Glocalism: Journal of Culture, Politics and Innovation, 2015
International human rights law relies on state sovereignty to localize suggested policy with codi... more International human rights law relies on state sovereignty to localize suggested policy with codification and enforcement in an attempt to reconcile universalism with particularity. However, amidst domestic governance developments from postconflict state building and self-determination, governmental instability complicates and often overlooks priorities of international human rights for more tangible domestic infrastructure, such as basic human needs rather than seemingly suggested rights ideals. This does not diminish the significance of human rights, though, pertaining to the rights of the child in addressing gender-based violence through the elimination of female genital mutilation, for example. While state-centric localization is currently prioritized for implementing international law, the rule of law is more integrated throughout the realms of societal structure, culture, and institutions in addition to the legal realm. If the legal realm is disrupted with instability, violenc...
LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been asso... more LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been associated with impaired insulin sensitivity and dysregulated lipid metabolism. We hypothesized that gain-of-function mutations in LRP5 would also affect these parameters. We therefore studied individuals with LRP5 gain-of-function mutations exhibiting high bone mass (HBM) phenotypes and found that while there was no detected change in insulin sensitivity, there was a significant reduction in serum LDL. Introduction-Wnt signaling through LRP5 represents a newly appreciated metabolic pathway, which potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia. Studies in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis; however, whether it plays a similar role in humans is unclear. As current literature links loss-of-function LRP5 to impaired glucose and lipid metabolism, we hypothesized that individuals with an HBM-causing mutation in LRP5 would exhibit improved glucose and lipid homeostasis. Since studies in animal models have suggested that Wnt signaling augments insulin secretion, we also examined the effect of Wnt signaling on glucose-stimulated insulin secretion on human pancreatic islets. Methods-This was a matched case-control study. We used several methods to assess glucose and lipid metabolism in 11 individuals with HBM-causing mutations in LRP5. Affected study participants were recruited from previously identified kindreds with HBM-causing LRP5 mutations and included 9 males and 2 females. Two subjects that were being treated with insulin K. L.
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis,... more Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various threedimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the complex tumor stroma interactions driving progression and determining chemioresistance.
The Ministry of Health in Italy considers risk management (RM) to be one of the specific objectiv... more The Ministry of Health in Italy considers risk management (RM) to be one of the specific objectives to be developed by its national policies, as suggested by the European Union recommendations and by several international organizations, such as the World Health Organization (WHO), the Council of Europe, and the Organization for Economic Cooperation and Development. The National Health Plan stated the need to guarantee and monitor safety of health care and biomedical technology, with the development of a standardized computerized method to collect and analyze data on adverse events and with specific actions for education and training of all stakeholders, which is to be conducted at different levels of the health system governance, national, regional, and local. Over a 4-year period, the National Observatory for the Monitoring of Sentinel Events has collected data on 385 sentinel events, with a mortality rate of 54.8%. Compared with earlier reports, we have observed a reduction from 41% to 17% of sentinel events classified in the "nonspecified sentinel event" and an increase from 20% to 40% of cases in which an action plan has been developed. A manual for root cause analysis has been released with the aim of offering health operators an instrument to analyze the occurrence of an adverse event. Ten recommendations and a manual for safety in the operating room, which includes a checklist for safe surgery adapted on the basis of WHO suggestions, have been published. To date, eight guidelines for safety have been released to improve stakeholders' accountability. The Ministry of Health has also elaborated a program of specific actions to be developed over the next 2 years in several areas of RM. These initiatives confirm the strategic role of policies for RM in our country, allowing for a dynamic and proactive process, ensuring continuity of action and promoting a deep understanding of patient safety issues.
