Archivio Istituzionale della Ricerca- Università del Piemonte Orientale
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Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia
No full textAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options
Assessing frailty in patients with relapsed/refractory multiple myeloma: A comparison between the patient-reported frailty phenotype and the International Myeloma Working Group frailty index
No full textIntroduction: The International Myeloma Working Group Frailty Index (IMWG FI) is one of the most used frailty assessment tools in patients with multiple myeloma (MM). A patient-centered frailty tool based on patient-reported outcomes (PROs) has been recently proposed for patients with relapsed/refractory MM (RRMM): the Patient-Reported Frailty Phenotype (PRFP). This cross-sectional analysis aimed to replicate the PRFP within a real-world setting and to describe health-related quality of life (HRQoL) profiles based on this new patient-centered frailty classification. Materials and Methods: This analysis was based on baseline data from a multi-center prospective observational study that included adult patients with RRMM. Frailty was assessed using the IMWG FI, and HRQoL was evaluated with the EORTC QLQ-C30 and its myeloma module (QLQ-MY20). For this analysis, the PRFP was also calculated, and Cohen's kappa was computed to examine the agreement between the two frailty assessment approaches. Descriptive statistics were used to investigate the HRQoL profiles of patients classified as frail, pre-frail, and fit. Results: Five hundred eleven patients were enrolled. The median age was 69.8 years, and 44 % were female. According to IMWG FI and PRFP, 24.5 % and 25.1 % of patients were classified as frail, with a weighted Cohen's kappa of 0.27, indicating fair agreement. Frail patients, as classified by the PRFP, reported higher treatment side effects, disease symptoms, and worse future perspectives and body image compared to pre-frail and fit patients. Discussion: Current findings suggest that the PRFP may be a valuable tool to assess frailty in patients with RRMM. However, further prospective studies are needed to better understand the value of PROs in a more accurate assessment of frailty in the RRMM setting. Trial registration: ClinicalTrials.gov: NCT0319052
Isolated C3 hypocomplementemia as an early predictor of chronic kidney disease in lupus nephritis
Get PDFObjective: The role of complement in the long-term renal survival of patients with lupus nephritis (LN) remains poorly understood. Recent studies suggest its potential impact; however, long-term data are lacking. Methods: This multicenter, observational, retrospective study aimed at investigating the influence of complement levels on long-term renal outcomes in LN patients. We evaluated whether isolated C3 hypocomplementemia (i-LowC3), defined as serum low C3 (≤80 mg/dL) and normal C4 (>10 mg/dL) six months after kidney biopsy is associated with subsequent risk of chronic kidney disease (CKD), End Stage Kidney Disease (ESKD) or death. Results: 445 patients with LN were studied (median follow-up 4.9 years). Based on six-month C3/C4 levels, patients were categorized into i-LowC3 (91 patients) and controls (354 patients). Over the first six months, serum C3 and C4 levels increased by a median of 20 mg/dL and 5 mg/dL, respectively. i-LowC3 was significantly associated with twice the risk of a poor outcome, including CKD, ESKD, composite outcome of CKD or death and ESKD or death, with lower survival rates for all these outcomes compared to controls (P < 0.001). Multivariate Cox regression analysis revealed a lower risk of CKD and CKD or death with increases in C3 levels during the first six months, while i-LowC3 was associated with an independent higher risk for these outcomes. Conclusion: The trajectory of serum C3 levels within the first six months appears to predict long-term renal prognosis of LN patients. These findings support the use of i-LowC3 as a low-cost, readily available biomarker to guide early treatment of LN patients
Fluorescent Isostere (Fluostere) of the Carboxylate: Design of hDHODH Fluorescent Inhibitors as Proof of Concept
No full textFluorescent probes targeting proteins are used to investigate biological processes, requiring strong binding affinity and favorable fluorescence. In this study, we present the first fluostere with optimized fluorescence properties. We started exploring the fluorescence of acidic pyrazolo[1,5-a]pyridin-2-ol, and, by the introduction of EWGs, π-conjugation, incorporation of push-pull systems and rigid structures, we optimized emission profiles and QY, providing a first Structure-Fluorescence relationship (SFR) of the system. To provide proof of concept in biological applications, the established SFR was integrated with hDHODHi, an important oncology target, enabling the SAR designing fluorescent hDHODHi 11a and 14, with 11a being the most potent IC50 = 170 nM. These inhibitors were validated in vitro for their antileukemic and antiviral activity. As they are both environmentally sensitive fluorescent probes that can highlight their binding to the target, their fluorescence was found to colocalize in the mitochondria, where hDHODH is located, in cellular experiments
Intracranial Nonstenosing Atherosclerotic Plaques Assessed With Vessel Wall MRI in Patients With Embolic Stroke of Undetermined Source
