An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor-associated osteolytic lesions in experimental models of breast cancer

We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.

Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile

Epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) have been associated with resistance to chemotherapy. Eighty percent of ovarian cancer patients initially respond to platinum-based combination therapy but most return with recurrence and ultimate demise. To better understand such chemoresistance we have assessed the potential role of EMT in tumor cells collected from advanced-stage ovarian cancer patients and the ovarian cancer cell line OVCA 433 in response to cisplatin in vitro. We demonstrate that cisplatin-induced transition from epithelial to mesenchymal morphology in residual cancer cells correlated with reduced E-cadherin, and increased N-cadherin and vimentin expression. The mRNA expression of Snail, Slug, Twist, and MMP-2 were significantly enhanced in response to cisplatin and correlated with increased migration. This coincided with increased cell surface expression of CSC-like markers such as CD44, α2 integrin subunit, CD117, CD133, EpCAM, and the expression of stem cell factors Nanog and Oct-4. EMT and CSC-like changes in response to cisplatin correlated with enhanced activation of extracellular signal-regulated kinase (ERK)1/2. The selective MEK inhibitor U0126 inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and CSC markers. In vivo xenotransplantation of cisplatin-treated OVCA 433 cells in zebrafish embryos demonstrated significantly enhanced migration of cells compared to control untreated cells. U0126 inhibited cisplatin-induced migration of cells in vivo, suggesting that ERK2 signaling is critical to cisplatin-induced EMT and CSC phenotypes, and that targeting ERK2 in the presence of cisplatin may reduce the burden of residual tumor, the ultimate cause of recurrence in ovarian cancer patients.

Laminin adhesion-selected primary human colon-cancer cells are more tumorigenic than the parenteral and nonadherent cells

Laminin has been shown to promote the malignant phenotype and the level of the 32/67 Kd laminin receptor has been found to correlate with Dukes' staging of colon cancer. A biopsy of a Dukes' stage B2 human colon carcinoma formed a tumor in a nude mouse after coinjection with Matrigel. The parental tumor and the murine tumor appeared identical at the histological level. A cell line LCC-C1 was established from the murine tumor. The cell line appeared moderately differentiated although it did not produce mucin in vitro; however, the xenograft in vivo did produce low levels of mucin. Laminin adherent and non-adherent cell lines were selected. The parental and the laminin-selected cell subclones adhered equally well to plastic and to fibronectin and showed similar growth rates on plastic. When injected subcutaneously into nude mice, the laminin-adherent cells formed relatively undifferentiated tumors that were twice as large as the parental cell tumors whereas the laminin non adherent cells formed very small, but highly differentiated tumors. These data demonstrate that subpopulations of tumor cells which differ in their tumorigenic properties can be selected based on their adhesion to laminin and thus provide models for studying the mechanisms of tumor growth.

Literacy assessment that counts : mediating, interpreting and contesting translocal policy in a primary school

In Australia, as in many western education systems over the last two decades, discourses of accountability and performativity have reshaped education policy that has in turn reorganised the work of school leaders and teachers. One of the effects of this reorganisation is increased attention to the production, analysis and display of student achievement data. In this paper we examine in detail a sequence of the production and reading of literacy assessment data in a small Catholic school. Our analysis uses institutional ethnography’s concept of the ‘active text’, the text as occurring in a specific place and time even as it is articulated to social relations beyond its immediate context. Through this process we learn from those involved how their everyday work brings into being formalised, textually authorised processes in a local site that ensure the school meets accountability requirements while enabling teachers to resist standardisation of literacy teaching and assessment.

Time course analysis of hypoxia, granulation tissue and blood vessel growth, and remodeling in healing rat cutaneous incisional primary intention wounds

