Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy

Feedback as intervention for team learning in virtual teams: the role of team cohesion and personality

Scholars and practitioners agree that virtual teams (VTs) have become commonplace in today's digital workplace. Relevant literature argues that learning constitutes a significant contributor to team member satisfaction and performance, and that, at least in face-to-face teams, team cohesion fosters team learning. Given the additional challenges VTs face, e.g. geographical dispersion, which are likely have a negative influence on cohesion, in this paper we shed light on the relationship between team cohesion and team learning. We adopted a quantitative approach and studied 54 VTs in our quest to understand the role of feedback in mediating this relationship and, more specifically, the role of personality traits in moderating the indirect effect of team feedback and guided reflection intervention on TL through team cohesion within the VT context. Our findings highlight the importance of considering aspects related to the team composition when devising intervention strategies for VTs, and provide empirical support for an interactionist model between personality and emergent states such as cohesion. Implications for theory and practice are also discussed

Mouse mammary stem cells express prognostic markers for triple-negative breast cancer

Introduction Triple negative breast cancer (TNBC) is a heterogeneous group of tumours in which chemotherapy, the current mainstay of systemic treatment, is often initially beneficial but with a high risk of relapse and metastasis. There is currently no means of predicting which TNBC will relapse. We tested the hypothesis that the biological properties of normal stem cells are re-activated in tumour metastasis and that, therefore, the activation of normal mammary stem cell-associated gene sets in primary TNBC would be highly prognostic for relapse and metastasis. Methods Mammary basal stem and myoepithelial cells were isolated by flow cytometry and tested in low dose transplant assays. Gene expression microarrays were used to establish expression profiles of the stem and myoepithelial populations; these were compared to each other and to our previously established mammary epithelial gene expression profiles. Stem cell genes were classified by Gene Ontology (GO) analysis and the expression of a subset analysed in the stem cell population at single cell resolution. Activation of stem cell genes was interrogated across different breast cancer cohorts and within specific subtypes and tested for clinical prognostic power. Results A set of 323 genes was identified that was expressed significantly more highly in the purified basal stem cells compared to all other cells of the mammary epithelium. 109 out of 323 genes had been associated with stem cell features in at least one other study in addition to our own, providing further support for their involvement in the biology of this cell type. GO analysis demonstrated an enrichment of these genes for an association with cell migration, cytoskeletal regulation and tissue morphogenesis, consistent with a role in invasion and metastasis. Single cell resolution analysis showed that individual cells co-expressed both epithelial- and mesenchymal-associated genes/proteins. Most strikingly, we demonstrated that strong activity of this stem cell gene set in TNBCs identified those tumours most likely to rapidly progress to metastasis. Conclusions Our findings support the hypothesis that the biological properties of normal stem cells are drivers of metastasis and that these properties can be used to stratify patients with a highly heterogeneous disease such as TNBC

Early childhood caries in preschool children of Kosovo - a serious public health problem

<p>Abstract</p> <p>Background</p> <p>Even though it has been widely studied, early childhood caries (ECC) remains a serious public health problem, especially in countries where there is no national program of oral health assessment and no genuine primary oral health care, such as in Kosovo. The purpose of this study was to assess the prevalence of ECC and analyze caries risk factors.</p> <p>Methods</p> <p>The subjects were 1,008 preschool children, selected by stratified random cluster sampling, in the municipality of Prishtina, capital of Kosovo. Data were collected through clinical examination and interviews. Dmft data were recorded according to WHO criteria. Bacterial examination (CRT bacteria test) and plaque test of Greene-Vermillion were used.</p> <p>Results</p> <p>The mean dmft of preschool children was found to be 5.8. The prevalence of ECC was 17.36%, with a mean dmft of 11 ± 3.6. Streptococcus mutans prevalence in ECC children was 98%. A significant correlation between dmft and S mutans counts (≥10⁵CFU/mL saliva) was demonstrated. A correlation was also found between daily sweets consumption and dmft in children with ECC (<it>P </it>< 0.001). Comparing the dmft of ECC children and duration of bottle feeding showed a statistical correlation (<it>P </it>< 0.001). The mean plaque test was 1.52. None of the examined children had ever used fluoride.</p> <p>Conclusion</p> <p>The prevalence of ECC was high among preschool children in the municipality of Kosovo. We recommend increasing parents' knowledge of proper feeding habits and oral health practices, and increasing preschool children's accessibility to dental services.</p

Stromal Genes Add Prognostic Information to Proliferation and Histoclinical Markers: A Basis for the Next Generation of Breast Cancer Gene Signatures

BACKGROUND: First-generation gene signatures that identify breast cancer patients at risk of recurrence are confined to estrogen-positive cases and are driven by genes involved in the cell cycle and proliferation. Previously we induced sets of stromal genes that are prognostic for both estrogen-positive and estrogen-negative samples. Creating risk-management tools that incorporate these stromal signatures, along with existing proliferation-based signatures and established clinicopathological measures such as lymph node status and tumor size, should better identify women at greatest risk for metastasis and death. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the strength and independence of the stromal and proliferation factors in estrogen-positive and estrogen-negative patients we constructed multivariate Cox proportional hazards models along with tree-based partitions of cancer cases for four breast cancer cohorts. Two sets of stromal genes, one consisting of DCN and FBLN1, and the other containing LAMA2, add substantial prognostic value to the proliferation signal and to clinical measures. For estrogen receptor-positive patients, the stromal-decorin set adds prognostic value independent of proliferation for three of the four datasets. For estrogen receptor-negative patients, the stromal-laminin set significantly adds prognostic value in two datasets, and marginally in a third. The stromal sets are most prognostic for the unselected population studies and may depend on the age distribution of the cohorts. CONCLUSION: The addition of stromal genes would measurably improve the performance of proliferation-based first-generation gene signatures, especially for older women. Incorporating indicators of the state of stromal cell types would mark a conceptual shift from epithelial-centric risk assessment to assessment based on the multiple cell types in the cancer-altered tissue

GOBO: Gene Expression-Based Outcome for Breast Cancer Online

Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo), allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1) rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2) identification of co-expressed genes for creation of potential metagenes, 3) association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881-sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform

Nanoscale Metallic Iron for Environmental Remediation: Prospects and Limitations

The amendment of the subsurface with nanoscale metallic iron particles (nano-Fe0) has been discussed in the literature as an efficient in situ technology for groundwater remediation. However, the introduction of this technology was controversial and its efficiency has never been univocally established. This unsatisfying situation has motivated this communication whose objective was a comprehensive discussion of the intrinsic reactivity of nano-Fe0 based on the contemporary knowledge on the mechanism of contaminant removal by Fe0 and a mathematical model. It is showed that due to limitations of the mass transfer of nano-Fe0 to contaminants, available concepts cannot explain the success of nano-Fe0 injection for in situ groundwater remediation. It is recommended to test the possibility of introducing nano-Fe0 to initiate the formation of roll-fronts which propagation would induce the reductive transformation of both dissolved and adsorbed contaminants. Within a roll-front, FeII from nano-Fe0 is the reducing agent for contaminants. FeII is recycled by biotic or abiotic FeIII reduction. While the roll-front concept could explain the success of already implemented reaction zones, more research is needed for a science-based recommendation of nano- Fe0 for subsurface treatment by roll-front