Purpose/methods
The determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still ...challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated.
Results
The samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients.
Conclusion
This study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The objective of this study was to evaluate the morphological and immunohistochemical alterations of tissue removed from the upper third of anterior vaginal wall in a sample group of the female ...population presenting homogenous risk factors associated with Pelvic Organ Prolapse (POP). The case study consisted of 14 patients with POP and there were 10 patients in the control group. Patient selection was carried on the basis of specific criteria and all of the patients involved in the study presented one or more of the recognized POP risk factors. Samples were taken from POP patients during vaginal plastic surgery following colpohysterectomy, and from control patients during closure of the posterior fornix following hysterectomy. Samples were processed for histological and immunohistochemical analyses for Collagen I and Collagen III, α-Smooth Muscle Actin (α-SMA), Platelet-Derived-Growth-Factor (PDGF), matrix metalloproteinase 3 (MMP3), Caspase3. Immunofluorescence analyses for Collagen I and III and PDGF were also carried out. In prolapsed specimens our results show a disorganization of smooth muscle cells that appeared to have been displaced by an increased collagen III deposition resulting in rearrangement of the muscularis propria architecture. These findings suggest that the increase in the expression of collagen fibers in muscularis could probably due to a phenotypic switch resulting in the dedifferentiation of smooth muscle cells into myofibroblasts. These alterations could be responsible for the compromising of the dynamic functionality of the pelvic floor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
15.
New insights into liver stem cells Gaudio, E; Carpino, G; Cardinale, V ...
Digestive and liver disease,
07/2009, Volume:
41, Issue:
7
Journal Article
Peer reviewed
Open access
Abstract Hepatic progenitor cells are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages. In adult ...livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate, representing a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication, or in cases of severe cell loss. Hepatic progenitor cell activation has been described in various acute and chronic liver diseases. Their niche is composed by numerous cells such as Hepatic Stellate Cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells, numerous hormones and growth factors could interact and cross-talk with progenitor cells influencing their proliferative and differentiative processes. Hepatic progenitor cells and their niche could represent, in the near future, a target for therapeutic approaches to liver disease based on cell-specific drug delivery systems. Isolation and transplantation of hepatic progenitor cells could represent a new approach for therapy of end-stage chronic liver diseases, as they offer many advantages to transplantation of mature hepatocytes. The possibility of applying stem cell therapy to liver diseases will represent a major goal in this field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mesenchymal cells transdifferentiation and extracellular matrix deposition are involved in the fibrotic process of Crohn's disease (CD). Mesenchymal smooth muscle cells (SMCs) de-differentiation, ...driven by Platelet-derived growth factor (PDGF) that counteracts Transforming growth factor (TGF-β) has been studied in vascular muscle. The role of SMCs in intestinal fibrogenesis is still not clearly elucidated. Aim of the study was to evaluate the possible myogenic contribution to CD fibrotic process through the comparative analysis of histological, morphometric and molecular alterations occurring in human smooth muscle. Full thickness specimens were obtained from CD (non-involved and stenotic tracts) and healthy (control) ileum. Tissues were processed for histological and immunohistochemical (IHC) analyses and SMCs were isolated from the muscularis propria for morphofunctional and molecular (qPCR) analyses. CD stenotic ileum showed a significant increased thickness of all layers compared to CD non-involved and control ileum. IHC revealed an overexpression of α-smooth muscle actin and collagens I-III throughout all intestinal layers only in stenotic tracts. The two growth factors, PDGF and TGF-β, showed a progressive increase in expression in the muscle layer from CD non-involved to stenotic tracts. Freshly isolated SMCs presented alterations in CD non-involved tracts that progressively increased in the stenotic tracts consisting in a statistical increase in mRNA encoding for PDGF-β and collagen III, paralleled to a decrease in TGF-β and Tribbles-like protein-3 mRNA, and altered morphofunctional parameters consisting in progressive decreases in cell length and contraction to acetylcholine. These findings indicate that intrinsic myogenic alterations occur in CD ileum, that they likely precede stricture formation, and might represent suitable new targets for anti-fibrotic interventions.
An abstract of the study of Gaudio et. al. about the novel BTK and PI3K-delta inhibitors acalabrutinib (ACP-196) and ACP-319 show activity in pre-clinical B-cell lymphoma models is presented. Among ...other things BTK and PI3K-delta inhibitors are among the most promising classes of anti-lymphoma agents, as demonstrated by the FDA approval of ibrutinib and idelalisib. Acalabrutinib (ACP-196) and ACP-319 are novel BTK and PIK3-delta selective inhibitors, respectively, under clinical evaluation. Acalabrutinib and ACP-319 showed both in vitro and in vivo anti-lymphoma activity. In vitro synergism was observed in some cell lines where single agent activity of either agent was modest or absent. Further preclinical and clinical studies are suggested.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This paper considers the problem of real-time control and learning in dynamic systems subjected to parametric uncertainties. We propose a combination of a Reinforcement Learning (RL) based policy in ...the outer loop suitably chosen to ensure stability and optimality for the nominal dynamics, together with Adaptive Control (AC) in the inner loop so that in real-time AC contracts the closed-loop dynamics towards a stable trajectory traced out by RL. Two classes of nonlinear dynamic systems are considered, both of which are control-affine. The first class of dynamic systems utilizes equilibrium points and a Lyapunov approach while second class of nonlinear systems uses contraction theory. AC-RL controllers are proposed for both classes of systems and shown to lead to online policies that guarantee stability using a high-order tuner and accommodate parametric uncertainties and magnitude limits on the input. In addition to establishing a stability guarantee with real-time control, the AC-RL controller is also shown to lead to parameter learning with persistent excitation for the first class of systems. Numerical validations of all algorithms are carried out using a quadrotor landing task on a moving platform.
Background Transforming growth factor‐β (TGF‐β)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of extracellular matrix (ECM) protein accumulation. The aim ...of this study was to evaluate the potential role of Smad3 in the pathogenesis of colonic fibrosis induced by trinitrobenzene sulfonic acid (TNBS) in Smad3 null mice.
Materials and methods Chronic colitis‐associated fibrosis was induced in 15 Smad3 null and 13 wild‐type mice by intra‐rectal administration of TNBS. Each mouse received an incremental dose of TNBS (0·5–1·0 mg per week) over a 6‐week period. The colon was excised for macroscopic examination and histological, morphometric and immunohistochemical analyses. For immunohistochemistry, alpha‐smooth muscle actin (α‐SMA), collagen types I–III, TGF‐β1, connective tissue growth factor (CTGF), Smad3, Smad7, and CD3 antibodies were used.
Results At macroscopic examination, the colon of Smad3 wild‐type mice appeared significantly harder, thicker and shorter than that of the Smad3 null mice. Of the wild‐type mice, 50% presented colonic adhesions and strictures. Histological and morphometric evaluation revealed a significantly higher degree of colonic fibrosis and accumulation of collagen in the Smad3 wild‐type compared to null mice, whereas the degree of colonic inflammation did not differ between the two groups of mice. Immunohistochemical evaluation showed a marked increase in CTGF, collagen I–III, TGF‐β and Smad3 staining in the colon of Smad3 wild‐type compared to null mice, whereas Smad7 was increased only in null mice.
Conclusions These results indicate that Smad3 loss confers resistance to the development of TNBS‐induced colonic fibrosis. The reduced fibrotic response appears to be due to a reduction in fibrogenic mesenchymal cell activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of intestinal fibrosis, especially in inflammatory bowel disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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