Hypoxia and the development and remodeling of blood vessels and connective tissue in granulation tissue that forms in a wound gap following full-thickness skin incision in the rat were examined as a function of time. A 1.5 cm-long incisional wound was created in rat groin skin and the opposed edges sutured together. Wounds were harvested between 3 days and 16 weeks and hypoxia, percent vascular volume, cell proliferation and apoptosis, α-smooth muscle actin, vascular endothelial growth factor-A, vascular endothelial growth factor receptor-2, and transforming growth factor-β 1 expression in granulation tissue were then assessed. Hypoxia was evident between 3 and 7 days while maximal cell proliferation at 3 days (123.6 ± 22.2 cells/mm 2, p < 0.001 when compared with normal skin) preceded the peak percent vascular volume that occurred at 7 days (15.83 ± 1.10%, p < 0.001 when compared with normal skin). The peak in cell apoptosis occurred at 3 weeks (12.1 ± 1.3 cells/mm 2, p < 0.001 when compared with normal skin). Intense α-smooth muscle actin labeling in myofibroblasts was evident at 7 and 10 days. Vascular endothelial growth factor receptor-2 and vascular endothelial growth factor-A were detectable until 2 and 3 weeks, respectively, while transforming growth factor-β 1 protein was detectable in endothelial cells and myofibroblasts until 3-4 weeks and in the extracellular matrix for 16 weeks. Incisional wound granulation tissue largely developed within 3-7 days in the presence of hypoxia. Remodeling, marked by a decline in the percent vascular volume and increased cellular apoptosis, occurred largely in the absence of detectable hypoxia. The expression of vascular endothelial growth factor-A, vascular endothelial growth factor receptor-2, and transforming growth factor-β 1 is evident prior, during, and after the peak of vascular volume reflecting multiple roles for these factors during wound healing.

Asthma interventions in primary schools : a review

Objective To explore, in depth, the literature for evidence supporting asthma interventions delivered within primary schools and to identify any “gaps” in this research area. Methods A literature search using electronic search engines (i.e. Medline, PubMed, Education Resources Information Center (ERIC), International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase and Informit) and the search terms “asthma”, “asthma intervention” and “school-based asthma education program” (and derivatives of these keywords) was conducted. Results Twenty-three articles met the inclusion criteria; of these eight were Randomised Controlled Trials. There was much variety in the type, content, delivery and outcome measures in these 23 studies. The most common intervention type was asthma education delivery. Most studies demonstrated improvement in clinical and humanistic markers, for example, asthma symptoms medication use (decrease in reliever medication use or decrease in the need for rescue oral steroid), inhaler use technique and spacer use competency, lung function and quality of life. Relatively few studies explored the effect of the intervention on academic outcomes. Most studies did not report on the sustainability or cost effectiveness of the intervention tested. Another drawback in the literature was the lack of details about the intervention and inconsistency in instruments selected for measuring outcomes. Conclusion School-based asthma interventions regardless of their heterogeneity have positive clinical, humanistic, health economical and academic outcomes.

Characteristics of ultrafine particle sources and deposition rates in primary school classrooms

The aim of this work was to investigate changes in particle number concentration (PNC) within naturally ventilated primary school classrooms arising from local sources either within or adjacent to the classrooms. We quantify the rate at which ultrafine particles were emitted either from printing, grilling, heating or cleaning activities and the rate at which the particles were removed by both deposition and air exchange processes. At each of 25 schools in Brisbane, Australia, two weeks of measurements of PNC and CO2 were taken both outdoors and in the two classrooms. Bayesian regression modelling was employed in order to estimate the relevant rates and analyse the relationship between air exchange rate (AER), particle infiltration and the deposition rates of particle generated from indoor activities in the classrooms. During schooling hours, grilling events at the school tuckshop as well as heating and printing in the classrooms led to indoor PNCs being elevated by a factor of more than four, with emission rates of (2.51 ± 0.25) x 1011 p min-1, (8.99 ± 6.70) x 1011 p min-1 and (5.17 ± 2.00) x 1011 p min-1, respectively. During non-school hours, cleaning events elevated indoor PNC by a factor of above five, with an average emission rate of (2.09 ± 6.30) x 1011 p min-1. Particles were removed by both air exchange and deposition; chiefly by ventilation when AER > 0.7 h-1 and by deposition when AER < 0.7 h-1.

Personality disorders

This chapter explains the main categories of personality disorders and their diagnosis.Nursing interventions are described, and challenges working with people who have personality disorders are discussed.Limitations in our understanding of personality disorders, and problems of categorisation, diagnosis and treatment are also discussed.

Efficiency of lexical access in children with autism spectrum disorders : does modality matter?

