to build predictors for ER, PR, HER2, and Ki67 markers. An in-house dataset was used, containing 92 multiparametric MRIs of patients with histologically proven BC and all four relevant biomarkers available. Thousands of radiomic features were extracted from post-contrast and subtracted Dynamic Contrast-Enanched (DCE) MRI images, Apparent Diffusion Coefficient (ADC) maps, and T2-weighted (T2) images. The two-step feature selection approach was used to identify significant radiomic features properly and then to build the final prediction models. They showed remarkable results in terms of F1-score for all the biomarkers: 84%, 63%, 90%, and 72% for ER, HER2, Ki67, and PR, respectively. When possible, the models were validated on the TCGA/TCIA Breast Cancer dataset, returning promising results (F1-score = 88% for the ER+/ER- classification task). The developed approach efficiently characterized BC heterogeneity according to the examined molecular biomarkers.
Tracheobronchopathia osteochondroplastica (TO) is a rare idiopathic and benign disease that is often underdiagnosed. TO is characterized by multiple submucosal cartilaginous and osseous ...tracheobronchial nodules that spare the posterior wall. It usually affects the elderly, developing when the person is around 60 years old without gender preference and has a reported incidence of 0.11%. TO can be symptomatic and should be considered in patients with chronic cough, dyspnea, and recurrent pulmonary infections. Diagnosis is usually incidental by computed tomography or bronchoscopy, the latter being the gold standard diagnostic test for TO. Many thoracic imagers are not well acquainted with TO; thus, these patients are often underdiagnosed or misdiagnosed. We came across 5 patients in our institution who were incidentally diagnosed with TO, inspiring us to review the available literature on this disease. A total of 33 patients diagnosed with TO between 2009 and 2019 were identified by our retrospective review. Clinical and imaging data were collected on these patients. We also included the clinical, radiological, and endoscopic data of our 5 cases. TO should be considered in patients with chronic cough, dyspnea, and recurrent pulmonary infections. Our experience is that both computed tomography and bronchoscopy can be used to make a reliable diagnosis. It is crucial for physicians, especially radiologists and pulmonologists, to be aware of the existence of TO in order to ensure proper diagnosis.
The sternum is considered an unusual tumor site, corresponding to 15% of all thoracic wall tumors. Primary sternal tumors are even rarer and most commonly malignant. We present the case of a young ...man who consulted with a painful sternal mass, which after its resection is confirmed to be a cavernous hemangioma.
A 39-year-old man, with unremarkable medical history besides a 2-year-long sternal pain, non-irradiated, which worsens over the last few months and is accompanied by the appearance of a sternal palpable mass. On physical exam, there was a bulging of the sternal manubrium, with no inflammatory changes. Thoracic CT scan shows an expansive and lytic lesion of the sternum, compromising the manubrium and extending to the third sternocostal joint, without intrathoracic compromise nor cleavage plane with mediastinal vascular structures. The patient is taken to resection of the mass and sternal reconstruction using prosthetic material and pectoral and fasciocutaneous muscular flaps. Histopathological findings: cavernous hemangioma with negative borders and no other malignant findings.
Sternal hemangiomas can cause defects in the bone structure and show an expansive growth, challenging the differentiation between a benign or malignant lesion. Therefore, they should be considered malignant until shown otherwise. Management involves radical surgery with curative purposes and posterior reconstruction to improve quality of life, as shown with our patient.
Aim
This study aimed to investigate the role of resistance‐associated substitutions (RASs) to direct‐acting‐antivirals (DAAs) in HCV genotype 3 (GT3).
Methods
Within the Italian VIRONET‐C network, a ...total of 539 GT3‐infected patients (417 DAA‐naïve and 135 DAA‐failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home‐made protocols.
Results
The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co‐infected. Phylogenetic analysis classified sequences as GT3a‐b‐g‐h (98%‐0.4%‐0.2%‐1.2%) respectively.
Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4).
RAS prevalence was 15.8% in DAA‐naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF‐failures. In NS5A‐failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA‐naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA‐naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A‐RASs was observed before treatment in DAA‐failures (5/13, 38.5%) vs DAA‐naïves (61/393, 15.5%, P = .04). Regarding 228 DAA‐naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A‐RASs (P = .002).
Conclusions
In this real‐life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A‐RASs, the most frequent being Y93H. The presence of natural NS5A‐RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
Since the beginning of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic an important tool for patients with Coronavirus Disease 2019 (COVID-19) has been the computed ...tomography (CT) scan, but not always available in some settings The aim was to find a cut-off that can predict worsening in patients with COVID-19 assessed with a computed tomography (CT) scan and to find laboratory, clinical or demographic parameters that may correlate with a higher CT score.
We performed a multi-center, observational, retrospective study involving seventeen COVID-19 Units in southern Italy, including all 321 adult patients hospitalized with a diagnosis of COVID-19 who underwent at admission a CT evaluated using Pan score.
Considering the clinical outcome and Pan score, the best cut-off point to discriminate a severe outcome was 12.5. High lactate dehydrogenase (LDH) serum value and low PaO2/FiO2 ratio (P/F) resulted independently associated with a high CT score. The Area Under Curve (AUC) analysis showed that the best cut-off point for LDH was 367.5 U/L and for P/F 164.5. Moreover, the patients with LDH> 367.5 U/L and P/F < 164.5 showed more frequently a severe CT score than those with LDH< 367.5 U/L and P/F> 164.5, 83.4%, vs 20%, respectively.
A direct correlation was observed between CT score value and outcome of COVID-19, such as CT score and high LDH levels and low P/F ratio at admission. Clinical or laboratory tools that predict the outcome at admission to hospital are useful to avoiding the overload of hospital facilities.
●prognostic factors of severe disease in COVID-19 are need to stratify patients.●a cut off of 12.5 at CT score predicts severe outcome in patients with COVID-19.●P/F and LDH value at admission can predict worse CT severity score.
PDF
