lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (c) 2005 by The American Society of Hematology

Natuurontwikkeling in de EHS, nu zorgen voor kwaliteit!

Momenteel werken de provincies aan het nieuwe subsidiestelsel voor (agrarisch) natuurbeheer, dat het huidige Programma Beheer gaat vervangen. Het streven is het nieuwe stelsel geïmplementeerd te krijgen in 2009. Met het stelsel is veel bereikt, maar er zijn zeker ook kansen gemist, namelijk om de ecologische kwaliteit van de EHS te realiseren. In dit artikel wordt een voorzet gegeven voor het inbedden van het realiseren van ecologische kwaliteit in een nieuwe regelgeving. Er valt namelijk een kwaliteitsslag te behalen bij het omvormen van landbouwgrond naar natuu

VoIP under the EU regulatory framework : preventing foreclosure?

In June 2004, the European Commission (EC) issued an "Information and Consultation Document" (European Commission 2004) that discussed how the Regulatory Framework of the European Union (EU) should be adapted to accommodate Voice over IP (VoIP) and invited relevant parties to comment on the Consultation Document. In our study, we use the responses of the different market parties to identify how incumbents seek to foreclose the market for VoIP telephony. From these responses we conclude that foreclosure is not only attempted by setting high prices for the use of infrastructure, but also by the strategic choice of infrastructure technology, which raises the cost of entry. We label the latter form of foreclosure "technological foreclosure" – as opposed to "market foreclosure". A simple modeling exercise shows that regulators seeking to avoid market foreclosure might trigger technological foreclosure. We argue that this has happened with the unbundling of the local loop in the EU, and that it might happen again with the transition to VoIP. We conclude that the current rights and obligations assigned to telecom companies effectively protect incumbents from competition by VoIP entrants. Moreover, the inaction of regulatory authorities when it comes to numbering and communication protocols is advantageous for incumbents and might obstruct the provision of new services in the future

An overview of the recent developments on fructooligosaccharide production and applications

Over the past years, many researchers have suggested that deficiencies in the diet can lead to disease states and that some diseases can be avoided through an adequate intake of relevant dietary components. Recently, a great interest in dietary modulation of the human gut has been registered. Prebiotics, such as fructooligosaccharides (FOS), play a key role in the improvement of gut microbiota balance and in individual health. FOS are generally used as components of functional foods, are generally regarded as safe (generally recognized as safe status—from the Food and Drug Administration, USA), and worth about 150€ per kilogram. Due to their nutrition- and health-relevant properties, such as moderate sweetness, low carcinogenicity, low calorimetric value, and low glycemic index, FOS have been increasingly used by the food industry. Conventionally, FOS are produced through a two-stage process that requires an enzyme production and purification step in order to proceed with the chemical reaction itself. Several studies have been conducted on the production of FOS, aiming its optimization toward the development of more efficient production processes and their potential as food ingredients. The improvement of FOS yield and productivity can be achieved by the use of different fermentative methods and different microbial sources of FOS producing enzymes and the optimization of nutritional and culture parameter; therefore, this review focuses on the latest progresses in FOS research such as its production, functional properties, and market data.Agencia de Inovacao (AdI)-Project BIOLIFE reference PRIME 03/347. Ana Dominguez acknowledges Fundacao para a Ciencia e a Tecnologia, Portugal, for her PhD grant reference SFRH/BD/23083/2005

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM

Physical therapy in patients with rheumatoid arthritis and axial spondyloarthritis: the patients' perspective

Objective: To assess the duration, frequency, and content of individual physical therapy (PT) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA). Method: In this cross-sectional study, an electronic questionnaire aimed at people with RA and axSpA was distributed through various communication channels of the Dutch Arthritis Foundation. It comprised questions on sociodemographic and health characteristics, received PT (currently and/or in the past year) and, if applicable, its duration, frequency, and content (active exercises, manual treatment, physical modalities, and/or counselling/education). Results: The study included 257 and 94 patients with self-reported diagnoses of RA and axSpA, of whom 163 (63%) and 77 (82%) currently or had recently received individual PT. The duration of individual PT was long-term (> 3 months) in 79% of RA and 83% of axSpA patients, with an average frequency of once per week in most. Although active exercises and counselling/education were each reported by >= 73% of the patients with RA and axSpA who received long-term individual PT, passive treatment modalities were also often offered (>= 89%), in particular massage, kinesiotaping, and/or passive mobilization. The same pattern was seen in patients receiving short-term PT. Conclusion: The majority of patients with RA and axSpA received PT currently or in the past year, usually individually, long-term, and at a frequency of once a week. Although active exercises and education are recommended in guidelines, passive treatment options that are not advised were relatively often reported. An implementation study to identify barriers and facilitators regarding adherence to clinical practice guidelines seems warranted.Orthopaedics, Trauma Surgery and Rehabilitatio

Fermentative production of isobutene

Isobutene (2-methylpropene) is one of those chemicals for which bio-based production might replace the petrochemical production in the future. Currently, more than 10 million metric tons of isobutene are produced on a yearly basis. Even though bio-based production might also be achieved through chemocatalytic or thermochemical methods, this review focuses on fermentative routes from sugars. Although biological isobutene formation is known since the 1970s, extensive metabolic engineering is required to achieve economically viable yields and productivities. Two recent metabolic engineering developments may enable anaerobic production close to the theoretical stoichiometry of 1isobutene + 2CO2 + 2H2O per mol of glucose. One relies on the conversion of 3-hydroxyisovalerate to isobutene as a side activity of mevalonate diphosphate decarboxylase and the other on isobutanol dehydration as a side activity of engineered oleate hydratase. The latter resembles the fermentative production of isobutanol followed by isobutanol recovery and chemocatalytic dehydration. The advantage of a completely biological route is that not isobutanol, but instead gaseous isobutene is recovered from the fermenter together with CO2. The low aqueous solubility of isobutene might also minimize product toxicity to the microorganisms. Although developments are at their infancy, the potential of a large scale fermentative isobutene production process is assessed. The production costs estimate is 0.9 € kg−1, which is reasonably competitive. About 70% of the production costs will be due to the costs of lignocellulose hydrolysate, which seems to be a preferred feedstock