Chronic liver disease is common in patients undergoing kidney transplantation. Infection caused b... more Chronic liver disease is common in patients undergoing kidney transplantation. Infection caused by hepatitis B virus, often associated with unfavorable clinical outcome, decreased after introduction of efficient measures of profilaxis and hepatitis B vaccine, in contrast it became apparent that many transplant recipients had chronic liver disease related with hepatitis C. In these patients prevalence of anti HCV antibodies reported from several studies ranged from 6.2 to 65.8 2, depending on the use of I or II generation immunoassays, but no many dates are available about prevalence of HCV RNA, which detect viremia and can identify patients with active infection. The aim of this study was to determine prevalence of HCV RNA and clinical correlations in patients undergoing kidney trasplantation at the Ospedale Maggiore of Milano between 1976 and 1991. 216 patients positive for anti HCV by ELISA and RIBA [I (ORTHO Diagnostic Systems, Raritan N.J.) were studied. Serum liver biochemical parameters were assayed every S months. Nested PCR for the detection of NOV RNA in serum was performed using primers of the 5’UTR. All samples were also tested for IgM anti c22 (Abbott Labs. IL/USA) to verify the presence of this marker in chronic disease.
Proceedings of the 1st international conference on Aspect-oriented software development - AOSD '02, 2002
When it comes to software that runs on devices as varied as cell phones, PDAs and desktops, one s... more When it comes to software that runs on devices as varied as cell phones, PDAs and desktops, one size does not fit all. This paper describes how mixin layers, a kind of nested generic type, can be used to implement a graphical user interface library that can be configured to run on platforms with widely dissimilar capabilities. We describe the language support needed to incrementally build software in layers, and we describe how crosscutting concerns can be encapsulated within a layer. We then show how layers can be reconfigured to meet changing requirements. We also show how a new design pattern, the Sibling pattern, can be used with mixin layers to coordinate changes to multiple classes in the same inheritance hierarchy. When used appropriately, the Sibling pattern increases our ability to separate design concerns and to reuse code.
Proceedings of the 23rd International Conference on Software Engineering. ICSE 2001
Object-oriented frameworks are a popular mechanism for building and evolving large applications a... more Object-oriented frameworks are a popular mechanism for building and evolving large applications and software product lines. This paper describes an alternative approach to software construction, Java Layers (JL), and evaluates JL and frameworks in terms of flexibility, ease of use, and support for evolution. Our experiment compares Schmidt's ACE framework against a set of ACE design patterns that have been implemented in JL. We show how problems of framework evolution and overfeaturing can be avoided using JL's component model, and we demonstrate that JL scales better than frameworks as the number of possible application features increases. Finally, we describe how constrained parametric polymorphism and a small number of language features can support JL's model of loosely coupled components and stepwise program refinement.
Proceedings of the 14th international conference on World Wide Web - WWW '05, 2005
The difficulty of developing and deploying commercial web applications increases as the number of... more The difficulty of developing and deploying commercial web applications increases as the number of technologies they use increases and as the interactions between these technologies become more complex. This paper describes a way to avoid this increasing complexity by reexamining the basic requirements of web applications. Our approach is to first separate client concerns from server concerns, and then to reduce the interaction between client and server to its most elemental: parameter passing. We define a simplified programming model for form-based web applications and we use XForms and a subset of J2EE as enabling technologies. We describe our implementation of an MVC-based application builder for this model, which automatically generates the code needed to marshal input and output data between clients and servers. This marshalling uses type checking and other forms of validation on both clients and servers. We also show how our programming model and application builder support the customization of web applications for different execution targets, including, for example, different client devices.
The main goal of the research proposed in this document is to reduce the cost of developing and m... more The main goal of the research proposed in this document is to reduce the cost of developing and maintaining large software applications. Our approach augments existing object-oriented languages with a small number of domain-independent features designed to enhance code reusability, thus making applications easier to build. This proposal describes the contributions we expect our research to make.
... 4C), a specific A2A adenosine receptor antagonist (Zoc-chi et al., 1996), nor 100 nM ZM 24138... more ... 4C), a specific A2A adenosine receptor antagonist (Zoc-chi et al., 1996), nor 100 nM ZM 241385 (Fig. 4D), an antagonist of both A2A and A2B receptors (Poucher et al., 1995; Ji & Jacobson, 1999), significantly altered the cal-cium response to 5 μM Cl-IB-MECA (+18.4 ± 19.7%, ...
