Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers

INTRODUCTION: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup. METHODS: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed. RESULTS: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification. CONCLUSION: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors

Central Nervous System Changes in Pediatric Heart Failure: A Volumetric Study

Autonomic dysfunction, mood disturbances, and memory deficits appear in pediatric and adult heart failure (HF). Brain areas controlling these functions show injury in adult HF patients, many of whom have comorbid cerebrovascular disease. We examined whether similar brain pathology develops in pediatric subjects without such comorbidities. In this study, high-resolution T1 brain magnetic resonance images were collected from seven severe HF subjects age (age 8–18 years [mean 13]; left ventricular shortening 9 to 19% [median 14%]) and seven age-matched healthy controls (age 8–18 years [mean 13]). After segmentation into gray matter (GM), white matter, and cerebrospinal fluid (CSF), regional volume loss between groups was determined by voxel-based morphometry. GM volume loss appeared on all HF scans, but ischemic changes and infarcts were absent. HF subjects showed greater CSF volume than controls (mean ± SD 0.30 ± 0.04 vs. 0.25 ± 0.04 l, P = 0.03), but total intracranial volume was identical (1.39 ± 0.11 vs. 1.39 ± 0.09 l, P = NS). Regional GM volume reduction appeared in the right and left posterior hippocampus, bilateral mid-insulae, and the superior medial frontal gyrus and mid-cingulate cortex of HF subjects (threshold P < 0.001). No volume-loss sites appeared in control brains. We conclude that pediatric HF patients show brain GM loss in areas similar to those of adult HF subjects. Substantial changes emerged in sites that regulate autonomic function as well as mood, personality and short-term memory. In the absence of thromboembolic disease and many comorbid conditions found in adult HF patients, pediatric HF patients show significant, focal GM volume loss, which may coincide with the multiple neurologic and psychological changes observed in patients with HF

Magnetic resonance imaging after most common form of concussion

<p>Abstract</p> <p>Background</p> <p>Until now there is a lack of carefully controlled studies with conventional MR imaging performed exclusively in concussion with short lasting loss of consciousness (LOC).</p> <p>Methods</p> <p>A MR investigation was performed within 24 hours and after 3 months in 20 patients who had suffered a concussion with a verified loss of consciousness of maximally 5 minutes. As a control group, 20 age- and gender matched patients with minor orthopaedic injuries had a MR investigation using the same protocol.</p> <p>Results</p> <p>In a concussion population with an average LOC duration of 1. 4 minutes no case with unequivocal intracranial traumatic pathology was detected.</p> <p>Conclusion</p> <p>An ordinary concussion with short lasting LOC does not or only seldom result in a degree of diffuse axonal injury (DAI) that is visualized by conventional MR with field strength of 1.0 Tesla (T). Analysis of earlier MR studies in concussion using field strength of 1.5 T as well as of studies with diffusion tensor MR imaging (MR DTI) reveal methodological shortcomings, in particular use of inadequate control groups. There is, therefore, a need for carefully controlled studies using MR of higher field strength and/or studies with MR DTI exclusively in common concussion with LOC of maximally 5 minutes.</p

Immunoglobulin E and Mast Cell Proteases Are Potential Risk Factors of Human Pre-Diabetes and Diabetes Mellitus

Recent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE) may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus. = 0.026) adjustment for common diabetes risk factors.Both IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus

Atrophy in the parahippocampal gyrus as an early biomarker of Alzheimer’s disease

The main aim of the present study was to compare volume differences in the hippocampus and parahippocampal gyrus as biomarkers of Alzheimer’s disease (AD). Based on the previous findings, we hypothesized that there would be significant volume differences between cases of healthy aging, amnestic mild cognitive impairment (aMCI), and mild AD. Furthermore, we hypothesized that there would be larger volume differences in the parahippocampal gyrus than in the hippocampus. In addition, we investigated differences between the anterior, middle, and posterior parts of both structures. We studied three groups of participants: 18 healthy participants without memory decline, 18 patients with aMCI, and 18 patients with mild AD. 3 T T1-weighted MRI scans were acquired and gray matter volumes of the anterior, middle, and posterior parts of both the hippocampus and parahippocampal gyrus were measured using a manual tracing approach. Volumes of both the hippocampus and parahippocampal gyrus were significantly different between the groups in the following order: healthy > aMCI > AD. Volume differences between the groups were relatively larger in the parahippocampal gyrus than in the hippocampus, in particular, when we compared healthy with aMCI. No substantial differences were found between the anterior, middle, and posterior parts of both structures. Our results suggest that parahippocampal volume discriminates better than hippocampal volume between cases of healthy aging, aMCI, and mild AD, in particular, in the early phase of the disease. The present results stress the importance of parahippocampal atrophy as an early biomarker of AD

