Benchmark of screening markers for KEAP1/NFE2L2 mutations and joint analysis with the K1N2-score.

Our recently published K1N2-score robustly predicts KEAP1/NFE2L2-mutations and pathway activation status, while its accessibility might be limited. We tested if the RNA expression data of six pathway-related genes and NQO1-IHC might be a reliable alternative using 348 KEAP1/NFE2L2 mutation-enriched NSCLC. While TXNRD1 RNA testing was the best-performing single-gene test, the combination of single-gene screening and validation with the K1N2-score achieved the highest performance when predicting mutation status or pathway activation.

KEAP1/NFE2L2 Pathway Signature Outperforms KEAP1/NFE2L2 Mutation Status and Reveals Alternative Pathway-Activating Mutations in NSCLC.

Introduction: Activation of the antioxidant KEAP1/NFE2L2 (NRF2) pathway leads to increased glutamine dependence and an aggressive phenotype in NSCLC. Because this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors.

Methods: A total of 971 NSCLC samples were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations.

Extracellular vesicle-derived CD14 is independently associated with the extent of cardiovascular disease burden in patients with manifest vascular disease.

Background: In patients with established cardiovascular disease, high levels of the extracellular vesicle (EV)-derived proteins cystatin C, CD14, and α2-antiplasmin predict recurrent cardiovascular events. We examined whether these proteins are associated with the extent of vascular disease.

Methods: In 1062 patients from the SMART (Secondary Manifestations in ARTerial disease) study, EVs were isolated from plasma at baseline.

Microvesicle protein levels are associated with increased risk for future vascular events and mortality in patients with clinically manifest vascular disease.

Background And Objectives: Microvesicles (MVs) are small membrane vesicles that are involved in atherotrombotic processes. In the present study, we evaluated the risk of MV protein levels on the occurrence of new vascular events in patients with clinically manifest vascular disease.

Methods: In this cohort study 1060 patients were prospectively followed for the occurrence of a new vascular event or death (median follow up 6.

Clinical prediction rule to estimate the absolute 3-year risk of major cardiovascular events after carotid endarterectomy.

Background And Purpose: Prognosis after carotid endarterectomy is mainly determined by the occurrence of major adverse cardiovascular events (MACEs). Optimal medical treatment to reduce risk is the mainstay of MACE prevention. The level of risk of MACE may determine the initiation and aggressiveness of medical treatment, yet a prediction rule to assess that absolute MACE risk after carotid endarterectomy is currently unavailable.

Biobanking in atherosclerotic disease, opportunities and pitfalls.

Cardiovascular disease is the leading cause of death in Western countries and current research is still focusing on optimizing therapeutic approaches in the battle against this multifactorial disease. Concepts regarding the pathogenesis of many cardiovascular diseases originate from observations of human atherosclerotic tissue obtained from autopsies or during vascular surgery. These observations have helped us to disentangle the pathophysiology of atherosclerosis.

High myeloid-related protein: 8/14 levels are related to an increased risk of cardiovascular events after carotid endarterectomy.

Background And Purpose: Myeloid-related protein (Mrp) 8/14 complex is the functional relevant form of Mrp-8 and Mrp-14. Mrp-8/14 complex is actively formed in the cytoplasm of circulating neutrophils and monocytes and then secreted. Plasma Mrp-8/14 complex is emerging as a new biomarker that may discriminate between patients with an acute coronary syndrome and those with stable coronary heart disease.

High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions.

Objective: To score the number of plaque neutrophils and relate the score to plaque morphology and inflammatory status.

Methods And Results: Neutrophils are inflammatory cells with tissue destruction capabilities that have been found at the site of an atherosclerotic plaque rupture or erosion. Poor evidence exists for neutrophil infiltration in human carotid atherosclerotic plaques, and its association with plaque morphology has not yet been described.

Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events.

Objective: Atherosclerotic cardiovascular disease is a major burden to health care. Because atherosclerosis is considered a systemic disease, we hypothesized that one single atherosclerotic plaque contains ample molecular information that predicts future cardiovascular events in all vascular territories.