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the Cystic Fibrosis... more Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the Cystic Fibrosis transmembrane conductance regulator protein (CFTR), a cAMPregulated chloride channel. One of the most common mutation of CFTR is the deletion of phenylalanine in 508 position (DF508-CFTR). This mutation induces small conformational change hence CFTR trafficking is no more effective due to its rapid degradation by means of chaperon machinery. In CF airways, abnormal epithelial ion transport mainly initiates mucus stasis resulting in infections. In this study we tried to (1) understand intracellular trafficking of CFTR and DF508-CFTR, (2) facilitate transport of DF508-CFTR by means of relieving it from degradation and (3) create assay for the robotized high-throughput drugs screening. Using broad spectrum of methods from recombinant DNA and immunocitochemistry to electron microscopy, we identified main ethiologic mechanisms of cystic fibrosis. Our data demonstrate what we believe is possible to find a small molecule (adaptors and potentiators) for facilitation of DF508-CFTR trafficking to the plasma membrane.
Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conduct... more Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conductance regulator and Na+/H+ exchanger isoform 3 in a renal polarized epithelial cell model
Report for early dissemination of its contents. In view of the transfer of copyright to the outsi... more Report for early dissemination of its contents. In view of the transfer of copyright to the outside publisher, its distribution outside of IBM prior to publication should be limited to peer communications and specific requests. After outside publication, requests should be filled only by reprints or legally obtained copies of the article (e.g. , payment of royalties). Copies may be requested from IBM T.
... Despite the testimony of eyewitnesses in the stadium, the military claimed that the musician ... more ... Despite the testimony of eyewitnesses in the stadium, the military claimed that the musician was never captured (Constable and Valenzuela 31 ... abilities to foretell the future and to summon forth effigies are employed first by the military government and later by her son to uncover ...
Glocalism: Journal of Culture, Politics and Innovation, 2015
International human rights law relies on state sovereignty to localize suggested policy with codi... more International human rights law relies on state sovereignty to localize suggested policy with codification and enforcement in an attempt to reconcile universalism with particularity. However, amidst domestic governance developments from postconflict state building and self-determination, governmental instability complicates and often overlooks priorities of international human rights for more tangible domestic infrastructure, such as basic human needs rather than seemingly suggested rights ideals. This does not diminish the significance of human rights, though, pertaining to the rights of the child in addressing gender-based violence through the elimination of female genital mutilation, for example. While state-centric localization is currently prioritized for implementing international law, the rule of law is more integrated throughout the realms of societal structure, culture, and institutions in addition to the legal realm. If the legal realm is disrupted with instability, violenc...
LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been asso... more LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been associated with impaired insulin sensitivity and dysregulated lipid metabolism. We hypothesized that gain-of-function mutations in LRP5 would also affect these parameters. We therefore studied individuals with LRP5 gain-of-function mutations exhibiting high bone mass (HBM) phenotypes and found that while there was no detected change in insulin sensitivity, there was a significant reduction in serum LDL. Introduction-Wnt signaling through LRP5 represents a newly appreciated metabolic pathway, which potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia. Studies in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis; however, whether it plays a similar role in humans is unclear. As current literature links loss-of-function LRP5 to impaired glucose and lipid metabolism, we hypothesized that individuals with an HBM-causing mutation in LRP5 would exhibit improved glucose and lipid homeostasis. Since studies in animal models have suggested that Wnt signaling augments insulin secretion, we also examined the effect of Wnt signaling on glucose-stimulated insulin secretion on human pancreatic islets. Methods-This was a matched case-control study. We used several methods to assess glucose and lipid metabolism in 11 individuals with HBM-causing mutations in LRP5. Affected study participants were recruited from previously identified kindreds with HBM-causing LRP5 mutations and included 9 males and 2 females. Two subjects that were being treated with insulin K. L.
