Generation of induced pluripotent stem cell line, CSSi004-A (2962), from a patient diagnosed with Huntington's disease at the presymptomatic stage

Huntington's disease (HD) is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presymptomatic life stage, carrying a polyglutamine expansion in HTT gene codifying Huntingtin protein. The iPSC line contained the expected CAG expansion, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had a normal karyotype

Generation of the induced pluripotent stem cell line CSSi006-A (3681) from a patient affected by advanced-stage Juvenile Onset Huntington's Disease

Abstract Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3–10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease

Generation of induced pluripotent stem cell line, CSSi002-A (2851), from a patient with juvenile Huntington Disease

Abstract Huntington Disease (HD) is an autosomal dominant disorder characterized by motor, cognitive and behavioral features caused by a CAG expansion in the HTT gene beyond 35 repeats. The juvenile form (JHD) may begin before the age of 20 years and is associated with expanded alleles as long as 60 or more CAG repeats. In this study, induced pluripotent stem cells were generated from skin fibroblasts of a 8-year-old child carrying a large size mutation of 84 CAG repeats in the HTT gene. HD appeared at age 3 with mixed psychiatric (i.e. autistic spectrum disorder) and motor (i.e. dystonia) manifestations

Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models

Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington's disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine-and temperaturedependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperatureand polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients

Association between amount of injured heart and Novel molecular/bio markers in myocardial infarction

Oggi l’infarto del miocardio, e la conseguente perdita della piena funzionalità del tessuto cardiaco, rappresenta la maggiore eziologia per lo scompenso cardiaco. Nonostante la terapia primaria aggressiva, la prognosi rimane grave in pazienti con infarto e grave disfunzione ventricolare sinistra. Sarebbe quindi altamente desiderabile poter influenzare la guarigione della lesione cardiaca per mantenere la struttura e la funzione del cuore. Il Fattore XIII (FXIII) viene attivato dalla trombina nella fase finale della cascata della coagulazione ed ha un ruolo prominente nel crosslinking della fibrina solubile verso un coagulo insolubile stabile. Evidenze sperimentali in modelli murini suggeriscono che il fattore XIII potrebbe svolgere un ruolo chiave nella guarigione dopo l’infarto miocardico. Per quantificare il reale contributo del FXIII in questo processo, e per esplorare il suo possibile ruolo prognostico, abbiamo monitorato i livelli FXIII-A in 350 pazienti con infarto miocardico acuto durante i primi sei giorni (D0-D5) più un controllo a 30-60 giorni (D30). Ad un anno il follow-up è stato effettuato per tutti i pazienti. Qui confrontiamo i livelli di FXIII a quelli dei marcatori cardiaci standard per prevedere il danno causato dall’infarto del miocardio e il relativo outcome clinico, ma anche per valutare il potenziale terapeutico di questa molecola. Il risultato principale della nostra ricerca traslazionale è stato quello di attribuire una prognosi più infausta per i pazienti con un più alto consumo di FXIII nei primi giorni post-IMA rispetto al sottogruppo di pazienti in cui il consumo di FXIII (valutato come livelli residui dello stesso) è stato trascurabile. Questa interessante osservazione è indipendente dalla quantità di Troponin_T e CK-MB, attribuendo così al FXIII un ruolo di fattore prognostico indipendente per l’infarto. Inoltre, varianti comuni del gene FXIII (Val34Leu, Pro564Leu, Tyr204Phe, Val650Ile, Glu651Gln) influenzano in modo significativo l'attività molecolare. Abbiamo così analizzato tutte le varianti citate coinvolte nel processo di guarigione del muscolo cardiaco e nel determinare l'estensione del danno, fattori che sono direttamente collegati all’insufficienza cardiaca e, di conseguenza, alla sopravvivenza. Diversi livelli e dinamiche del FXIII-A potrebbero essere utilizzati come i primi indicatori prognostici durante l’infarto miocardico acuto, assieme ai marcatori tradizionali di ischemia eseguiti di routine, nei pazienti con sospetta o conclamata insufficienza cardiaca in modo da da personalizzare il trattamento. Inoltre potrebbero rappresentare un metodo alternativo per studi su biomarcatori finalizzati a una più pratica valutazione della progressione di patologia.Today, myocardial infarction and the consequent loss of fully functional myocardium is the major aetiology for heart failure. Despite aggressive primary therapy, prognosis remains serious in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to influence healing of the cardiac wound to maintain structure and function of the heart. Factor XIII (FXIII) is activated by thrombin in the final step of the clotting cascade coagulation and it has a prominent role in cross-linking soluble fibrin to a stable insoluble clot. Experimental evidence in mouse models suggests that Factor XIII might play a key role in myocardial healing after infarction. To quantify the real contribution of FXIII in this process, and to explore its possible prognostic role, we monitored the FXIII-A subunit levels in 350 acute MI patients during the first six days (d0-d5) plus a control at 30-60 days (d30). A one-year follow-up was performed for all the patients. Here, we compare FXIII levels to those of standard cardiac markers to predict the damage due to the infarction and the clinical outcome, but also to evaluate the therapeutic potential of this molecule. The main result of our translational research was to attribute a poor prognosis for patients with higher consumption of FXIII in the early days post-MI when compared with the subgroup of patients in whom FXIII consumption (rated as residual levels of the same) was negligible. This interesting observation is independent of the amount of Troponin_T and CK-MB, thus attributing to FXIII a role as an independent prognostic factor in heart attacks. Furthermore, common FXIII gene variants (Val34Leu, Pro564Leu, Tyr204Phe, Val650Ile, Glu651Gln) significantly influence molecular activity. So, in addition, we have analyzed all mentioned variants involved in the healing process of the heart muscle and in determining the extention of the damage, factors that are with directly related to heart failure and, consequently, to survival. Different FXIII-A dynamics and levels could be utilized as early prognostic indicators during acute MI, toghether with traditional markers of ischemia routinely performed, in patients with suspected or overt heart failure to personalize treatment. Furthermore, they could be an alternative method for biomarker studies aimed to more practical assesment of progression

Generation of the induced pluripotent stem cell line CSSi006-A (3681) from a patient affected by advanced-stage Juvenile Onset Huntington's Disease

Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3–10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease

Generation of induced pluripotent stem cell line, CSSi002-A (2851), from a patient with juvenile Huntington Disease

Huntington Disease (HD) is an autosomal dominant disorder characterized by motor, cognitive and behavioral features caused by a CAG expansion in the HTT gene beyond 35 repeats. The juvenile form (JHD) may begin before the age of 20 years and is associated with expanded alleles as long as 60 or more CAG repeats. In this study, induced pluripotent stem cells were generated from skin fibroblasts of a 8-year-old child carrying a large size mutation of 84 CAG repeats in the HTT gene. HD appeared at age 3 with mixed psychiatric (i.e. autistic spectrum disorder) and motor (i.e. dystonia) manifestations

Typical breakfast food consumption and risk factors for cardiovascular disease in a large sample of Italian adults.

16nonenonedi Giuseppe R; Di Castelnuovo A; Melegari C; De Lucia F; Santimone I; Sciarretta A; Barisciano P; Persichillo M; De Curtis A; Zito F; Krogh V; Donati MB; de Gaetano G; Iacoviello ; D.Assanelli; Moli-sani Project Investigators.di Giuseppe, R; Di Castelnuovo, A; Melegari, C; De Lucia, F; Santimone, I; Sciarretta, A; Barisciano, P; Persichillo, M; De Curtis, A; Zito, F; Krogh, V; Donati, Mb; de Gaetano, G; Iacoviello, ; Assanelli, Deodato; Moli sani Project, Investigator