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Lanzoni G.,Diabetes Research InstituteUniversity of MiamiMiami | Carpino G.,Foro Italico University of Rome
Hepatology | Year: 2015

Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. © 2015 by the American Association for the Study of Liver Diseases.


Grant
Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2011.5.2 | Award Amount: 2.95M | Year: 2013

The MISSION-T2D aims at developing and validating an integrated, multilevel patient-specific model for the simulation and prediction of metabolic and inflammatory processes in the onset and progress of the type 2 diabetes (T2D). The ultimate goal is to provide a diagnostic tool to estimate the risk of developing T2D and to predict its progression in response to possible therapies. In Europe, T2D is one of the most common age-related diseases and a major public health concern. Recent data show that T2D and its complications (heart, kidney, retina, diabetic foot) should be considered a systemic disease sustained by a pervasive, metabolically driven state of inflammation. Accordingly, there is an urgent need to (a) understand the complex mechanisms underpinning the onset of T2D and (b) to identify early diagnostic parameters and related inflammatory indicators, by following a personalized medicine approach. This mission will be accomplished by setting up a multi-scale model to study the systemic interactions of the involved biological mechanisms (immunological/inflammatory processes, energy intake/expenditure ratio and cell cycle rate) in response to a variety of nutritional and metabolic stimuli/stressors. The overall architecture will exploit an already established immune system simulator as well as several discrete and continuous mathematical methods for the modeling of the processes critically involved in the onset and progression of T2D. The crucial validation work will compare simulation predictions with actual biological and clinical data. MISSION-T2D aims at paving the way for translating validated multilevel immune-metabolic models into the clinical setting of T2D. Indeed, this approach will eventually generate predictive biomarkers from the integration of metabolic, nutritional, immune/inflammatory, genetic and gut microbiota profiles, as well as of clinical data, suitable to be translated into cost-effective mobile-based diagnostic tools.


Romagnani P.,University of Florence | Crescioli C.,Foro Italico University of Rome
Clinica Chimica Acta | Year: 2012

Interferon (IFN) γ-induced protein 10. kDa (IP-10) or C-X-C motif chemokine 10 (CXCL10) is a small cytokine belonging to the CXC chemokine family. This family of signaling molecules is known to control several biological functions and to also play pivotal roles in disease initiation and progression. By binding to its specific cognate receptor CXCR3, CXCL10 critically regulates chemotaxis during several immune-inflammatory processes. In particular, this chemokine controls chemotaxis during the inflammatory response resulting from allograft rejection after transplantation.Interestingly, a strong association has been described between CXCL10 production, immune response and the fate of the graft following allotransplantation. Enhanced CXCL10 production has been observed in recipients of transplants of different organs. This enhanced production likely comes from either the graft or the immune cells and is correlated with an increase in the concentration of circulating CXCL10. Because CXCL10 can be easily measured in the serum and plasma from a patient, the detection and quantitation of circulating CXCL10 could be used to reveal a transplant recipient's immune status.The purpose of this review is to examine the critical role of CXCL10 in the pathogenesis of allograft rejection following organ transplantation. This important role highlights the potential utilization of CXCL10 not only as a therapeutic target but also as a biomarker to predict the severity of rejection, to monitor the inflammatory status of organ recipients and, hopefully, to fine-tune patient therapy in transplantation. © 2012 Elsevier B.V..


Crescioli C.,Foro Italico University of Rome
Clinical Biochemistry | Year: 2015

Improving long-term management, life-quality and outcome of transplant recipients continues to be a challenge. The impact of highly chemoattractant proteins as chemokines on transplant outcome is undeniable. These immunoactive molecules are critical in a wide variety of physiological and pathological processes, such as immunosurveillance, inflammation, infection, cancer, and rejection or tolerance after organ transplantation. Chemokines, playing an essential role in immune cell recruitment and localization within the graft, mirror the complex processes occurring in host-graft dialogue. In particular, the system of inflammatory chemokines and their receptors is modulated throughout all stages of transplantation and its inhibition counteracts rejection processes. The increase in chemokine expression at gene or protein level is, indeed, associated to multiorgan rejection. Thus, chemokines could serve as markers for risk of organ dysfunction/rejection and outcome predictors. This review intends to summarize chemokine function in transplantation and particularly focuses onto proinflammatory molecules such as CXC chemokines, which mediate early graft rejection in different organs and warrant consideration as predictors of outcome. The potentiality of chemokines - CXCL10 in particular - as systemic, robust, non-invasive, reliable and reproducible biomarkers for post-transplantation surveillance is addressed. Ideally, chemokines, as potential tools to predict and improve outcome, could give clinicians the opportunity to ameliorate patients' life-quality. © 2015 The Canadian Society of Clinical Chemists.


