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1.
Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer-Evidence from a 17-Year Follow-Up Study.
Ruscica, M, Macchi, C, Gandini, S, Macis, D, Guerrieri-Gonzaga, A, Aristarco, V, Serrano, D, Lazzeroni, M, Rizzuto, AS, Gaeta, A, et al
Cancers. 2024;(7)
Abstract
BACKGROUND AND AIM The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.
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Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review.
Gianazza, E, Macchi, C, Banfi, C, Ruscica, M
Frontiers in cardiovascular medicine. 2023;:1191303
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of genetic PCSK9 polymorphisms have enabled to reveal the role of PCSK9 in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.
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Relationship between Nutritional Risk, Clinical and Demographic Characteristics, and Pressure Ulcers in Patients with Severe Acquired Brain Injuries Attending a Rehabilitative Program.
Gheri, CF, Scalfi, L, Biffi, B, Pancani, S, Madiai, S, Di Vincenzo, O, Ghaderi, M, Celoni, R, Dalladonna, M, Draghi, F, et al
Nutrients. 2023;(15)
Abstract
Preliminary evidence in the literature suggests a high prevalence of malnutrition (undernutrition) in patients with severe acquired brain injuries (sABI), with an expected negative impact on clinical outcomes and pressure ulcers (PUs) in particular. In a retrospective cohort study on patients discharged from intensive care units (ICU) and admitted to an intensive rehabilitation unit (IRU), the risk of malnutrition was systematically assessed, in addition to standard clinical procedures (including PUs evaluation), using two different tools: the Malnutrition Universal Screening Tool (MUST) and the Controlling Nutritional Status (CONUT) tool. Eighty-eight patients were included in the analysis. A high proportion (79.5%) of patients with sABI suffered from PUs, being older and more frequently men, with a longer ICU stay between the event and admission to IRU, and a greater MUST score. At discharge, when compared to patients whose PUs had healed, those with persisting PUs were more often men and had the worst cognitive performance at admission. As for nutritional risk, the baseline CONUT score was identified as an independent negative predictor of PUs at discharge by the logistic regression model. In conclusion, the assessment of nutritional risk using simple standard tools may be useful in the clinical evaluation of sABI patients with PUs.
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Lipid and metabolite correlation networks specific to clinical and biochemical covariate show differences associated with sexual dimorphism in a cohort of nonagenarians.
Di Cesare, F, Tenori, L, Meoni, G, Gori, AM, Marcucci, R, Giusti, B, Molino-Lova, R, Macchi, C, Pancani, S, Luchinat, C, et al
GeroScience. 2022;(2):1109-1128
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Abstract
This study defines and estimates the metabolite-lipidic component association networks constructed from an array of 20 metabolites and 114 lipids identified and quantified via NMR spectroscopy in the serum of a cohort of 355 Italian nonagenarians and ultra-nonagenarian. Metabolite-lipid association networks were built for men and women and related to an array of 101 clinical and biochemical parameters, including the presence of diseases, bio-humoral parameters, familiarity diseases, drugs treatments, and risk factors. Different connectivity patterns were observed in lipids, branched chains amino acids, alanine, and ketone bodies, suggesting their association with the sex-related and sex-clinical condition-related intrinsic metabolic changes. Furthermore, our results demonstrate, using a holistic system biology approach, that the characterization of metabolic structures and their dynamic inter-connections is a promising tool to shed light on the dimorphic pathophysiological mechanisms of aging at the molecular level.
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TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models.
Longo, M, Meroni, M, Paolini, E, Erconi, V, Carli, F, Fortunato, F, Ronchi, D, Piciotti, R, Sabatini, S, Macchi, C, et al
Cellular and molecular gastroenterology and hepatology. 2022;(3):759-788
Abstract
BACKGROUND & AIMS The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. METHODS NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). RESULTS In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed microvesicular/macrovesicular pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum and mitochondria ultrastructures, thus increasing endoplasmic reticulum/oxidative stress. The mitochondrial number was increased in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reversed the metabolic and tumorigenic features observed in the compound knockout model. CONCLUSIONS The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
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BMI, functional and cognitive status in a cohort of nonagenarians: results from the Mugello study.
