Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.

Desenvolupament de vacunes peptídiques y dendrímers basats en polietilenglicol per al tractament del càncer

El principal problema de les teràpies actuals contra el càncer es la baixa especificitat envers les cèl•lules tumorals, cosa que comporta gran quantitat d’efectes secundaris. Per això es important el desenvolupament de nous tipus de teràpies i sistemes d’alliberament efectius per als fàrmacs ja existents al mercat. En la immunoteràpia contra el càncer es pretén estimular el sistema immunològic per a eliminar les cèl•lules canceroses de manera selectiva. En aquest projecte s’han sintetitzat derivats de l’antigen peptídic de melanoma NY-ESO1 i s’ha estudiat la seva capacitat per a estimular el sistema immunològic com a vacunes contra el càncer. També s’han encapsulat el antígens peptídics en liposomes com a adjuvants i sistemes d’alliberament. De totes les variants peptídiques la que resultà més immunogènica fou la que contenia el grup palmitoil i el fragment toxoide tetànic en la seva estructura. La utilització de liposomes com a sistema adjuvant sembla una estratègia interessant per al disseny de vacunes contra el càncer donat que l’encapsulació del pèptid en liposomes va augmentar notablement la resposta immunològica de l’antigen. Per altra banda, s’han desenvolupat dendrímers basats en polietilenglicol com a sistemes alliberadors de fàrmacs per al tractament de tumors. El polietilenglicol és àmpliament utilitzat com a sistema d’alliberament de fàrmacs degut a les seves interessants propietats, augment de la solubilitat i dels temps de residència en plasma, entre d’altres. La metodologia química descrita permet la diferenciació controlada de varies posicions en la superfície del dendrímer a més del creixement del dendrímer fins a una segona generació. S’ha sintetitzat la primera generació del dendrímer contenint el fàrmac antitumoral 5-fluorouracil i s’han realitzat estudis de citotoxicitat comprovant que l’activitat del nanoconjugat és del mateix ordre de magnitud que el 5-fluorouracil sense conjugar.

Ophtalmologie. Rétinopathie diabétique: nouvelles possibilités thérapeutiques [Diabetic retinopathy: new therapeutic possibilities].

La rétinopathie diabétique touche un nombre croissant de personnes, soit quatre millions en Europe, ce chiffre va probablement doubler d'ici 2030. Si l'on considère que 25-30% de ces patients sont atteints de rétinopathie diabétique, un dépistage et un traitement précoce permettent d'éviter les complications oculaires sévères telles que l'oedème maculaire cystoïde où la rétinopathie diabétique proliférative. Un résumé des dernières données de la littérature ophtalmologique est présenté en insistant sur le rôle de l'anti-VEGF (vascular endothelial growth factor) et des implants intravitréens de corticostéroïdes pour une pathologie oculaire récemment classée dans les pathologies inflammatoires. Diabetic retinopathy affects an increasing number of persons, about 4 millions in Europe, a number that will probably double until 2030. If we consider that 25-30% of patients are affected by diabetic retinopathy, an ophthalmologic screening and early therapy will allow a better visual prognosis and avoid severe ocular complications such as diabetic macular edema and proliferative diabetic retinopathy. A summary of current ophthalmologic literature was performed and was focused on the role of anti-VEGF (vascular endothelial growth factor) therapies and intraocular drug delivery of corticosteroids in a pathology that was recently classified in inflammatory pathologies.

Persistent inhibition of FLIP(L) expression by lentiviral small hairpin RNA delivery restores death-receptor-induced apoptosis in neuroblastoma cells.

Neuroblastoma represents the most common and deadly solid tumour of childhood, which disparate biological and clinical behaviour can be explained by differential regulation of apoptosis. To understand mechanisms underlying death resistance in neuroblastoma cells, we developed small hairpin of RNA produced by lentiviral vectors as tools to selectively interfere with FLIP(L), a major negative regulator of death receptor-induced apoptosis. Such tools revealed highly efficient in interfering with FLIP(L) expression and function as they almost completely repressed endogenous and/or exogenously overexpressed FLIP(L) protein and fully reversed FLIP(L)-mediated TRAIL resistance. Moreover, interference with endogenous FLIP(L) and FLIP(S) significantly restored FasL sensitivity in SH-EP neuroblastoma cell line. These results reveal the ability of lentivirus-mediated shRNAs to specifically and persistently interfere with FLIP expression and support involvement of FLIP in the regulation of death receptor-mediated apoptosis in neuroblastoma cells. Combining such tools with other therapeutic modalities may improve treatment of resistant tumours such as neuroblastoma.

Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells.

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

Let-7a Is a Direct EWS-FLI-1 Target Implicated in Ewing's Sarcoma Development.

Ewing's sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA) expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC) and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17-92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.

Perinatal nitric oxide therapy prevents adverse effects of perinatal hypoxia on the adult pulmonary circulation.