Methods And Results: AtheroExpress is a biobank collecting atherosclerotic lesions during surgery, with a 3-year follow-up.

Australia's national trends in the incidence of Type 1 diabetes in 0-14-year-olds, 2000-2006.

Aims: To determine the national incidence of Type 1 diabetes in children aged 0-14 years and examine trends in incidence between 2000 and 2006 by age, sex and calendar year.

Methods: Case ascertainment was from the Australian National Diabetes Register, a prospective population-based incidence register established in 1999, with two sources of ascertainment: the National Diabetes Services Scheme and the Australasian Paediatric Endocrine Group's state-based registers. Denominator data were from the Australian Bureau of Statistics.

Bone metastases revealing primary tumors. Comparison of two series separated by 30 years.

Objective: To compare two series of patients admitted to a rheumatology department for bone metastases 30 years apart and to obtain a pragmatic estimation of the percentage of bone metastases revealing cancer.

Methods: The recent series was composed of 132 patients seen between 1989 and 1996 and the earlier series of 50 patients admitted between 1958 and 1967. All patients were admitted to the same rheumatology department for bone metastases from a diagnosed or undiagnosed primary.

Bone mineral density changes in hypercalciuretic osteoporotic men treated with thiazide diuretics.

Unlabelled: A few studies suggest that thiazide diuretic agents may have modest beneficial effects on bone. Few data are available on the effects of these medications in patients with osteoporosis and hypercalciuria.

Objective: To evaluate the effects of thiazide diuretic therapy on bone mass and urinary calcium excretion in hypercalciuretic osteoporotic male patients.

Management of male osteoporosis.

Unlabelled: The objective of this study was to evaluate the efficacy of treatments for male osteoporosis selected based on the cause of the disease.

Methods: Sixty-three men with osteoporosis (T-score at the lumbar spine and/or femoral neck lower than -2.5) with a mean age of 53+/-11 years were studied.

A novel mobile element inserted in the alpha spectrin gene: spectrin dayton. A truncated alpha spectrin associated with hereditary elliptocytosis.

Nonviral retrotransposons, retropseudogenes, and short interspersed nuclear elements (SINEs) are mobile DNA segments capable of transposition to new genomic locations, where they may alter gene expression. De novo integration into specific genes has been described in both germ and somatic cells. We report a family with hereditary elliptocytosis and pyropoikilocytosis associated with a truncated alpha-spectrin protein.

Activation of cAMP-dependent protein kinase alters the chromatin structure of the urokinase-type plasminogen activator gene promoter.

In LLC-PK1 cells, the urokinase-type plasminogen activator (uPA) gene is induced by two of the major signal transduction pathways, the protein kinase C (PKC) and the cAMP-dependent protein kinase (PKA) pathways. We have analyzed the chromatin structure of 26 kb of the uPA gene locus and have shown that PKA activation but not PKC activation induce major chromatin structural alterations in the uPA gene promoter. In uninduced cells, several DNase I hypersensitive (HS) sites were detected in the 5' and 3' flanking regions but not in the transcribed region.

A novel expression system for Gs-coupled receptors.

Renal epithelial cells LLC-PK1 secrete high amounts of urokinase-type plasminogen activator (uPA) when stimulated through the cAMP-signaling pathway. Here we show that this characteristic can be used to identify rapidly LLC-PK1-derived cell lines expressing heterologous receptors that couple to Gs-proteins. A genomic clone encoding the mouse beta 2 adrenergic receptor (beta 2AR) was transfected stably into LLC-PK1 cells.

A recombinant calcitonin receptor independently stimulates 3',5'-cyclic adenosine monophosphate and Ca2+/inositol phosphate signaling pathways.

Calcitonin (CT), a polypeptide hormone, regulates calcium homeostasis by activating surface receptors coupled to stimulation of adenylyl cyclase in bone and kidney cells. CT has also been reported to increase cytoplasmic Ca2+ in osteoclasts and renal tubule cells. Signaling pathways activated by a recombinant porcine renal calcitonin receptor transiently expressed in HEK-293 cells were studied.