Mariani P.P.,Foro Italico University of Rome
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2010

Fibroarthrosis following knee injury or synovial disease is characterized by the presence of dense adhesions filling the entire joint cavity and the fibrotic involvement of periarticular structures. In this particular subset of knee stiffness, both the open and the arthroscopic treatment may fail not addressing all pathology. The aim of the present study was to evaluate the efficacy of an all-arthroscopic treatment for the flexion contractures addressing both the intra-articular posterior adhesions and the fibrotic periarticular structures. From 2003 through 2007, 18 patients of the knee underwent on arthroscopic posterior arthrolysis with release of both gastrocnemius tendons using the trans-septal technique. The median interval between the index procedure and the arthrolysis was 15 (4-22) months. Eight patients had a previous arthroscopic arthrolysis, performed in other hospitals, and two patients had two arthroscopic procedures after the index procedure which failed to regain the extension deficit. The passive extension deficit averaged 34° preoperatively (16°-44°). Six patients underwent a two-staged procedure: the first surgery addressed the presence of adhesions in the suprapatellar pouch and the medial and/or lateral gutters, to regain the flexion of the knee. At final follow-up, the passive extension deficit averaged 3° (0°-5°). In all patients, total knee arc of motion increased from 60° (30°-85°) to 95° (5°-110°). The trans-septal portal allows a safe approach of the posterior compartments and allows addressing pathology of both compartments and the release of gastrocnemius tendons. © Springer-Verlag 2009.


Lanzoni G.,University of Miami | Cardinale V.,University of Rome La Sapienza | Carpino G.,Foro Italico University of Rome
Hepatology | Year: 2016

Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (Hepatology 2016;64:277-286). © 2015 by the American Association for the Study of Liver Diseases


Paronetto M.P.,Foro Italico University of Rome | Paronetto M.P.,Laboratory of Cellular and Molecular Neurobiology
International Journal of Cell Biology | Year: 2013

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells. © 2013 Maria Paola Paronetto.


Crescioli C.,Foro Italico University of Rome
Current Opinion in Organ Transplantation | Year: 2013

Purpose of review: To summarize the promises and limitations of candidate noninvasive immunological biomarkers in cardiac rejection, with a special focus on the chemokine CXCL10, as a pretransplant predictive marker of early heart acute rejection. Potential issues for transfer from research to the clinic are addressed. Recent findings: Early changes of immune biomolecules in peripheral blood, reflecting graft or heart recipient's immune status, are candidate biomarkers able to diagnose or predict cardiac rejection, ideally giving an opportunity to intervene before heart failure occurs. The support of robust analytical methodologies is necessary for the transition from biomarker discovery to clinical implementation. Summary: Cardiac rejection represents the main problem after heart transplantation. Endomyocardial biopsy, although invasive and not risk free, is the gold-standard procedure for rejection monitoring. Noninvasive heart damage biomarkers manifest substantially after rejection occurrence. The goal is to detect graft injury at the earliest possible stage in disease initiation. Some biomolecules associated with the early immune response to cardiac allograft retain the power to be diagnostic and, even better, predictive of acute rejection, as in the case of pretransplant CXCL10 serum level. Multicenter studies for assay validation and standardization, integrated analysis of multiple biomarkers, and cost-effectiveness evaluation are mandatory efforts. Copyright © 2013, Lippincott Williams & Wilkins.


Pitzalis S.,Foro Italico University of Rome
PloS one | Year: 2012

Neuroimaging studies have identified several motion-sensitive visual areas in the human brain, but the time course of their activation cannot be measured with these techniques. In the present study, we combined electrophysiological and neuroimaging methods (including retinotopic brain mapping) to determine the spatio-temporal profile of motion-onset visual evoked potentials for slow and fast motion stimuli and to localize its neural generators. We found that cortical activity initiates in the primary visual area (V1) for slow stimuli, peaking 100 ms after the onset of motion. Subsequently, activity in the mid-temporal motion-sensitive areas, MT+, peaked at 120 ms, followed by peaks in activity in the more dorsal area, V3A, at 160 ms and the lateral occipital complex at 180 ms. Approximately 250 ms after stimulus onset, activity fast motion stimuli was predominant in area V6 along the parieto-occipital sulcus. Finally, at 350 ms (100 ms after the motion offset) brain activity was visible again in area V1. For fast motion stimuli, the spatio-temporal brain pattern was similar, except that the first activity was detected at 70 ms in area MT+. Comparing functional magnetic resonance data for slow vs. fast motion, we found signs of slow-fast motion stimulus topography along the posterior brain in at least three cortical regions (MT+, V3A and LOR).


Mariani P.P.,Foro Italico University of Rome
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2011

Purpose: In longstanding chronic anterior cruciate ligament (ACL) insufficiency, we identified an abnormal movement of the posterior medial meniscal horn, likely due to insufficiency of the posteromedial meniscotibial ligament. Passing from extension to flexion or vice versa, the medial posterior horn slides below the posterior rim of the tibia exposing the tibial plateau. Fixation with suture anchors of the meniscotibial ligament through a posteromedial portal restored normal meniscotibial tension and reduced instability of the meniscal posterior horn. The purpose of the present study was to present the arthroscopic features of posterior medial meniscus instability and to report results following arthroscopic repair. Methods: During the two-year study period, from 2007 through 2008, this arthroscopic feature was detected in 12 patients, 5 patients had failure of a previous ACL reconstruction and 7 patients had delay in ligamentous reconstruction for various reasons. All patients were affected by severe anterior-posterior translation with 11.3 ± 4.3 mm of side-to-side difference at KT-2000 and by associated rotatory laxity with grade 3 of pivot shift. Results: At follow-up of 1 year, the combined ACL reconstruction and fixation of the posteromedial horn showed a reduction in the rotatory and anteroposterior laxity. Conclusions: This study suggests the importance of a proper arthroscopic evaluation of the posterior medial capsule in patients with chronic ACL insufficiency and highlights the potential presence of an unstable posterior horn of the medial meniscus as an indirect arthroscopic sign of peripheral laxity. Level of evidence: Retrospective chart review, Level IV. © 2011 Springer-Verlag.

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