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis,... more Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various threedimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the complex tumor stroma interactions driving progression and determining chemioresistance.
The Ministry of Health in Italy considers risk management (RM) to be one of the specific objectiv... more The Ministry of Health in Italy considers risk management (RM) to be one of the specific objectives to be developed by its national policies, as suggested by the European Union recommendations and by several international organizations, such as the World Health Organization (WHO), the Council of Europe, and the Organization for Economic Cooperation and Development. The National Health Plan stated the need to guarantee and monitor safety of health care and biomedical technology, with the development of a standardized computerized method to collect and analyze data on adverse events and with specific actions for education and training of all stakeholders, which is to be conducted at different levels of the health system governance, national, regional, and local. Over a 4-year period, the National Observatory for the Monitoring of Sentinel Events has collected data on 385 sentinel events, with a mortality rate of 54.8%. Compared with earlier reports, we have observed a reduction from 41% to 17% of sentinel events classified in the "nonspecified sentinel event" and an increase from 20% to 40% of cases in which an action plan has been developed. A manual for root cause analysis has been released with the aim of offering health operators an instrument to analyze the occurrence of an adverse event. Ten recommendations and a manual for safety in the operating room, which includes a checklist for safe surgery adapted on the basis of WHO suggestions, have been published. To date, eight guidelines for safety have been released to improve stakeholders' accountability. The Ministry of Health has also elaborated a program of specific actions to be developed over the next 2 years in several areas of RM. These initiatives confirm the strategic role of policies for RM in our country, allowing for a dynamic and proactive process, ensuring continuity of action and promoting a deep understanding of patient safety issues.
Chronic liver disease is common in patients undergoing kidney transplantation. Infection caused b... more Chronic liver disease is common in patients undergoing kidney transplantation. Infection caused by hepatitis B virus, often associated with unfavorable clinical outcome, decreased after introduction of efficient measures of profilaxis and hepatitis B vaccine, in contrast it became apparent that many transplant recipients had chronic liver disease related with hepatitis C. In these patients prevalence of anti HCV antibodies reported from several studies ranged from 6.2 to 65.8 2, depending on the use of I or II generation immunoassays, but no many dates are available about prevalence of HCV RNA, which detect viremia and can identify patients with active infection. The aim of this study was to determine prevalence of HCV RNA and clinical correlations in patients undergoing kidney trasplantation at the Ospedale Maggiore of Milano between 1976 and 1991. 216 patients positive for anti HCV by ELISA and RIBA [I (ORTHO Diagnostic Systems, Raritan N.J.) were studied. Serum liver biochemical parameters were assayed every S months. Nested PCR for the detection of NOV RNA in serum was performed using primers of the 5’UTR. All samples were also tested for IgM anti c22 (Abbott Labs. IL/USA) to verify the presence of this marker in chronic disease.
Proceedings of the 1st international conference on Aspect-oriented software development - AOSD '02, 2002
When it comes to software that runs on devices as varied as cell phones, PDAs and desktops, one s... more When it comes to software that runs on devices as varied as cell phones, PDAs and desktops, one size does not fit all. This paper describes how mixin layers, a kind of nested generic type, can be used to implement a graphical user interface library that can be configured to run on platforms with widely dissimilar capabilities. We describe the language support needed to incrementally build software in layers, and we describe how crosscutting concerns can be encapsulated within a layer. We then show how layers can be reconfigured to meet changing requirements. We also show how a new design pattern, the Sibling pattern, can be used with mixin layers to coordinate changes to multiple classes in the same inheritance hierarchy. When used appropriately, the Sibling pattern increases our ability to separate design concerns and to reuse code.
