57 research outputs found
Orthogonal-Array based Design Methodology for Complex, Coupled Space Systems
No full textThe process of designing a complex system, formed by many elements and sub-elements interacting between each other, is usually completed at a system level and in the preliminary phases in two major steps: design-space exploration and optimization. In a classical approach, especially in a company environment, the two steps are usually performed together, by experts of the field inferring on major phenomena, making assumptions and doing some trial-and-error runs on the available mathematical models. To support designers and decision makers during the design phases of this kind of complex systems, and to enable early discovery of emergent behaviours arising from interactions between the various elements being designed, the authors implemented a parametric methodology for the design-space exploration and optimization. The parametric technique is based on the utilization of a particular type of matrix design of experiments, the orthogonal arrays. Through successive design iterations with orthogonal arrays, the optimal solution is reached with a reduced effort if compared to more computationally-intense techniques, providing sensitivity and robustness information. The paper describes the design methodology in detail providing an application example that is the design of a human mission to support a lunar base
A methodology for system-of-systems design in support of the engineering team
No full textSpace missions have experienced a trend of increasing complexity in the last decades, resulting in the design of very complex systems formed by many elements and sub-elements working together to meet the requirements. In a classical approach, especially in a company environment, the two steps of design-space exploration and optimization are usually performed by experts inferring on major phenomena, making assumptions and doing some trial-and-error runs on the available mathematical models. This is done especially in the very early design phases where most of the costs are locked-in. With the objective of supporting the engineering team and the decision-makers during the design of complex systems, the authors developed a modelling framework for a particular category of complex, coupled space systems called System-of-Systems. Once modelled, the System-of-Systems is solved using a computationally cheap parametric methodology, named the mixed-hypercube approach, based on the utilization of a particular type of fractional factorial design-of-experiments, and analysis of the results via global sensitivity analysis and response surfaces. As an applicative example, a system-of-systems of a hypothetical human space exploration scenario for the support of a manned lunar base is presented. The results demonstrate that using the mixed-hypercube to sample the design space, an optimal solution is reached with a limited computational effort, providing support to the engineering team and decision makers thanks to sensitivity and robustness informa- tion. The analysis of the system-of-systems model that was implemented shows that the logistic support of a human outpost on the Moon for 15 years is still feasible with currently available launcher classes. The results presented in this paper have been obtained in cooperation with Thales Alenia Space—Italy, in the framework of a regional programme called STEP
MIR002: a new POLA1 inhibitor endowed with a large spectrum of antitumor activity
No full textAbstract
A recent work from Han et al. disclosed DNA polymerase 1 alpha (POLA1) as the key target for the anti-cancer effects of CD437, a molecule belonging to the class of Retinoid Related Molecules (RRMs). Before this evidence, this family of compounds, of which CD437 and ST1926 represent the prototypes, has been characterized for its antiproliferative, antitumor and pro-apoptotic activity. With aim to identify a new RRM with an improved pharmacological profile, we recently selected MIR002 as a novel compound endowed with a potent antitumor activity and a peculiar pharmacological profile. In vitro treatment with MIR002 leads to a G1/S arrest and exerts a potent anti-tumor/proapoptotic activity in a wide range of cancer cell lines, including H460-R9A cells, which are cross resistant to ST1926 and CD437 (IC50>70 fold of H460-R9A vs H460). Moreover, in H460-R9A cells, we identified the L764F mutation in POLA1, already described as a mutation conferring resistance to CD437. We also demonstrated that POLA1 is the molecular target of both MIR002 and ST1926 and that, interestingly, the expression of the L764F mutant, although associated with the resistance to RRM’s, only marginally reduces the cytotoxic effects of MIR002. In order to investigate the activity of MIR002 against tumor growth, we examined a panel of in vivo xenograft tumor models, including those originating from human Non-Small Cell Lung Cancer (NSCLC) and Malignant Pleural Mesothelioma (MPM). In these models, using a q2dx5x3w schedule in doses ranging from 50 to 70 mg/Kg administered orally, we observed a strong tumor growth inhibition (TGI>70%). Interestingly, the combination of MIR002 with Cisplatin (4mg/Kg; qd7x3w; i.v.) in MPM models showed a synergistic antitumor efficacy, reaching a TGI>90%, and cured animals. Interestingly, we previously identified POLA1 as a key pro-proliferative player in 9 primary MPM samples. The ex-vivo analyses indicated that POLA1 expression was strongly modulated upon MIR002 treatment. Furthermore, in the same models, we also observed that the expression/secretion of multiple circulating factors is affected by MIR002 and we identified some of them as potential biomarkers of tumor responsiveness to MIR002. Taken together, our results identify MIR002 as a novel anti-cancer compound and suggest POLA1 as a target for new antitumor strategies to be investigated in Clinical Trials.
