New routes for allergen immunotherapy

IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review

Regulatory Reform and the National Energy Board

Government regulation has been increasing rapidly for the past five decades. At present, boards, commissions, and other variously named administrative agencies pervade nearly every phrase of the nation\u27s economic and social activity. At the federal level, these groups are involved in formulating economic policy; they control the construction and operation of pipelines and other means of transport; they supervise most facets of the telecommunications and broadcasting industries; they regulate, in many ways, the exploration for and manufacturing and marketing of raw materials. At the provincial level, they are concerned with labour relations, education, and the use of property. In addition, an assortment of fire marshalls, engineers, inspectors, and registrars are among those who operate under municipal ordinances to maintain property according to certain guidelines, to regulate how and where structures will be built and maintained and, in many circumstances, to control how, when, and where individuals may operate businesses

Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans

BackgroundSubcutaneous venom immunotherapy (VIT) represents an effective treatment against bee venom allergy. However, it involves long treatment times, high costs, and the risk of adverse events (AEs). Shorter, safer, and cheaper treatment options are therefore pursued.ObjectiveTo determine the safety, immunogenicity, and efficacy of bee venom intralymphatic immunotherapy (ILIT).MethodsIn an open pilot study, 12 patients received bee venom ILIT in three sessions with 14-day intervals: 0.1–5 μg/dose. Ultrasound imaging was applied to guide an injection and to document the lymph node structure. In a second study, 67 patients from 15 centers in Europe and Australia were randomized to receive four doses of either 10- or 20-μg bee venom ILIT with 28-day intervals. Clinical endpoints included specific IgE and IgG and protection after a bee sting challenge. These studies were performed in the years 2000–2003.ResultsIn a proof-of-concept study, no serious AEs were observed. An increase in allergen-specific IgG1 but no IgG4 and IgE was observed. ILIT induced the protection against a bee sting challenge in 7 out of 8 challenged patients. In a multicenter study, an increase in allergen-specific IgG and IgE was observed, with the highest increase in patients receiving a higher ILIT dose. The study was terminated due to several serious AEs upon the sting challenge provocation after the completion of treatment. However, out of 45 patients challenged, 15 (65%) and 18 (82%) patients in the 10- and 20-μg group, respectively, showed an improvement of two grades or more. No correlation was observed between antibody levels and sting protection.ConclusionsWhile a pilot study suggested the safety and efficacy of bee venom ILIT, a high number of AEs seen after the sting challenge following a randomized study indicate that the immunology protection offered by bee venom ILIT is insufficient. Of note, the bee venom allergen extract used in the two studies were from the two different providers. While the first study used a formulation approved for use in subcutaneous VIT, the second study used a nonapproved formulation never tested in humans. Further studies on approved formulations should be performed to generate conclusive results regarding the safety and efficacy of bee venom ILIT

Sextupole correction magnets for the Large Hadron Collider

About 2500 superconducting sextupole corrector magnets (MCS) are needed for the Large Hadron Collider (LHC) at CERN to compensate persistent current sextupole fields of the main dipoles. The MCS is a cold bore magnet with iron yoke. The coils are made from a NbTi conductor, which is cooled to 1.9 K. In the original CERN design 6 individual sub-coils, made from a monolithic composite conductor, are assembled and spliced together to form the sextupole. The coils are individually wound around precision-machined central islands and stabilized with matching saddle pieces at both ends. The Advanced Magnet Lab, Inc. (AML) has produced an alternative design, which gives improved performance and reliability at reduced manufacturing cost. In the AML design, the magnet consists of three splice-free sub-coils, which are placed with an automated winding process into pockets of prefabricated G-11 support cylinders. Any assembly process of sub-coils with potential misalignment is eliminated. The AML magnet uses a Kapton-wrapped mini-cable, which allows helium penetration into the vicinity of the conductor, increasing its cryogenic stability. Eliminating all internal splices from the magnet significantly reduces heat loads and the risk of magnet failure during operation. A tested prototype reached the critical current limit of the conductor in the first quench. (3 refs)

mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond

mRNA-based vaccines are emerging as a promising alternative to standard cancer treatments and the conventional vaccines. Moreover, the FDA-approval of three nucleic acid based therapeutics (Onpattro, BNT162b2 and mRNA-1273) has further increased the interest and trust on this type of therapeutics. In order to achieve a significant therapeutic efficacy, the mRNA needs from a drug delivery system. In the last years, several delivery platforms have been explored, being the lipid nanoparticles (LNPs) the most well characterized and studied. A better understanding on how mRNA-based therapeutics operate (both the mRNA itself and the drug delivery system) will help to further improve their efficacy and safety. In this review, we will provide an overview of what mRNA cancer vaccines are and their mode of action and we will highlight the advantages and challenges of the different delivery platforms that are under investigation

Prognostic factors associated with survival and recurrence in resectable gastroesophageal cancer: retrospective analysis of 338 patients operated at the Hospital of Cremona in ten years' time

n/

Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina

Background: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. Methods/Design: Sixty patients with stable angina will be recruited and randomised 1: 1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. Discussion: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training

Systematic Identification of Genes that Regulate Neuronal Wiring in the Drosophila Visual System

Forward genetic screens in model organisms are an attractive means to identify those genes involved in any complex biological process, including neural circuit assembly. Although mutagenesis screens are readily performed to saturation, gene identification rarely is, being limited by the considerable effort generally required for positional cloning. Here, we apply a systematic positional cloning strategy to identify many of the genes required for neuronal wiring in the Drosophila visual system. From a large-scale forward genetic screen selecting for visual system wiring defects with a normal retinal pattern, we recovered 122 mutations in 42 genetic loci. For 6 of these loci, the underlying genetic lesions were previously identified using traditional methods. Using SNP-based mapping approaches, we have now identified 30 additional genes. Neuronal phenotypes have not previously been reported for 20 of these genes, and no mutant phenotype has been previously described for 5 genes. The genes encode a variety of proteins implicated in cellular processes such as gene regulation, cytoskeletal dynamics, axonal transport, and cell signalling. We conducted a comprehensive phenotypic analysis of 35 genes, scoring wiring defects according to 33 criteria. This work demonstrates the feasibility of combining large-scale gene identification with large-scale mutagenesis in Drosophila, and provides a comprehensive overview of the molecular mechanisms that regulate visual system wiring