Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon

Allergen immunotherapy is currently the only causal treatment for allergic diseases in human beings and animals. It aims to re-direct the immune system into a tolerogenic or desensitized state. Requirements include clinical efficacy, safety, and schedules optimizing patient or owner compliance. To achieve these goals, specific allergens can be formulated with adjuvants that prolong tissue deposition and support uptake by antigen presenting cells, and/or provide a beneficial immunomodulatory action. Here, we depict adjuvant formulations being investigated for human and veterinary allergen immunotherapy

A comparative approach of tumor associated inflammation in mammary cancer between humans and dogs

Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seems to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor growth factor EGF, the angiogenic growth factor VEGF, other proangiogenic factors and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by Tlymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.The work was supported partially by the Strategic Research project Pest-OE/AGR/UI0772/2011 and the Research Project UID/AGR/04033/2013, by a Ph.D. scholarship SFRH/BD/ 78771/2011 financed by the Portuguese Foundation for Science and Technology (FCT), and in part by the Austrian Science Fund (FWF), SFB F4606-B28, to Erika Jensen Jarolim

Aging (Albany NY)

The combination of functional genomics with next generation sequencing facilitates new experimental strategies for addressing complex biological phenomena. Here, we report the identification of a gain-of-function allele of peroxiredoxin (thioredoxin peroxidase, Tsa1p) via whole-genome re-sequencing of a dominantSaccharomyces cerevisiae mutant obtained by chemical mutagenesis. Yeast strain K6001, a screening system for lifespan phenotypes, was treated with ethyl methanesulfonate (EMS). We isolated an oxidative stress-resistant mutant (B7) which transmitted this phenotype in a background-independent, monogenic and dominant way. By massive parallel pyrosequencing, we generated an 38.8 fold whole-genome coverage of the strains, which differed in 12,482 positions from the reference (S288c) genome. Via a subtraction strategy, we could narrow this number to 13 total and 4 missense nucleotide variations that were specific for the mutant. Via expression in wild type backgrounds, we show that one of these mutations, exchanging a residue in the peroxiredoxin Tsa1p, was responsible for the mutant phenotype causing background-independent dominant oxidative stress-resistance. These effects were not provoked by altered Tsa1p levels, nor could they be simulated by deletion, haploinsufficiency or over-expression of the wild-type allele. Furthermore, via both a mother-enrichment technique and a micromanipulation assay, we found a robust premature aging phenotype of this oxidant-resistant strain. Thus, TSA1-B7 encodes for a novel dominant form of peroxiredoxin, and establishes a new connection between oxidative stress and aging. In addition, this study shows that the re-sequencing of entire genomes is becoming a promising alternative for the identification of functional alleles in approaches of classic molecular genetics

Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes

ObjectivesThis study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non–ST-segment elevation acute coronary syndrome (NSTE-ACS).BackgroundPAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality.MethodsWe measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 μIU/ml was chosen from pilot work in this cohort.ResultsPAPP-A >6.0 μIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 μg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine.ConclusionsPAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications

Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms

In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms

Major Allergen Content in Allergen Immunotherapy Products: The Limited Value of Numbers

The prevalence of allergic disorders has increased drastically over the last 50 years to the extent that they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy that targets the underlying cause of allergic disorders, and evidence of its superiority is based on data accumulated from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unresolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and the establishment of international reference standards for many allergens. This article discusses issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products from different manufacturers is an appropriate basis for selecting a specific AIT product. Allergen standardization in immunotherapy products is critical for ensuring quality and, thereby, safety and efficacy. However, lack of harmonization in manufacturing processes, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products based solely on major allergen amounts is not rational and, in fact, impossible. Moreover, when rating the information given for a specific product, it is necessary to take into account further inherent characteristics of products and their application in clinical practice, such as the state of extract modification, addition of adjuvant or adjuvant system, route of administration (sublingual/ subcutaneous), and cumulative dose as per posology (including the volume per administration). Finally, only convincing clinical data can serve as the basis for product-specific evaluation and cross-product comparability of individual products

Blood group terminology 2004: from the International Society of Blood Transfusion committee on terminology for red cell surface antigens

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73460/1/j.1423-0410.2004.00564.x.pd

B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients

Approximately 200,000 kidney transplant recipients are living in the US; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the FAVORIT (Folic Acid for Vascular Outcome Reduction In Transplantation) trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients

State‐of‐the‐art in marketed adjuvants and formulations in Allergen Immunotherapy: a position paper of the European Academy of Allergy and Clinical Immunology (EAACI)

Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)3) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre‐existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is pre‐sensitized to the allergen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilised in AIT redirect the Th2 immune response toward Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three‐to‐five‐year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need