Proceedings of the 23rd International Conference on Software Engineering. ICSE 2001
Object-oriented frameworks are a popular mechanism for building and evolving large applications a... more Object-oriented frameworks are a popular mechanism for building and evolving large applications and software product lines. This paper describes an alternative approach to software construction, Java Layers (JL), and evaluates JL and frameworks in terms of flexibility, ease of use, and support for evolution. Our experiment compares Schmidt's ACE framework against a set of ACE design patterns that have been implemented in JL. We show how problems of framework evolution and overfeaturing can be avoided using JL's component model, and we demonstrate that JL scales better than frameworks as the number of possible application features increases. Finally, we describe how constrained parametric polymorphism and a small number of language features can support JL's model of loosely coupled components and stepwise program refinement.
Proceedings of the 14th international conference on World Wide Web - WWW '05, 2005
The difficulty of developing and deploying commercial web applications increases as the number of... more The difficulty of developing and deploying commercial web applications increases as the number of technologies they use increases and as the interactions between these technologies become more complex. This paper describes a way to avoid this increasing complexity by reexamining the basic requirements of web applications. Our approach is to first separate client concerns from server concerns, and then to reduce the interaction between client and server to its most elemental: parameter passing. We define a simplified programming model for form-based web applications and we use XForms and a subset of J2EE as enabling technologies. We describe our implementation of an MVC-based application builder for this model, which automatically generates the code needed to marshal input and output data between clients and servers. This marshalling uses type checking and other forms of validation on both clients and servers. We also show how our programming model and application builder support the customization of web applications for different execution targets, including, for example, different client devices.
The main goal of the research proposed in this document is to reduce the cost of developing and m... more The main goal of the research proposed in this document is to reduce the cost of developing and maintaining large software applications. Our approach augments existing object-oriented languages with a small number of domain-independent features designed to enhance code reusability, thus making applications easier to build. This proposal describes the contributions we expect our research to make.
... 4C), a specific A2A adenosine receptor antagonist (Zoc-chi et al., 1996), nor 100 nM ZM 24138... more ... 4C), a specific A2A adenosine receptor antagonist (Zoc-chi et al., 1996), nor 100 nM ZM 241385 (Fig. 4D), an antagonist of both A2A and A2B receptors (Poucher et al., 1995; Ji & Jacobson, 1999), significantly altered the cal-cium response to 5 μM Cl-IB-MECA (+18.4 ± 19.7%, ...
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the Cystic Fibrosis... more Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the Cystic Fibrosis transmembrane conductance regulator protein (CFTR), a cAMPregulated chloride channel. One of the most common mutation of CFTR is the deletion of phenylalanine in 508 position (DF508-CFTR). This mutation induces small conformational change hence CFTR trafficking is no more effective due to its rapid degradation by means of chaperon machinery. In CF airways, abnormal epithelial ion transport mainly initiates mucus stasis resulting in infections. In this study we tried to (1) understand intracellular trafficking of CFTR and DF508-CFTR, (2) facilitate transport of DF508-CFTR by means of relieving it from degradation and (3) create assay for the robotized high-throughput drugs screening. Using broad spectrum of methods from recombinant DNA and immunocitochemistry to electron microscopy, we identified main ethiologic mechanisms of cystic fibrosis. Our data demonstrate what we believe is possible to find a small molecule (adaptors and potentiators) for facilitation of DF508-CFTR trafficking to the plasma membrane.
Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conduct... more Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conductance regulator and Na+/H+ exchanger isoform 3 in a renal polarized epithelial cell model
Report for early dissemination of its contents. In view of the transfer of copyright to the outsi... more Report for early dissemination of its contents. In view of the transfer of copyright to the outside publisher, its distribution outside of IBM prior to publication should be limited to peer communications and specific requests. After outside publication, requests should be filled only by reprints or legally obtained copies of the article (e.g. , payment of royalties). Copies may be requested from IBM T.
... Despite the testimony of eyewitnesses in the stadium, the military claimed that the musician ... more ... Despite the testimony of eyewitnesses in the stadium, the military claimed that the musician was never captured (Constable and Valenzuela 31 ... abilities to foretell the future and to summon forth effigies are employed first by the military government and later by her son to uncover ...
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