👤 Vera Cappelletti

Neuronal ceroid lipofuscinosis type 3 (CLN3) is a rare lysosomal storage disorder characterized by progressive neurodegeneration. No disease-modifying treatments are currently available. Miglustat, a substrate reduction therapy, has shown preclinical efficacy in CLN3 models (conference abstract). The aim of this study was to assess the long-term safety and clinical impact of miglustat in patients with CLN3 disease. This was an open-label, single-center study conducted at Bambino Gesù Children's Hospital in Rome, Italy. Oral miglustat was titrated to 15 mg/kg/d or a maximum of 600 mg/d. Patients were assessed every 6 months using the Unified Batten Disease Rating Scale (UBDRS). The primary outcome was the annual rate of change in the UBDRS physical subscale. Clinical data were analyzed descriptively. Six patients (33% female) with a median age of 20.34 years (interquartile range [IQR] 18.25-23.84) were treated and followed for a median of 3.9 years (IQR 3.32-4.34). The mean annual change in the UBDRS physical score was +1.96 points per year (SD ± 0.80). Miglustat was well tolerated, with only mild, self-limiting gastrointestinal side effects observed. Miglustat showed a favorable safety profile and was associated with a slower rate of physical decline compared with historical controls. Limitations include small sample size, genetic heterogeneity, and open-label design. Show less

Progression to stage IV disease remains the main cause of breast cancer-related deaths. Increasing knowledge on the hematogenous phase of metastasis is key for exploiting the entire window of opportunity to interfere with early dissemination and to achieve a more effective disease control. Recent evidence suggests that circulating tumor cells (CTCs) possess diverse adaptive mechanisms to survive in blood and eventually metastasize, encouraging research into CTC-directed therapies. On the hypothesis that the distinguishing molecular features of CTCs reveal useful information on metastasis biology and disease outcome, we compared the transcriptome of CTCs, primary tumors, lymph-node and lung metastases of the MDA-MB-231 xenograft model, and assessed the biological role of a panel of selected genes, by in vitro and in vivo functional assays, and their clinical significance in M0 and M+ breast cancer patients. We found that hematogenous dissemination is governed by a transcriptional program and identified a CTC signature that includes 192 up-regulated genes, mainly related to cell plasticity and adaptation, and 282 down-regulated genes, involved in chromatin remodeling and transcription. Among genes up-regulated in CTCs, FADS3 was found to increases cell membrane fluidity and promote hematogenous diffusion and lung metastasis formation. TFF3 was observed to be associated with a subset of CTCs with epithelial-like features in the experimental model and in a cohort of 44 breast cancer patients, and to play a role in cell migration, invasion and blood-borne dissemination. The analysis of clinical samples with a panel of CTC-specific genes (ADPRHL1, ELF3, FCF1, TFF1 and TFF3) considerably improved CTC detection as compared with epithelial and tumor-associated markers both in M0 and stage IV patients, and CTC kinetics informed disease relapse in the neoadjuvant setting. Our findings provide evidence on the potential of a CTC-specific molecular profile as source of metastasis-relevant genes in breast cancer experimental models and in patients. Thanks to transcriptome analysis we generated a novel CTC signature in the MDA-MB-231 xenograft model, adding a new piece to the current knowledge on the key players that orchestrate tumor cell hematogenous dissemination and breast cancer metastasis, and expanding the list of CTC-related biomarkers for future validation studies. Show less

Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson's disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specific expression was identified for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show significant allele-specific effects. Allele-specific effects were confirmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specific allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specific expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development. Show less