The provision of visual support to individuals with an autism spectrum disorder (ASD) is widely recommended. We explored one mechanism underlying the use of visual supports: efficiency of language processing. Two groups of children, one with and one without an ASD, participated. The groups had comparable oral and written language skills and nonverbal cognitive abilities. In two semantic priming experiments, prime modality and prime–target relatedness were manipulated. Response time and accuracy of lexical decisions on the spoken word targets were measured. In the first uni-modal experiment, both groups demonstrated significant priming effects. In the second experiment which was cross-modal, no effect for relatedness or group was found. This result is considered in the light of the attentional capacity required for access to the lexicon via written stimuli within the developing semantic system. These preliminary findings are also considered with respect to the use of visual support for children with ASD.

Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks

Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single-stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability.

Development and pilot study of the Primary Care Practice Improvement Tool (PC-PIT) : an innovative approach

Objective To assess the usability and validity of the Primary Care Practice Improvement Tool (PC-PIT), a practice performance improvement tool based on 13 key elements identified by a systematic review. It was co-created with a range of partners and designed specifically for primary health care. Design This pilot study examined the PC-PIT using a formative assessment framework and mixed-methods research design. Setting and participants Six high-functioning general practices in Queensland, Australia, between February and July 2013. A total of 28 staff participated — 10 general practitioners, six practice or community nurses, 12 administrators (four practice managers; one business manager and eight reception or general administrative staff). Main outcome measures Readability, content validity and staff perceptions of the PC-PIT. Results The PC-PIT offers an appropriate and acceptable approach to internal quality improvement in general practice. Quantitative assessment scores and qualitative data from all staff identified two areas in which the PC-PIT required modification: a reduction in the indicative reading age, and simplification of governance-related terms and concepts. Conclusion The PC-PIT provides an innovative approach to address the complexity of organisational improvement in general practice and primary health care. This initial validation will be used to develop a suite of supporting, high-quality and free-to-access resources to enhance the use of the PC-PIT in general practice. Based on these findings, a national trial is now underway.

Consumers persepctive on pharmacists integration into private primary healthcare clinics in Malaysia

Background: Pharmacists are considered medication experts but are underutilised mainly at the periphery of the primary healthcare team. General medical practitioners (GPs) in Malaysian private healthcare clinics are granted rights to prescribe and dispense medications, thus furhter limiting pharmacists involvement in ensuring safe use of medicines. The integration of pharmacist into private primary healthcare clinics has the potential to reduce medication-relation problems. Objective: To explore the views of consumers on the integration of pharmacists within private primary healthcare clinics in Malaysia. Method: A purposive sample of healthcare consumers in Selangor and Kuala Lumpur, Malaysia were invited to participate in focus groups and semi-structured interviews. Sessions were audio recorded and transcribed verbatim and thematically analysed using NVivo 10. Results: A total of 24 healthcare consumers particpated in two focus groups and six semi-structured interviews. Four major themes were identified: (1) Pharmacists role viewed mainly as supplying medications, (2) Readiness to accept pharmacists in private healthcare clinics, (3) Willingness to pay for pharmacy services, and (4) Concerns about GPs resistance to pharmacist integration. Consumers felt that a pharmacist integrated into private prumary healthcare clinics could offer potential benefits such as counter-checking prescriptions to ensure correct medication is supplied and counselling consumers on their medications and the potential side effects. The potential to increase in costs to consumers and GPs reluctance were perceived as barriers to integration. Conclusion: This study provides insights into consumers perspectives on the roles of pharmacists within private primary healthcare clinics in Malaysia. Consumers generally supported pharmacist integration into private primary healthcare clinics. However, for pharmacists to expand their capacity in providing integrated and collaborative primary care services to consumers, barriers to pharmacist integration need to be addressed.