Dinu, M, Colombini, B, Pagliai, G, Vannetti, F, Pasquini, G, Molino Lova, R, Cecchi, F, Sorbi, S, Sofi, F, Macchi, C, et al
European geriatric medicine. 2021;(2):379-386
Abstract
PURPOSE The study of the relationship between body weight and health in old age has attracted increasing interest. The aim of the present study is to investigate the association of body mass index (BMI) with functional and cognitive status in a group of nonagenarians. METHODS We analyzed 475 participants (348 women, 127 men; median age 92 years) from the Mugello study. Participants were evaluated through laboratory, instrumental examinations and questionnaires. RESULTS By grouping the participants according to BMI categories, a better perception of health and nutritional status and a lower prevalence of sarcopenia (p < 0.05) were observed in participants with overweight and obesity compared to participants with normal weight or underweight. Concerning functional and cognitive measures, overweight and obese participants showed significantly worse performance on short physical performance battery and timed up and go tests and better performance on the mini-mental state examination (MMSE). As regards the other tests performed, no statistically significant differences were observed. In a multivariate logistic regression analysis adjusted for possible confounding factors, participants with BMI ≥ 30 kg/m2 showed lower probability to achieve poor performance on the MMSE (OR 0.42; 95% CI 0.19-0.94; p = 0.035). CONCLUSION Our results support the hypothesis that in nonagenarians, a higher BMI is associated with better cognitive ability. Further studies are needed to explore the mechanisms underlying this association.
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Impact of occupational complexity on cognitive decline in the oldest-old.
Hakiki, B, Pancani, S, Portaccio, E, Molino-Lova, R, Sofi, F, Macchi, C, Cecchi, F
Aging & mental health. 2021;(9):1630-1635
Abstract
OBJECTIVES The theory of "Cognitive Reserve" assumes that premorbid factors such as high educational and occupational attainment may enable a better way of coping with brain damage. It has been suggested that more stimulating lifestyles, including more complex work environments, may provide a buffer against cognitive decline in later life. This study aimed to investigate the association between occupational history and cognitive decline in a large cohort of Italian oldest-old. METHODS 392 individuals (266 women/126 men, mean age 93 ± 3 years) enrolled in the "Mugello study" provided information about their work history. Jobs were classified in nine categories, according to the level of expertise required to perform them, as suggested by the Italian National Institute for Statistics (ISTAT). In addition, socio-demographic characteristics, comorbidities, level of independence, depression, and cognitive status were assessed. The presence of dementia was established based on cognitive status and independence in performing four selected instrumental activities of daily living (ability to manage telephone, transportation, medications, and budget). RESULTS Neither work complexity (p = 0.995) nor work duration (p = 0.701) showed a significant effect on the likelihood of presenting a lower cognitive profile or developing dementia (p = 0.385 and p = 0.096, for work complexity and work duration, respectively). CONCLUSION In the observed sample of oldest-old individuals, cognitive decline did not seem to be influenced by cognitive reserve as assessed through the evaluation of cognitive status and level of independence. It is conceivable that in this population, the decline of the brain reserve has a preponderant role in the definition of the cognitive profile.
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Proprotein Convertase Subtilisin/Kexin Type 9: A View beyond the Canonical Cholesterol-Lowering Impact.
Macchi, C, Ferri, N, Sirtori, CR, Corsini, A, Banach, M, Ruscica, M
The American journal of pathology. 2021;(8):1385-1397
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly synthetized and released by the liver, represents one of the key regulators of low-density lipoprotein cholesterol. Although genetic and interventional studies have demonstrated that lowering PCSK9 levels corresponds to a cardiovascular benefit, identification of non-cholesterol-related processes has emerged since its discovery. Besides liver, PCSK9 is also expressed in many tissues (eg, intestine, endocrine pancreas, and brain). The aim of the present review is to describe and discuss PCSK9 pathophysiology and possible non-lipid-lowering effects whether already extensively characterized (eg, inflammatory burden of atherosclerosis, triglyceride-rich lipoprotein metabolism, and platelet activation), or to be unraveled (eg, in adipose tissue). The identification of novel transcriptional factors in the promoter region of human PCSK9 (eg, ChREBP) characterizes new mechanisms explaining how controlling intrahepatic glucose may be a therapeutic strategy to reduce cardiovascular risk in type 2 diabetes. Finally, the evidence describing PCSK9 as involved in cell proliferation and apoptosis raises the possibility of this protein being involved in cancer risk.
