Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG. We previously identified miR-21, miR-222 and miR-124-3p purified from serum exosomes as molecular signature to help pre-operative clinical diagnosis and grading of gliomas. The aim of the present study was to verify this signature as a tool to assess the effect of treatment and for the early identification of progression in newly diagnosed HGG patients. Material and Methods: Major inclusion criteria were newly diagnosed, histologically confirmed HGG patients, no prior chemotherapy, ECOG PS 0-2 and patients scheduled for radiochemotherapy with temozolomide as first-line treatment after surgery. RANO criteria were used for response assessment. Serum was collected at baseline and subsequently at each neuroradiological assessment. mir-21, -222 and -124-3p expression in serum exosomes was measured in all samples. Results: A total number of 57 patients were enrolled; 41 were male, 52 with glioblastoma and 5 with anaplastic astrocytoma; 18 received radical surgery. HGG patients with higher exosomal miRNA expression displayed a statistically significant lower progression-free survival and overall survival. Increased expression of miR-21, -222 and -124-3p during post-operative follow-up was associated with HGG progression. Conclusions: These data indicate that miR-21, -222 and -124-3p in serum exosomes may be useful molecular biomarkers for complementing clinical evaluation of early tumor progression during post-surgical therapy in patients with HGG.

Cystic fibrosis (CF), is an autosomal recessive disease affecting different organs. The lung disease, characterized by recurrent and chronic bacterial infection and inflammation since infancy, is the main cause of morbidity and precocious mortality of these individuals. The innovative therapies directed to repair the defective CF gene should account for the presence of more than 200 disease-causing mutations of the CF transmembrane conductance regulator (CFTR) gene. The review will recall the different experimental approaches in discovering CFTR protein targeted molecules, such as the high throughput screening on chemical libraries to discover correctors and potentiators of CFTR protein, dual-acting compounds, read-through molecules, splicing defects repairing tools, CFTR “amplifiers”.

The psoralen-related compound, 4,6,4′-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4.

No single circulating biomarker has been put to practice for malignant gliomas so far, the most lethal primary brain tumors. Many promising protein biomarkers such as the mutant EGFRvIII or glial fibrillary acidic protein (GFAP) have already been detected in the blood and cerebrospinal fluid (CSF) of patients with gliomas, but their clinical value is still pending validation. Furthermore, these and other proteins seem to lack sufficient sensitivity and specificity required for a successful biomarker in this clinical setting. The expression profiling of microRNAs (miRNAs) has already entered cancer clinics as diagnostic and prognostic biomarkers, for assessing tumor initiation, progression and response to treatment. Large-scale miRNA expression analyses reported both up-regulation and down-regulation of several miRNAs in tumour tissues from patients with gliomas compared to normal brain tissue, thus supporting the development of miRNA-based biomarkers. Using comprehensive high-throughput approaches, such as microarrays, different circulating miRNAs were proposed as potential biomarkers of gliomas. This review is aimed to summarize the clinical evidence about circulating miRNA biomarkers discovered to date. Mandatory issues to develop clinically validated biomarkers to improve time of diagnosis, predicting response to treatment and prognosis of patients with gliomas are also herein addresses.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.