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

Atmospheric oxygen regulation at low Proterozoic levels by incomplete oxidative weathering of sedimentary organic carbon

It is unclear why atmospheric oxygen remained trapped at low levels for more than 1.5 billion years following the Paleoproterozoic Great Oxidation Event. Here, we use models for erosion, weathering and biogeochemical cycling to show that this can be explained by the tectonic recycling of previously accumulated sedimentary organic carbon, combined with the oxygen sensitivity of oxidative weathering. Our results indicate a strong negative feedback regime when atmospheric oxygen concentration is of order pO2∼0.1 PAL (present atmospheric level), but that stability is lost at pO2<0.01 PAL. Within these limits, the carbonate carbon isotope (δ13C) record becomes insensitive to changes in organic carbon burial rate, due to counterbalancing changes in the weathering of isotopically light organic carbon. This can explain the lack of secular trend in the Precambrian δ13C record, and reopens the possibility that increased biological productivity and resultant organic carbon burial drove the Great Oxidation Event

Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study

Raised risks of several cancers have been found in patients with type II diabetes, but there are few data on cancer risk in type I diabetes. We conducted a cohort study of 28 900 UK patients with insulin-treated diabetes followed for 520 517 person-years, and compared their cancer incidence and mortality with national expectations. To analyse by diabetes type, we examined risks separately in 23 834 patients diagnosed with diabetes under the age of 30 years, who will almost all have had type I diabetes, and 5066 patients diagnosed at ages 30–49 years, who probably mainly had type II. Relative risks of cancer overall were close to unity, but ovarian cancer risk was highly significantly raised in patients with diabetes diagnosed under age 30 years (standardised incidence ratio (SIR)=2.14; 95% confidence interval (CI) 1.22–3.48; standardised mortality ratio (SMR)=2.90; 95% CI 1.45–5.19), with greatest risks for those with diabetes diagnosed at ages 10–19 years. Risks of cancer at other major sites were not substantially raised for type I patients. The excesses of obesity- and alcohol-related cancers in type II diabetes may be due to confounding rather than diabetes per se

Central blood pressure and pulse wave velocity: relationship to target organ damage and cardiovascular morbidity-mortality in diabetic patients or metabolic syndrome. An observational prospective study. LOD-DIABETES study protocol

<p>Abstract</p> <p>Background</p> <p>Diabetic patients show an increased prevalence of non-dipping arterial pressure pattern, target organ damage and elevated arterial stiffness. These alterations are associated with increased cardiovascular risk.</p> <p>The objectives of this study are the following: to evaluate the prognostic value of central arterial pressure and pulse wave velocity in relation to the incidence and outcome of target organ damage and the appearance of cardiovascular episodes (cardiovascular mortality, myocardial infarction, chest pain and stroke) in patients with type 2 diabetes mellitus or metabolic syndrome.</p> <p>Methods/Design</p> <p><b>Design</b>: This is an observational prospective study with 5 years duration, of which the first year corresponds to patient inclusion and initial evaluation, and the remaining four years to follow-up.</p> <p><b>Setting</b>: The study will be carried out in the urban primary care setting.</p> <p><b>Study population</b>: Consecutive sampling will be used to include patients diagnosed with type 2 diabetes between 20-80 years of age. A total of 110 patients meeting all the inclusion criteria and none of the exclusion criteria will be included.</p> <p><b>Measurements</b>: Patient age and sex, family and personal history of cardiovascular disease, and cardiovascular risk factors. Height, weight, heart rate and abdominal circumference. Laboratory tests: hemoglobin, lipid profile, creatinine, microalbuminuria, glomerular filtration rate, blood glucose, glycosylated hemoglobin, blood insulin, fibrinogen and high sensitivity C-reactive protein. Clinical and 24-hour ambulatory (home) blood pressure monitoring and self-measured blood pressure. Common carotid artery ultrasound for the determination of mean carotid intima-media thickness. Electrocardiogram for assessing left ventricular hypertrophy. Ankle-brachial index. Retinal vascular study based on funduscopy with non-mydriatic retinography and evaluation of pulse wave morphology and pulse wave velocity using the SphygmoCor system. The medication used for diabetes, arterial hypertension and hyperlipidemia will be registered, together with antiplatelet drugs.</p> <p>Discussion</p> <p>The results of this study will help to know and quantify the prognostic value of central arterial pressure and pulse wave velocity in relation to the evolution of the subclinical target organ damage markers and the possible incidence of cardiovascular events in patients with type 2 diabetes mellitus.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT01065155</p