👤 Giusy Cirillo

Chronic kidney disease (CKD) is a growing global health burden, strongly associated with cardiovascular disease, the leading cause of mortality in this population. Dyslipidemia is a key metabolic abnormality in CKD, but traditional lipid measures such as total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides often fail to capture the complexity of lipid disturbances in CKD and after kidney transplantation. Apolipoproteins have emerged as more reliable markers of cardiovascular and renal risk. Elevated apolipoprotein B (ApoB), reduced apolipoprotein A1 (ApoA1), and a higher ApoB/ApoA1 ratio are linked to CKD progression, cardiovascular events, and post-transplant complications, including post-transplant diabetes mellitus. Lipoprotein(a), a genetically determined atherogenic lipoprotein, accumulates in CKD due to impaired clearance and further increases cardiovascular risk. Other apolipoproteins, such as APOL1 and APOE, modulate CKD susceptibility through lipid-dependent and independent mechanisms. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of lipid metabolism, and PCSK9 inhibitors may represent a promising therapeutic option, though evidence in advanced CKD and transplant recipients is still limited, especially regarding their effects on apolipoproteins. This review summarizes current evidence on apolipoproteins and PCSK9 in CKD and transplantation, with attention to their potential as biomarkers and therapeutic targets. Show less

This study aimed to assess the extent to which human participants co-represent the lexico-semantic processing of a humanoid robot partner. Specifically, we investigated whether participants would engage their speech production system to predict the robot's upcoming words, and how they would progressively adapt to the robot's verbal behaviour. In the experiment, a human participant and a robot alternated in naming pictures of objects from 15 semantic categories, while the participant's electrophysiological activity was recorded. We manipulated word frequency as a measure of lexical access, with half of the pictures associated with high-frequency names and the other half with low-frequency names. In addition, the robot was programmed to provide semantic category labels (e.g., "tool" for the picture of a hammer) instead of the more typical basic-level names (e.g., "hammer") for items in five categories. Analysis of the stimulus-locked activity revealed a comparable event-related potential (ERP) associated with word frequency both when it was the participant's and the robot's turn to speak. Analysis of the response-locked activity showed a different pattern for the category and basic-level responses in the first but not in the second part of the experiment, suggesting that participants adapted to the robot's lexico-semantic patterns over time. These findings provide empirical evidence for two key points: (1) participants engage their speech production system to predict the robot's upcoming words and (2) partner-adaptive behaviour facilitates comprehension of the robot's speech. Show less

The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real-life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity. We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3-13.7] years, 3.6 [3.3-4.0] z-BMI) in Verona and 183 (11.3 [8.4-12.2] years, 3.2 [2.7-3.9] z-BMI) in Naples from January 2020 to February 2023. In March-July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation. We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow-up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant-carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2. Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time. Show less

The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat Familial Chylomicronemia Syndrome (FCS). Cases of decreased platelet count are reported among patients treated with volanesorsen. The aim of the study was to evaluate platelet function and thrombin generation (TG) assessment in FCS patients receiving volanesorsen. We performed a cross-sectional study on FCS patients treated with volanesorsen. Changes in platelet count PLC were assessed from baseline to Tw12 and Tw36. To assess TG, samples were processed by CAT (with PPP-reagent LOW). The results were expressed by the thrombogram graphic (thrombin variation over time); LagTime; endogenous thrombin potential (ETP); peak; time to reach peak (ttpeak), StartTail and Velocity Index. Platelet aggregation was assessed by testing different agonists using the turbidimetry method. Four FCS patients and four matched healthy controls were included in the present study. Changes in PLC were 30% at Tw12 and 34% at Tw36. Thrombin generation results showed values in the normal range (for patients and controls, respectively, LagTime:10.42 ± 4.40 and 9.25 ± 0.99; ttPeak:14.33 ± 4.01 and 13.10 ± 0.67; StartTail: 32.13 ± 3.54 and 29.46 ± 1.69; Velocity Index: 20.21 ± 3.63 and 33.05 ± 13.21; ETP: 599.80 ± 73.47 and 900.2 ± 210.99; peak value: 76.84 ± 1.07 and 123.30 ± 39.45) and no significant difference between cases and controls. Platelet aggregation test showed values in range, with no significant difference compared to healthy controls. Our study showed for the first time that no significant changes in general hemostasis assessed by TG and in platelet function were observed in FCS patients receiving volanesorsen. Show less

Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. Show less

Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-β levels and EMT signaling. Given that many drugs targeting TGF-β have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-β/EMT axis. Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-β and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-β levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-β/SMAD2&3) and non-canonical (TGF-β/PI3K/AKT, TGF-β/RAS/RAF/MEK/ERK, and TGF-β/WNT/β-catenin) TGF-β signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, β-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-β and inhibiting EMT in a diverse range of cancers. Show less

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM. Show less

The widespread use of Array Comparative Genomic Hybridization (aCGH) technology has enabled the identification of several syndromes associated with copy number variants (CNVs) including the 17q21.31 microdeletion. The 17q21.31 microdeletion syndrome, also known as Koolen-de Vries syndrome, was first described in 2006 in individuals with intellectual disabilities and organ abnormalities. We report the clinical, instrumental, cytogenetic and molecular investigations of a boy admitted for epilepsy and intellectual disabilities. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis by using aCGH. We identified a de novo microdeletion on chromosome 17q21.31, compatible with Koolen-de Vries syndrome. Our case shares some of the typical characteristics of the syndrome already described by other authors: delayed psychomotor development, primarily affecting the expressive language, dysmorphic facial features, and epilepsy. However the clinical outcome was not severe as the intellectual disabilities were moderate with good adaptive and functional behaviour. Epilepsy was easily controlled by a single drug, and he never needed surgery for organ abnormalities. Show less

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis. Show less