Studio multidisciplinare finalizzato alla riqualificazione ambientale della valle del Rio della Rocca (Comune di Castellarano, Provincia di Reggio Emilia)

La valle del Rio della Rocca nel Comune di Castellarano (Reggio Emilia) è stata interessata a partire dagli anni ‘50 del secolo scorso da attività estrattive che in parte ne hanno profondamente modificato le caratteristiche ambientali, in particolare quelle geomorfologiche. In considerazione dell’interesse paesaggistico della valle e ai fini di una riqualificazione ambientale del territorio, è stato realizzato uno studio multidisciplinare volto a delineare i principali aspetti geologici, paleontologici, floristici e faunistici. Specifica attenzione è stata posta alla valutazione dell’instabilità dei versanti e alla individuazione dei geositi presenti nell’area. Sulla scorta dei risultati delle ricerche effettuate sono state elaborate proposte di riqualificazione del territorio che prevedono una valorizzazione della valle a fini geoturistici e ricreativi

Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy

A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene

Background Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. Results A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. Conclusions GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene

Severe hypertriglyceridemia in a newborn with monogenic lipoprotein lipase deficiency: an unconventional therapeutic approach with exchange transfusion.

Severe hypertriglyceridemia (sHTG) (plasma triglyceride level > 10 mmol/L) due to lipoprotein lipase (LPL) deficiency is a known risk factor for acute pancreatitis. A 23-day-old male with sHTG was admitted to the Neonatal Intensive Care Unit for plasmapheresis being at high risk for acute pancreatitis. Given the potential hazard of an extracorporeal technique in a very young infant, we decided to perform an exchange transfusion (ET), a procedure widely used by neonatologists and less invasive than plasmapheresis. ET led to a dramatic reduction in plasma triglyceride level, from 93.2 to 3.8 mmol/L at the end of the procedure, without adverse events. The subsequent administration of a special formula low in fat and high in medium-chain triglycerides was effective in keeping fasting plasma triglyceride level below 5.6 mmol/L during the first 5 months of life. The sequence of LPL gene revealed that the patient was apparently homozygous for a novel nucleotide deletion (c.840delG) in exon 6 leading to a premature termination codon (p.N281Mfs*23). However, family studies revealed that while the patient's mother was heterozygous for this mutation, the father was heterozygous for a novel deletion eliminating the whole LPL gene. The patient therefore turned out to be a compound heterozygous for two LPL gene mutations predicted to abolish LPL activity. This is the first case of sHTG treated with ET in a neonate reported in the literature. ET appears to be a safe procedure, alternative to plasmapheresis, to prevent acute pancreatitis in young infants with sHTG due to LPL deficiency

Incidental finding of severe hypertriglyceridemia in children. Role of multiple rare variants in genes affecting plasma triglyceride.

BACKGROUND: The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL). OBJECTIVE: Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. METHODS: We performed the parallel sequencing of 20 plasma TG-related genes. RESULTS: Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant. CONCLUSIONS: Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG

An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia.

BackgroundFamilial Hypercholesterolemia (FH), the most common form of autosomal co-dominant hypercholesterolemia, is due to mutations in the LDLR gene, mostly minute or point mutations in the coding sequence.MethodsAnalysis of LDLR gene was performed by direct resequencing and multiplex ligation-dependent probe amplification (MLPA).ResultsLDLR gene resequencing showed that proband I.G., with the clinical diagnosis of homozygous FH, was homozygous for a mutation in exon 12 (c.1775 G>A, G571E) known to be pathogenic, and heterozygous for a mutation in intron 14 (c.2140 +5G>A). Proband's daughter with heterozygous FH carried only the intron 14 mutation. To explain this inconsistency we assumed that the proband was a carrier of a gene deletion. MLPA showed that the proband and her daughter were heterozygous for a deletion of exons 11 and 12. This explains the apparent homozygosity of the c.1175 G>A mutation in the proband. Ex 11–12 deletion was linked to the c.2140 +5G>A mutation. Other FH patients, heterozygotes for c.2140 +5G>A, were found to carry the Ex 11–12 deletion found in the proband or other pathogenic mutations.ConclusionsInconsistencies in the parent to offspring transmission of point mutations in LDLR gene may be due to a large deletion not detected by resequencing