Citation Format: Claudio Pisano, Lucio Merlini, Sergio Penco, Raffaella Cincinelli, Nadine Darwiche, Mario B. Guglielmi, Antonietta Esposito, Ilaria La Porta, Giacomo Signorino, Gabriele De Rubis, Fabiana Colelli, Francesco Cardile, Alessandra Fucci, Egildo L. D'Andrea, Sabrina Dallavalle. MIR002: a new POLA1 inhibitor endowed with a large spectrum of antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4195. doi:10.1158/1538-7445.AM2017-4195</jats:p
Ketogenic Diet in Children and Adolescents: the Effects on Growth and Nutritional Status
No full textThe ketogenic diet is known to be a possible adjuvant treatment in several medical conditions, such as in patients with severe or drug-resistant forms of epilepsy. Its use has recently been increasing among adolescents and young adults due to its supposed weight-loss effect, mediated by lipolysis and lowered insulin levels. However, there are still no precise indications on the possible use of ketogenic diets in pediatric age for weight loss. This approach has also recently been proposed for other types of disorder such as inherited metabolic disorders, Prader-Willi syndrome, and some specific types of cancers. Due to its unbalanced ratio of lipids, carbohydrates and proteins, a clinical evaluation of possible side effects with a strict evaluation of growth and nutritional status is essential in all patients following a long-term restrictive diet such as the ketogenic one. The prophylactic use of micronutrients supplementation should be considered before starting any ketogenic diet. Lastly, while there is sufficient literature on possible short-term side effects of ketogenic diets, their possible long-term impact on growth and nutritional status is not yet fully understood, especially when started in pediatric age
Natural history of pancreatic involvement in paediatric inflammatory bowel disease
No full textBackground: Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease. Aim: To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia. Methods: We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year. Results: From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis (p= 0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia. Conclusions: In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve
Twelve Novel Mutations in the SLC26A3 Gene in 17 Sporadic Cases of Congenital Chloride Diarrhea
No full textObjectives: We aimed to improve the knowledge of pathogenic mutations in
sporadic cases of congenital chloride diarrhea (CCD) and emphasize the
importance of functional studies to define the effect of novel mutations.
Methods: All member 3 of solute carrier family 26 (SLC26A3) coding
regions were sequenced in 17 sporadic patients with CCD. Moreover, the
minigene system was used to analyze the effect of 2 novel splicing
mutations.
Results: We defined the SLC26A3 genotype of all 17 patients with CDD
and identified 12 novel mutations. Using the minigene system, we confirmed
the in silico prediction of a complete disruption of splicing pattern caused
by 2 of these novel mutations: the c.971þ3_971þ4delAA and
c.735þ4_c.735þ7delAGTA. Moreover, several prediction tools and a
structure-function prediction defined the pathogenic role of 6 novel
missense mutations.
Conclusions: We confirm the molecular heterogeneity of sporadic CDD
adding 12 novel mutations to the list of known pathogenic mutations.
Moreover, we underline the importance, for laboratories that offer
molecular diagnosis and genetic counseling, to perform fast functional
analysis of novel mutation
Clinical Features and Risk Factors of Autoimmune Liver Involvement in Pediatric Inflammatory Bowel Disease
No full textOBJECTIVES:Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease.
METHODS:Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared.
RESULTS:Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up.
CONCLUSIONS:Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended
Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors
No full textRecent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability
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