Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and -negative colorectal cancers based on protein marker expression and molecular features

CpG island methylator phenotype (CIMP) is being investigated for its role in the molecular and prognostic classification of colorectal cancer patients but is also emerging as a factor with the potential to influence clinical decision-making. We report a comprehensive analysis of clinico-pathological and molecular features (KRAS, BRAF and microsatellite instability, MSI) as well as of selected tumour- and host-related protein markers characterizing CIMP-high (CIMP-H), -low, and -negative colorectal cancers. Immunohistochemical analysis for 48 protein markers and molecular analysis of CIMP (CIMP-H: ? 4/5 methylated genes), MSI (MSI-H: ? 2 instable genes), KRAS, and BRAF were performed on 337 colorectal cancers. Simple and multiple regression analysis and receiver operating characteristic (ROC) curve analysis were performed. CIMP-H was found in 24 cases (7.1%) and linked (p < 0.0001) to more proximal tumour location, BRAF mutation, MSI-H, MGMT methylation (p = 0.022), advanced pT classification (p = 0.03), mucinous histology (p = 0.069), and less frequent KRAS mutation (p = 0.067) compared to CIMP-low or -negative cases. Of the 48 protein markers, decreased levels of RKIP (p = 0.0056), EphB2 (p = 0.0045), CK20 (p = 0.002), and Cdx2 (p < 0.0001) and increased numbers of CD8+ intra-epithelial lymphocytes (p < 0.0001) were related to CIMP-H, independently of MSI status. In addition to the expected clinico-pathological and molecular associations, CIMP-H colorectal cancers are characterized by a loss of protein markers associated with differentiation, and metastasis suppression, and have increased CD8+ T-lymphocytes regardless of MSI status. In particular, Cdx2 loss seems to strongly predict CIMP-H in both microsatellite-stable (MSS) and MSI-H colorectal cancers. Cdx2 is proposed as a surrogate marker for CIMP-H.

A subset of metzincins and related genes constitutes a marker of human solid organ fibrosis

Metzincins and functionally related genes play important roles in extracellular matrix remodeling both in healthy and fibrotic conditions. We recently presented a transcriptomic classifier consisting of 19 metzincins and related genes (MARGS) discriminating biopsies from renal transplant patients with or without interstitial fibrosis/tubular atrophy (IF/TA) by virtue of gene expression measurement (Roedder et al., Am J Transplant 9:517-526, 2009). Here we demonstrate that the same algorithm has diagnostic value in non-transplant solid organ fibrosis. We used publically available microarray datasets of 325 human heart, liver, lung, kidney cortex, and pancreas microarray samples (265 with fibrosis, 60 healthy controls). Expression of nine commonly differentially expressed genes was confirmed by TaqMan low-density arrays (Applied Biosystems, USA) in 50 independent archival tissue specimens with matched histological diagnoses to microarray patients. In separate and in combined, integrated microarray data analyses of five datasets with 325 samples, the previously published MARGS classifier for renal post-transplant IF/TA had a mean AUC of 87% and 82%, respectively. These data demonstrate that the MARGS gene panel classifier not only discriminates IF/TA from normal renal transplant tissue, but also classifies solid organ fibrotic conditions of human pancreas, liver, heart, kidney, and lung tissue samples with high specificity and accuracy, suggesting that the MARGS classifier is a cross-platform, cross-organ classifier of fibrotic conditions of different etiologies when compared to normal tissue.

Robust expression of CCR3 as a single basophil selection marker in flow cytometry

Basophil activation tests (BAT) rely on different combinations of basophil selection and activation markers. Whereas activation markers, especially CD63, are widely validated, the most suitable and robust marker for basophil selection is still a matter of debate.

PRO_10--a new tissue-based prognostic multigene marker in patients with early estrogen receptor-positive breast cancer

Clinicopathological and molecular factors determine the prognosis of breast cancer. PRO_10 is a prognostic score based on quantitative RT-PCR of 10 proliferation-associated genes obtained from formalin-fixed, paraffin-embedded breast cancer tissues. We revalidated PRO_10 in patients treated in a non-trial setting.

