Stimulation of CYP450-Mediated omega-3 Docosahexaenoic Acid (DHA) Metabolism via MFSD2A as a Novel Therapy for Inflammatory Bowel Disease

Background and Aims: New evidences indicate that defects in pro-resolving pathways might underlie the pathogenesis of IBD. The resolution process is regulated by lipid mediators, such as those derived from the w-3 docosahexaenoic acid (DHA), whose esterified form is transported by the Major Facilitator Superfamily Domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A may modulate the lipid metabolism of gut endothelial cells, thus promoting the resolution of intestinal inflammation. Methods Lipidomic analysis was performed by Liquid chromatography-mass spectrometry on both mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMEC) isolated from surgical specimens of active, drug-induced resolving patients and healthy non-IBD subjects. By using a lentiviral strategy, healthy HIMEC were transduced with a lentivirus carrying GFP-tagged MFSD2A overexpressing vector (MFSD2A-OE), and assayed for their angiogenic properties and response to inflammatory stimuli. Adoptive transfer of human circulating endothelial progenitor cells (ECFCs), genetically engineered to overexpress MFSD2A, was performed in CD1 nude colitic mice, along with orally administered DHA. Results The lipidomic analysis revealed a reduced percentage of pro-resolving metabolites derived from Cytochrome P450 epoxygenation of DHA (epoxy-DHA derivatives) in the inflamed mucosa, when compared with samples from healthy and resolving tissues (1,40% \ub10,09 vs 0,85%\ub1 0,15 over total fatty acids; p<0,05). Interestingly, we found that reduced level of epoxy DHA-derivatives in active tissues correlated with lower amounts of MFSD2A compared to resolving mucosa (2\ub10,3 vs 1\ub10,1; p<0,01). MFSD2A, found exclusively expressed by gut endothelium, exerted pro-resolving effects in HIMEC in terms of reduced pro-inflammatory markers and anti-angiogenic functions, and promoted the release of beneficial epoxy-DHA derivatives. Transplantation of engineered human MFSD2A-OE ECFCs in DHA-fed colitic mice, resulted in amelioration of intestinal inflammation, through the stimulation of epoxy-DHA derivative release in the inflamed mucosa. These pro-resolving effects of MFSD2A were completely abolished by CYP2C inhibitor both in vitro and in vivo, demonstrating that protective functions exerted by MFSD2A depends on epoxy metabolites of DHA. Conclusion Our study provides not only important insights into the molecular mechanisms regulating resolution of intestinal inflammation, but also a strong rationale for the development of novel therapeutic strategies to treat IBD. Our cellbased therapeutic approach may help a selective cohort of non-responding patients, with the potential advantage of avoiding immune suppression, and using natural endogenous pathways to resolve inflammation

The human role in telerobotics

This chapter introduces the main topics of a telerobotic system. It describes the architecture of such a system from a general point of view and emphasizes the interaction between a human operator and a robot that performs the task in the remote environment. Furthermore it focuses on multi-modal human system interfaces and explains the main features of haptic, auditory, and visual interfaces. Finally important issues for the measurement and evaluation of the attribute telepresence are described. © 2007 Springer-Verlag Berlin Heidelberg

Treatment of Psoriasis Vulgaris with Calcipotriol Betamethasone Dipropionate Combination Followed by Calcipotriol and Assessment of the Adjuvant Basic Use of Urea-Based Emollients

A new combination product containing betamethasone dipropionate and calcipotriol (Dovobet® ointment) has been proven very effective and well tolerated in patients with psoriasis vulgaris. Emollients are adjunctive modalities commonly used in psoriasis; however, their actual role in combination with topical drugs as well as well as their compatibility with these drugs have not been well elucidated. In 313 adult patients with psoriasis vulgaris, we studied the efficacy and tolerability of treatment with Dovobet® ointment combined with urea-based emollients (Excipial U®) for 4 weeks, followed by treatment with calcipotriol (Daivonex®) either alone (group A) or combined with urea-containing emollients (Excipial U®, group B) for 8 weeks. Clinical evaluations were performed at baseline, at 4 and 12 weeks, assessing the clinical score for erythema, scaling, infiltration and pruritus, graded on the basis of a 5-point scale. After the initial 4-week treatment, a significant improvement of all clinical parameters was observed (p<0.05). Overall, clinical results improved further during the maintenance treatment phase; significant changes (p<0.05) were observed in each group. Most patients considered treatment efficacy positively at both 4 weeks and 12 weeks. Interestingly, at the end of the study, a greater percentage of patients in group B than in group A judged the efficacy as excellent. Treatment was very well tolerated. Only two patients complained of mild and transient burning sensation during the first days of treatment. The results of this study confirm the great efficacy and tolerability of sequential treatment with Dovobet®, and Daivonex® in psoriasis vulgaris and show the enhanced acceptability of this treatment associated with urea-based emollients

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A&gt;G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only &lt;0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer