Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

The risk for Staphylococcus aureus bloodstream infection (BSI) is increased in immunocompromised individuals, including patients with hematologic malignancy and/or chemotherapy. Due to the emergence of antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), staphylococcal BSI in cancer patients is associated with high mortality; however, neither a protective vaccine nor pathogen-specific immunotherapy is currently available. Here, we modeled staphylococcal BSI in leukopenic CD-1 mice that had been treated with cyclophosphamide, a drug for leukemia and lymphoma patients. Cyclophosphamide-treated mice were highly sensitive to S. aureus BSI and developed infectious lesions lacking immune cell infiltrates. Virulence factors of S. aureus that are key for disease establishment in immunocompetent hosts—α-hemolysin (Hla), iron-regulated surface determinants (IsdA and IsdB), coagulase (Coa), and von Willebrand factor binding protein (vWbp)—are dispensable for the pathogenesis of BSI in leukopenic mice. In contrast, sortase A mutants, which cannot assemble surface proteins, display delayed time to death and increased survival in this model. A vaccine with four surface antigens (ClfA, FnBPB, SdrD, and SpA_KKAA), which was identified by genetic vaccinology using sortase A mutants, raised antigen-specific immune responses that protected leukopenic mice against staphylococcal BSI.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

Postoperative impaired glucose tolerance is an early predictor of pancreas graft failure

Aims/hypothesis

The management of pancreatic transplantation is limited by a lack of clinically relevant early markers of graft dysfunction to enable intervention prior to irreversible damage. The aim of this study was to assess the OGTT as an early predictor of pancreatic graft failure.

Methods

Patients with graft failure (return to insulin dependence) were identified from a prospectively maintained clinical database. Data from OGTTs performed within 2 weeks of the transplant were retrospectively collected for 210 subjects, 42 with graft failure (21 after simultaneous pancreas–kidney transplant and 21 after isolated pancreas transplant) matched to 168 with functioning grafts. The groups were compared to assess the relationship between early OGTT result and pancreas graft failure.

Results

Mean 2 h glucose from the OGTT was significantly higher in the overall graft failure group compared with the control group (8.36 vs 6.81 mmol/l, p?=?0.014). When interpreted in combination with fasting glucose, abnormal glucose tolerance was more common in the failed graft group (50% vs 22%, p?=?0.001). In an adjusted model, abnormal glucose tolerance emerged as the most predictive independent factor for graft failure, HR 1.66 (95% CI 1.22, 2.24), p?=?0.001. These findings were consistent between the different transplant procedures performed.

Conclusions/interpretation

We conclude that early post-transplant abnormal glucose tolerance is associated with later whole organ pancreas graft failure. An OGTT performed within the first month postoperatively provides an easily measurable assessment of an independent early risk factor of pancreatic graft dysfunction.     

Recent advances in incretin‐based therapies

The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin‐based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon‐like peptide‐1 receptor agonists [liraglutide and exenatide (twice‐daily and once‐weekly)] and dipeptidyl peptidase‐4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin‐based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors currently under development.     

Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme

Aim: Effective type 2 diabetes management requires a multifactorial approach extending beyond glycaemic control. Clinical practice guidelines suggest targets for HbA1c, blood pressure and lipids, and emphasize weight reduction and avoiding hypoglycaemia. The phase 3 clinical trial programme for liraglutide, a human glucagon‐like peptide 1 analogue, showed significant improvements in HbA1c and weight with a low risk of hypoglycaemia compared to other diabetes therapies. In this context, we performed a meta‐analysis of data from these trials evaluating the proportion of patients achieving a clinically relevant composite measure of diabetes control consisting of an HbA1c <7% without weight gain or hypoglycaemia. Methods: A prespecified meta‐analysis was performed on 26‐week patient‐level data from seven trials (N = 4625) evaluating liraglutide with commonly used therapies for type 2 diabetes: glimepiride, rosiglitazone, glargine, exenatide, sitagliptin or placebo, adjusting for baseline HbA1c and weight, for a composite outcome of HbA1c <7.0%, no weight gain and no hypoglycaemic events. Results: At 26 weeks, 40% of the liraglutide 1.8 mg group, 32% of the liraglutide 1.2 mg group and 6–25% of comparators (6% rosiglitazone, 8% glimepiride, 15% glargine, 25% exenatide, 11% sitagliptin, 8% placebo) achieved this composite outcome. Odds ratios favoured liraglutide 1.8 mg by 2.0‐ to 10.5‐fold over comparators. Conclusions: As assessed by the composite outcome of HbA1c <7%, no hypoglycaemia and no weight gain, liraglutide was clearly superior to the other commonly used therapies. However, the long‐term clinical impact of this observation remains to be shown.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.     

Profile and Predictors of Long-term Morbidity in Breast Cancer Survivors

Background

A sound understanding of the benefits of different treatment options and their health-related quality of life (HRQoL) impacts is required for optimal breast cancer care.

Methods

A cross-sectional cohort study was conducted to determine the prevalence and severity of persistent functional decrements and symptoms and identify demographic, clinical and treatment variables associated with poorer outcomes. Four hundred English-speaking women treated for ductal carcinoma-in-situ or stage I to III breast cancer between 1999 and 2009, at least 12 months after surgery and currently disease free, were randomly selected and invited to complete (1) the Breast Cancer Treatment Outcome Scale and (2) the EORTC core Quality of Life Questionnaire, version 3.

Results

The response rate was 85.60 %. Many participants reported moderate to severe decrements in a number of HRQoL domains, including functional well-being (15 %), cosmetic status (32 %) and overall quality of life (21 %). There were significant associations (p < .05) between younger age and poorer HRQoL but none between time since surgery and morbidity (p > .05). Different treatments were associated with different HRQoL impacts. Poorer functional status was predicted by axillary dissection (p = .011), and adjuvant radiotherapy was a significant predictor of breast-specific pain (p < .05).

Conclusions

Many breast cancer survivors report long-term morbidity that is unaffected by time since surgery. The significant associations between the extent of locoregional therapies and poorer HRQoL outcomes emphasize the importance of the safe tailoring of these treatments.     

Hair Mercury and Fish Consumption in Residents of O‘ahu,Hawai‘i

Recent studies have established that men are susceptible to cardiotoxicity from methylmercury exposure, which also poses risks to the pregnant woman. Hair samples were obtained and questionnaires for methylmercury exposure assessment were administered to 110 adults (57 men, 53 women) throughout O‘ahu, Hawai‘i during December 2010 to January 2011. Hair samples were analyzed for total mercury with a direct mercury analyzer. Men ≥ 46 years had a median of 2.0 µg/g, which was above the reference dose of 1 µg/g, as compared to younger men with a median 1.0 µg/g (P < 0.05). Hair concentrations from older women had a median of 1.2 µg/g of mercury compared to 0.6 µg/g for younger women. Additionally, 38% of women of childbearing age had a Hazard Index > 1.0. This indicates that both men and women were at risk for excessive methylmercury exposure. In the final regression model, male gender, age > 45 years, length of residency > 10 years in Hawai‘i, and fish consumption frequency > 1 meal per week were significant factors in increased hair mercury levels. Following safe fish consumption practices allows residents to reap health benefits of fish consumption without excessive toxicant exposure.