Job Burnout in Public Accounting: Understanding Gender Differences

Job burnout is linked to job outcomes in public accounting professionals (Fogarty et al., 2000; Jones et al., 2010; Jones et al., 2012). Although women and men have entered the profession in relatively equal numbers, there is a significantly lower percentage of women partners (AICPA, 2011). Extant research has not sufficiently explored how burnout may affect the genders distinctly and whether these differences may lend insight as to women’s choices to exit. A large participant group with a similar proportion of women (n=836) and men (n=845) allowed examination of the burnout construct on a more profound level than extant studies. The three dimensions of job burnout in women and men public accountants were analyzed, not only in total, but also by functional area and position level. Overall findings are that women report higher levels of reduced personal accomplishment and men report higher levels of depersonalization. In light of these findings, suggestions are made for firm and individual actions that may mitigate the intensity of burnout experienced by both women and men public accountants.

Role Stress and Job Outcomes in Public Accounting: Have the Gender Experiences Converged?

Using data collected from professionals in a large U.S. national public accounting firm, we explored gender differences in perceived levels of role stress and job outcomes as well as the effects of a healthy lifestyle as a coping mechanism for role stress, burnout and related job outcomes. Our large sample size (1,681) and equal participation by women (49.7%) and men (50.3%) allowed us to analyze the causal relationships of these variables using a previously tested multi-disciplinary research model (Jones, Norman, & Wier, 2010). We found that women and men perceive similar levels of role stress as defined by role ambiguity and role overload, and that women perceive less role conflict. Men and women perceive similar levels of job satisfaction and job performance. Contrary to earlier studies, women do not report higher levels of turnover intentions. Results show that efforts of the public accounting firms over the past decade may be somewhat successful in reducing the levels of role stress and turnover intentions among women. Another plausible explanation could be that an expansionist theory of gender, work and family (Barnett & Hyde, 2001) may now be responsible for improved well-being of females to the point where the genders have converged in their experience of role stress and job outcomes in public accounting.

Ethyl sulphate and ethyl glucuronide in vitreous humor as postmortem evidence marker for ethanol consumption prior to death

To clarify the circumstances of death, the degree of inebriation is of importance in many cases, but for several reasons the determination of the ethanol concentration in post-mortem samples can be challenging and the synopsis of ethanol and the direct consumption markers ethyl glucuronide (EtG) and ethyl sulphate (EtS) has proved to be useful. The use of a rather stable matrix like vitreous humor offers further advantages. The aim of this study was to determine the concentrations of ethanol and the biomarkers in the robust matrix of vitreous humor and to compare them with the respective levels in peripheral venous blood and urine. Samples of urine, blood from the femoral vein and vitreous humor were taken from 26 deceased with suspected ethanol consumption prior to death and analyzed for ethanol, EtS and EtG. In the urine samples creatinine was also determined. The personal data, the circumstances of death, the post-mortem interval and the information about ethanol consumption prior to death were recorded. EtG and EtS analysis in urine was performed by LC-ESI-MS/MS, creatinine concentration was determined using the Jaffé reaction and ethanol was detected by HS-GC-FID and by an ADH-based method. In general, the highest concentrations of the analytes were found in urine and showed statistical significance. The mean concentrations of EtG were 62.8mg/L (EtG100 206.5mg/L) in urine, 4.3mg/L in blood and 2.1mg/L in vitreous humor. EtS was found in the following mean concentrations: 54.6mg/L in urine (EtS100 123.1mg/L), 1.8mg/L in blood and 0.9mg/L in vitreous humor. Ethanol was detected in more vitreous humor samples (mean concentration 2.0g/kg) than in blood and urine (mean concentration 1.6g/kg and 2.1g/kg respectively). There was no correlation between the ethanol and the marker concentrations and no statistical conclusions could be drawn between the markers and matrices.