No abstract

Cancer-associated autoantibodies hold promise as sensitive biomarkers for early detection of cancer. Aberrant posttranslational variants of proteins are likely to induce autoantibodies, and changes in O-linked glycosylation represent one of the most important cancer-associated post-translational modifications (PTMs). Short aberrant O-glycans on proteins may introduce novel glycopeptide epitopes that can elicit autoantibodies because of lack of tolerance. Technical barriers, however, have hampered detection of such glycopeptide-specific autoantibodies. Here, we have constructed an expanded glycopeptide array displaying a comprehensive library of glycopeptides and glycoproteins derived from a panel of human mucins (MUC1, MUC2, MUC4, MUC5AC, MUC6 and MUC7) known to have altered glycosylation and expression in cancer. Seromic profiling of patients with colorectal cancer identified cancer-associated autoantibodies to a set of aberrant glycopeptides derived from MUC1 and MUC4. The cumulative sensitivity of the array analysis was 79% with a specificity of 92%. The most prevalent of the identified autoantibody targets were validated as authentic cancer immunogens by showing expression of the epitopes in cancer using novel monoclonal antibodies. Our study provides evidence for the value of glycopeptides and other PTM-peptide arrays in diagnostic measures.Colorectal cancer develops in a multistep process that arises from genetic or epigenetic alterations.1 Most colorectal cancers can be treated by removal of early malignant lesions, 2,3 but despite this colorectal cancer remains the second most common cause of cancer-related death in the western world. 4 Current screening techniques, which include fecal occult blood, sigmoid and colonoscopy and computed tomographic colonography, are complicated with low compliance and high cost.5 Therefore, there is a need for biomarkers, which can identify colorectal cancer at early stages and aid in the surveillance and identification of high-risk populations.Broad genomic and proteomic approaches for identification of biomarkers have so far failed to develop simple, reliable and noninvasive screening test for early detection of colorectal cancer.6 Current serum assays detecting cancer glycoproteins such as CEA and CA-19-9 have limited use for early stages with low specificity and sensitivity. 7,8 As an alternative, circulating autoantibodies elicited by exposure to aberrant cancer proteins lacking immunological tolerance are emerging as promising biomarkers for the early detection of cancer.9-13 However, relatively few autoantibody epitopes have been identified and characterized to date.14 In a small study, we recently demonstrated the existence of such cancerassociated autoantibodies to the aberrantly O-glycosylated MUC1 mucin in patients with breast, ovarian and prostate cancer at time of diagnosis.15 These results provide basis for further discovery of autoantibody targets with the aim to increase sensitivity and organ specificity of biomarker assays through signatures of autoantibo...

A model of ascending unobstructed urinary tract infection (UTI) in mice was developed to study the significance of the antibiotic concentration in urine, serum, and kidney tissue for efficacy of treatment of UTI in general and pyelonephritis in particular. Outbred Ssc-CF1 female mice were used throughout the study, and Escherichia coli was used as the pathogen. The virulence of 11 uropathogenic E. coli isolates and 1 nonpathogenic laboratory E. coli strain was examined. Strain C175-94 achieved the highest counts in the kidneys, and this strain was subsequently used as the infecting organism. The model gave reproducible bladder infections, i.e., bacteria were recovered from 22 of 23 control mice after 3 days, and histological examination of kidney tissue showed that of 14 infected kidneys, 7 (50%) showed major histological changes, whereas 3 of 36 uninfected kidneys showed major histological changes (P ‫؍‬ 0.018). Once the model was established, the efficacies of different doses of cefuroxime and gentamicin, corresponding to active concentrations in urine only or in urine, serum, and kidney tissue simultaneously, were examined. All cefuroxime doses resulted in significantly lower counts in urine than control treatments, but the dose which produced concentrations of cefuroxime only in urine and not in serum or kidney tissue had no effect on kidney infection. Even low doses of gentamicin (0.05 mg/mouse) resulted in concentrations in renal tissue for prolonged times due to accumulation. All gentamicin doses had a significant effect (compared to the effect of the control treatment) on bacterial counts in urine and kidneys. The antibiotic effect on bacterial counts in bladders was negligible for unknown reasons. Use of the mouse UTI model is feasible for study of the effect of an antibiotic in the urinary system, although the missing antibacterial effect in the bladder needs further evaluation.Urinary tract infections (UTIs) are among the most commonly observed infections in clinical practice, and more than 25% of all women experience an UTI at least once during their lifetimes (6). The majority of UTIs are far from severe; i.e., they are not life-threatening and do not produce any irreversible damage. However, when the kidneys are involved in the infection, there is a risk of irreversible kidney tissue damage as well as an increased risk of bacteremia (6).Escherichia coli is the causative agent in about 85% of community-acquired UTIs, 50% of nosocomial UTIs, and more than 80% of cases of uncomplicated pyelonephritis (6, 35). Several virulence factors among uropathogenic strains of E. coli have been recognized, including different types of adhesins, serum resistance, iron sequestration, and hemolysin production (17,22,30,31).Treatments for cystitis are well documented, especially different strategies concerning short-term treatment with a number of antibiotics (15,21,28), while the documentation concerning the duration of treatment of pyelonephritis is poor (1, 6, 27), with the failure rate for the treatment of pyelon...

In our region with borderline iodine deficiency more than 5% of the general population has clinical or subclinical thyroid dysfunction. We found a relatively high prevalence of hyperthyroidism, especially previously undiagnosed disease, but a low prevalence of hypothyroidism as would be expected in an area of iodine deficiency. Hypothyroidism was related to TPO Ab titres of>200 kU/l. Thyroid hormone levels varied with age and sex.