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Predictors of Function, Activity, and Participation of Stroke Patients Undergoing Intensive Rehabilitation: A Multicenter Prospective Observational Study Protocol.
Hakiki, B, Paperini, A, Castagnoli, C, Hochleitner, I, Verdesca, S, Grippo, A, Scarpino, M, Maiorelli, A, Mosca, IE, Gemignani, P, et al
Frontiers in neurology. 2021;:632672
Abstract
Background: The complex nature of stroke sequelae, the heterogeneity in rehabilitation pathways, and the lack of validated prediction models of rehabilitation outcomes challenge stroke rehabilitation quality assessment and clinical research. An integrated care pathway (ICP), defining a reproducible rehabilitation assessment and process, may provide a structured frame within investigated outcomes and individual predictors of response to treatment, including neurophysiological and neurogenetic biomarkers. Predictors may differ for different interventions, suggesting clues to personalize and optimize rehabilitation. To date, a large representative Italian cohort study focusing on individual variability of response to an evidence-based ICP is lacking, and predictors of individual response to rehabilitation are largely unexplored. This paper describes a multicenter study protocol to prospectively investigate outcomes and predictors of response to an evidence-based ICP in a large Italian cohort of stroke survivors undergoing post-acute inpatient rehabilitation. Methods: All patients with diagnosis of ischemic or hemorrhagic stroke confirmed both by clinical and brain imaging evaluation, admitted to four intensive rehabilitation units (adopting the same stroke rehabilitation ICP) within 30 days from the acute event, aged 18+, and providing informed consent will be enrolled (expected sample: 270 patients). Measures will be taken at admission (T0), at discharge (T1), and at follow-up 6 months after a stroke (T2), including clinical data, nutritional, functional, neurological, and neuropsychological measures, electroencephalography and motor evoked potentials, and analysis of neurogenetic biomarkers. Statistics: In addition to classical multivariate logistic regression analysis, advanced machine learning algorithms will be cross-validated to achieve data-driven prognosis prediction models. Discussion: By identifying data-driven prognosis prediction models in stroke rehabilitation, this study might contribute to the development of patient-oriented therapy and to optimize rehabilitation outcomes. Clinical Trial Registration: ClinicalTrials.gov, NCT03968627. https://www.clinicaltrials.gov/ct2/show/NCT03968627?term=Cecchi&cond=Stroke&draw=2&rank=2.
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Sex-specific predictors of PCSK9 levels in a European population: The IMPROVE study.
Ferri, N, Ruscica, M, Coggi, D, Bonomi, A, Amato, M, Frigerio, B, Sansaro, D, Ravani, A, Veglia, F, Capra, N, et al
Atherosclerosis. 2020;:39-46
Abstract
BACKGROUND AND AIMS Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels. Circulating PCSK9, which differs between genders, represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations between PCSK9 plasma levels and biochemical and anthropomorphic factors, and familial and personal morbidities, in a large European cohort (n = 3673) of men (47.9%) and women (52.1%). METHODS Individuals (aged 54-79 years) free of CV diseases were enrolled in seven centers of five European countries: Finland, France, Italy, the Netherlands, and Sweden. PCSK9 plasma levels were measured by ELISA. RESULTS PCSK9 was higher in women than in men. Multiple linear regression analysis showed that latitude, sex, and treatments with statins and fibrates were the strongest predictors of PCSK9 in the whole group. These variables, together with triglycerides and high-density lipoprotein cholesterol, were also associated with PCSK9 in men or women. Mean corpuscular hemoglobin concentration and pack-years were PCSK9 independent predictors in women, whereas hypercholesterolemia and physical activity were independent predictors in men. The associations between PCSK9 and latitude, uric acid, diabetes, hypercholesterolemia and physical activity were significantly different in men and women (pinteraction <0.05 for all). CONCLUSIONS Besides confirming the association with lipids in the whole group, our study revealed previously unknown differences in PCSK9 predictors in men and women. These might be taken into account when defining individual risk for CV events and/or for refining PCSK9 lowering treatments.