Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage.

GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors.

Allergies to sulfonamide antibiotics and sulfur-containing drugs.

OBJECTIVE: To provide a literature review and clinical summary of the evaluation and management of sulfonamide drug reactions. DATA SOURCES: Published English-language medical literature. STUDY SELECTION: Selected trials of drug desensitization protocols. RESULTS: Obtaining a detailed history is invaluable in assessing a history of reactions to sulfonamide medications, because allergy to these drugs remains a clinical diagnosis at present. Numerous efficacious drug desensitization protocols for management have been published and are reviewed in detail. CONCLUSIONS: The term sulfa allergy is imprecise and misleading and therefore should be discouraged. There are important distinctions between sulfonylarylamines (antimicrobial sulfonamides), nonarylamine (nonantimicrobial) sulfonamides, and sulfones, with regard to allergic and other adverse drug reactions. Most reactions to sulfonylarylamines probably result from multifactorial immunologic and toxic metabolic mechanisms, whereas less is known about the precise mechanisms of reactions to other sulfur-containing drugs.

Symptoms and immunologic markers among vulcanization workers in rubber industries in southern Sweden.

OBJECTIVES: The aim of this study was to estimate the risk of symptoms and the possible derangement of levels of immunologic markers for contemporary Swedish rubber workers. Furthermore, the relation between exposure and these biomarkers of response was examined using urinary levels of 2-thiothiazolidine-4-carboxylic acid (TTCA), which reflect the exposure. METHODS: Included in the study were 166 exposed workers and 117 controls. Medical and occupational histories were obtained in structured interviews. Symptoms were recorded, and immunologic markers were analyzed in blood. Urinary levels of TTCA were determined by liquid chromatography tandem mass spectrometry. RESULTS: Compared with the controls, the exposed workers had increased risks of eye symptoms [odds ratio (OR) 3.0], nose bleeds (OR 4.0), burning and dry throat (OR 3.0), hoarseness (OR 2.4), severe dry cough (OR 3.8), nausea (OR 4.3), and headache (OR 2.5). When the exposed workers were divided into three groups according to the TTCA levels, the highest risks were observed among the exposed workers with intermediate TTCA levels. Furthermore, the exposed workers in all of the TTCA subgroups had elevated concentrations of total immunoglobulin G when compared with the controls. Elevated concentrations of leukocytes, neutrophils, and eosinophils were observed in the group with high TTCA levels. CONCLUSIONS: This work shows an increased risk of several symptoms and elevated levels of some immunologic markers among exposed workers in Swedish rubber industries. In addition, relationships between urinary levels of TTCA and some biomarkers of response were reported.