No full textBackground and ObjectivesArtery-to-artery embolization from vulnerable intracranial nonstenosing atherosclerotic plaques (vNSPs) has been proposed as a major contributor to embolic stroke of undetermined source (ESUS). Vessel wall MRI (VWMRI) offers the potential to identify culprit vNSPs, yet prospective studies in ESUS populations are lacking. This study aimed to assess the role of vNSPs in single-territory ESUS and to evaluate the utility of intracranial VWMRI in the diagnostic workup.MethodsConsecutive patients admitted to the Stroke Unit of the IRCCS Mondino Foundation (Pavia, Italy) with a confirmed ESUS diagnosis after a complete etiologic workup were prospectively enrolled in the study. Patients with multiterritorial ischemic lesions, complicated aortic arch atherosclerosis, or a probable patent foramen ovale-associated stroke were excluded. Intracranial VWMRI at 3-T was performed within 1 month of the index event. Atherosclerotic lesions were considered culprit if demonstrating postcontrast enhancement on T1-weighted images and a location consistent with ischemic lesions' distribution. Quantitative radiologic features of vNSPs were also analyzed.ResultsA total of 80 patients (mean age 65.6 years, 34 [42.5%] women) were included. VWMRI identified a potentially culprit vNSP in 23 of 80 patients (28.8%, 95% CI 20-39.5). Patients with symptomatic vNSPs were older (72.7 vs 62.8 years, p = 0.002) and more frequently current (43.5 vs 35.1%) or former (30.4 vs 8.8%) smokers (p = 0.014). In a multivariable logistic regression model including major risk factors of intracranial atherosclerosis (age, smoking, hypertension, diabetes, and dyslipidemia), both age (adjusted odds ratio [aOR] 1.12, 95% CI 1.05-1.22, p = 0.002) and smoking status (active smokers: aOR 7.99, 95% CI 1.81-47.8, p = 0.011; former smokers: aOR 8.79, 95% CI 1.73-55.0, p = 0.012) were significantly associated with symptomatic vNSP.DiscussionIntracranial vNSPs may represent a significant underlying cause of single-territory ESUS, and VWMRI could provide an added value in the diagnostic workup of these patients. Older age and smoking exposure were found to be independently associated with the presence of culprit intracranial vNSPs. Further studies are needed to confirm our findings because of the relatively small and monocentric cohort.Classification of EvidenceThis study provides Class IV evidence that VWMRI improves the identification of culprit vNSPs in patients with ESUS
Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia
Get PDFSkeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia
Central Nervous System Involvement in CLL: An International Retrospective Study by ERIC, the European Research Initiative on CLL
No full textCNS involvement (CNSi) of chronic lymphocytic leukemia (CLL) is a rare condition with no consensus on diagnosis and limited evidence for management and outcome. Here we report an international, multicenter, retrospective study conducted by the European Research Initiative on CLL (ERIC). The study defined CNSi of CLL by: 1) detection of CLL cells in the cerebrospinal fluid or confirmation of CLL infiltration of the CNS based on a tissue biopsy, 2) clinical or radiographic evidence of neurologic disease, and 3) the absence of other explanations for the neurologic findings. A total of 48 patients from 26 centers in 15 countries met all three diagnostic criteria of CLL-CNSi. Median age at diagnosis of CNSi was 64 years. Most patients were males (73%), had Binet stage A at CLL diagnosis (61%), and had untreated CLL at the time of CNSi (63%). Motor impairment was the most common symptom (38%) followed by visual impairment (32%). Of 47 patients who received treatment for CNSi, half (51%) received targeted agents, most commonly a BTK inhibitor (BTKi), and 34% received chemoimmunotherapy (CIT). Initial treatment was highly effective, leading to a reduction (83%) or complete resolution (71%) of neurologic symptoms and imaging findings in most patients. The estimated 5-year overall survival (OS) from the CNSi diagnosis was 77.1%. 5-year time-to-next-treatment or death was 94% for patients treated with BTKis compared to 64% for those treated with CIT. Treatment-sensitive disease, represented by attainment of CNS complete response after initial therapy, was associated with longer OS
Il ruolo dell’ecodesign e la misurazione della circolarità nelle dichiarazioni sulla sostenibilità.
No full textL’economia circolare si afferma come paradigma di riferimento per un nuovo modello
di sviluppo, fondato sull’ottimizzazione delle risorse, sulla prevenzione dei rifiuti e
sull’allungamento del ciclo di vita dei materiali. L’articolo esplora il ruolo della
rendicontazione di sostenibilità e della relazione sulla gestione come strumenti di
trasparenza e "accountability" verso gli stakeholder e le potenzialità e i limiti
dell’attuale quadro normativo in materia di misurazione della performance circolare,
con attenzione agli aspetti metodologici e all’integrazione tra indicatori qualitativi e
quantitativi
Impact on well-being and motivation to physical activity practice by ‘Moving Park’ project in Italy
Get PDFIt is widely known that regular physical activity (PA) can provide substantial benefits to health and well-being. Green spaces and supervised PA interventions by trainers are also effective factors in increasing participation in PA. Hence, the “Moving Parks” project conducted by the Municipality of Bologna, Italy, emerged out of necessity. This study aimed to measure the effectiveness and the reasonableness of the project by investigating the effects of Moving Park intervention on participants’ well-being and motivations for future PA engagement. Two questionnaire surveys before and after the participation in the project were administered and 138 valid results were analyzed. The results suggest a significant improvement in well-being after participating in the outdoor sessions provided by the present study; the most possible motivation which drives to practice PA is the feeling of guilt, especially for females. Overall, the continuation of the “Moving Parks” project is rewarding to the residents, reducing stress, and improving wellbeing