Adverse events in utero are associated with the occurrence of chronic diseases in adulthood. We previously demonstrated in mice that perinatal hypoxia resulted in altered pulmonary circulation in adulthood, with a decreased endothelium-dependent relaxation of pulmonary arteries, associated with long-term alterations in the nitric oxide (NO)/cyclic GMP pathway. The present study investigated whether inhaled NO (iNO) administered simultaneously to perinatal hypoxia could have potential beneficial effects on the adult pulmonary circulation. Indeed, iNO is the therapy of choice in humans presenting neonatal pulmonary hypertension. Long-term effects of neonatal iNO therapy on adult pulmonary circulation have not yet been investigated. Pregnant mice were placed in hypoxia (13% O2) with simultaneous administration of iNO 5 days before delivery until 5 days after birth. Pups were then raised in normoxia until adulthood. Perinatal iNO administration completely restored acetylcholine-induced relaxation, as well as endothelial nitric oxide synthase protein content, in isolated pulmonary arteries of adult mice born in hypoxia. Right ventricular hypertrophy observed in old mice born in hypoxia compared to controls was also prevented by perinatal iNO treatment. Therefore, simultaneous administration of iNO during perinatal hypoxic exposure seems able to prevent adverse effects of perinatal hypoxia on the adult pulmonary circulation.

Turnaround across diverse global supply chains using shared metrics and change methodology: The Case of Amer Sports Corporation

Purpose - The purpose of this paper is to document the outcome of a global three-year long supply chain improvement initiative at a multi-national producer of branded sporting goods that is transforming from a holding structure to an integrated company. The case company is comprised of seven internationally well-known sport brands, which form a diverse set of independent sub-cases, on which the same supply chain metrics and change project approach was applied to improve supply chain performance. Design/methodology/approach - By using in-depth case study and statistical analysis the paper analyzes across the brands how supply chain complexity (SKU count), supply chain type (make or buy) and seasonality affect completeness and punctuality of deliveries, and inventory as the change project progresses. Findings - Results show that reduction in supply chain complexity improves delivery performance, but has no impact on inventory. Supply chain type has no impact on service level, but brands with in-house production are better in improving inventory than those with outsourced production. Non-seasonal business units improve service faster than seasonal ones, yet there is no impact on inventory. Research limitations/implications - The longitudinal data used for the analysis is biased with the general business trend, yet the rich data from different cases and three-years of data collection enables generalizations to a certain level. Practical implications - The in-depth case study serves as an example for other companies on how to initiate a supply chain improvement project across business units with tangible results. Originality/value - The seven sub-cases with their different characteristics on which the same improvement initiative was applied sets a unique ground for longitudinal analysis to study supply chain complexity, type and seasonality.

A biodegradable drug delivery system for the treatment of postoperative inflammation

Cataract surgery is often performed in patients suffering from associated pathologies. Our goal is to develop a biodegradable drug delivery system (DDS) combined with the artificial intraocular lens (IOL). DDS were manufactured using poly(D,L-lactide-co-glycolide), or PLGA, and were loaded with triamcinolone acetonide (TA). The loading capacity was approximately 1050 microg of TA per DDS. The higher the molecular weight of PLGA (34,000, 48,000 and 80,000Da), the slower was the release of TA in vitro. Cataract surgery was performed on the right eye of rabbits. IOL was inserted with (i) no DDS, (ii) unloaded DDS PLGA48000, (iii) one loaded DDS PLGA48000, (iv) two loaded DDS. The number of inflammatory cells and the protein concentration were measured in the aqueous humor (AH). Unloaded DDS showed good ocular biocompatibility. One DDS PLGA48000 loaded with TA significantly reduced postoperative ocular inflammation. Two loaded DDS PLGA48000 was even more effective in inhibiting such inflammation. On long-term observation (days 63 and 84), reduction of inflammation could be obtained by insertion of one DDS PLGA48000 and a second DDS PLGA80000. Therefore, our "all in one" system is very promising since it could replace oral treatment and reduce the number of intraocular injections

DETERMINE Working document #4 'Economic arguments for addressing social determinants of health inequalities'

The Institute of Public Health in Ireland (IPH) is a partner in the European project DETERMINE, building on its previous involvement in the Closing the Gap project in 2004-2006. In Year 2 the DETERMINE project  focused on identifying and exploring economic arguments to support action on social determinants of health inequalities.  Working document #4 'Economic arguments for addressing social determinants of health inequalities' presents the findings.

DETERMINE Working Document #1 'Policies and actions addressing the social determinants of health inequalities: examples of activity at EU member state level in Europe'

The Institute of Public Health in Ireland (IPH) is a partner in the European project DETERMINE, building on its previous involvement in the Closing the Gap project in 2004-2006. In the first year of the project (2007-2008) 15 DETERMINE partners identified policies and actions that have taken place within countries, and at the EU level, to address Social Determinants of Health Inequalities. These policies and actions were identified via a questionnaire, which also identified structures and tools/mechanisms being used in the country to support a 'health in all policy' approach.