The expression profiles of the galectin gene family in primary and metastatic papillary thyroid carcinoma with particular emphasis on galectin-1 and galectin-3 expression

INTRODUCTION: Galectin family members have been demonstrated to be abnormally expressed in cancer at the protein and mRNA level. This study investigated the levels of galectin proteins and mRNA expression in a large cohort of patients with papillary thyroid carcinoma and matched lymph node metastases with particular emphasis on galectin-1 and galectin-3. METHODS: mRNA expression of galectin family members (1, 2, 3, 4, 7, 8, 9, 10 and 12) were analysed by real-time polymerase chain reaction in 65 papillary thyroid carcinomas, 30 matched lymph nodes with metastatic papillary thyroid carcinoma and 5 non-cancer thyroid tissues. Galectin-1 and 3 protein expression was determined by immunohistochemistry in these samples. RESULTS: Significant expression differences in all tested galectin family members (1, 2, 3, 4, 7, 8, 9, 10 and 12) were noted for mRNA in papillary thyroid carcinomas, with and without lymph node metastasis. Galectin-1 protein was more strongly expressed than galectin-3 protein in papillary thyroid carcinoma. Galectin-1 protein was found to be overexpressed in 32% of primary papillary thyroid carcinomas. A majority of lymph nodes with metastatic papillary thyroid carcinoma (53%) had significantly increased expression of galectin-1 protein, as did 47% of primaries with metastases. Galectin-1 mRNA levels were decreased in the vast majority (94%) of primary thyroid carcinomas that did not have metastases present. Galectin-3 protein levels were noted to be overexpressed in 15% of primary papillary thyroid carcinomas. In primary papillary thyroid carcinoma with lymph node metastases, 32% had over expression of galectin-3 protein. Overexpression of galectin-3 mRNA was noted in 58% of papillary thyroid carcinomas and 64% of lymph nodes bearing metastatic papillary thyroid carcinoma. Also, primary papillary thyroid carcinoma with lymph node metastases had significantly higher expression of galectin-3 mRNA compared to those without lymph node metastases. CONCLUSION: Galectin family members show altered expression at the mRNA level in papillary thyroid cancers. Overexpression of galectin-1 and 3 proteins were noted in papillary thyroid carcinoma with lymph node metastases. The results presented here demonstrated that galectin-1 and galectin-3 expression have important roles in clinical progression of papillary thyroid carcinoma.

Detection of dynamic primary user with cooperative spectrum sensing

In this paper we demonstrate that existing cooperative spectrum sensing formulated for static primary users cannot accurately detect dynamic primary users regardless of the information fusion method. Performance error occurs as the sensing parameters calculated by the conventional detector result in sensing performance that violates the sensing requirements. Furthermore, the error is accumulated and compounded by the number of cooperating nodes. To address this limitation, we design and implement the duty cycle detection model for the context of cooperative spectrum sensing to accurately calculate the sensing parameters that satisfy the sensing requirements. We show that longer sensing duration is required to compensate for dynamic primary user traffic.

BDNF SNPs are implicated in comorbid alcohol dependence in schizophrenia but not in alcohol-dependent patients without schizophrenia

Aims The functional BDNF single nucleotide polymorphism (SNP) rs6265 has been associated with many disorders including schizophrenia and alcohol dependence. However, studies have been inconsistent, reporting both positive and negative associations. Comorbid alcohol dependence has a high prevalence in schizophrenia so we investigated the role of rs6265 in alcohol dependence in Australian populations of schizophrenia and alcohol dependent patients. Methods Two BDNF SNPs rs6265 and a nearby SNP rs7103411 were genotyped in a total of 848 individuals. These included a schizophrenia group (n = 157) and a second schizophrenia replication group (n = 235), an alcohol dependent group (n = 231) that had no schizophrenia diagnosis and a group of healthy controls (n = 225). Results Allelic association between rs7103411 and comorbid alcohol dependence was identified (P = 0.044) in the primary schizophrenia sample. In the replication study, we were able to detect allelic associations between both BDNF SNPs and comorbid alcohol dependence (rs6265, P = 0.006; rs7103411, P = 0.014). Moreover, we detected association between both SNPs and risk-taking behaviour after drinking (rs6265, P = 0.005; rs7103411, P = 0.009) and we detected strong association between both SNPs and alcohol dependence in males (rs6265, P = 0.009; rs7103411, P = 0.013) while females showed association with multiple behavioural measures reflecting repetitive alcohol consumption. Haplotype analysis revealed the rs6265-rs7103411 A/C haplotype is associated with comorbid alcohol dependence (P = 0.002). When these SNPs were tested in the non-schizophrenia alcohol dependent group we were unable to detect association. Conclusion We conclude that these BDNF SNPs play a role in development of comorbid alcohol dependence in schizophrenia while our data does not indicate that they play a role in alcohol dependent patients who do not have schizophrenia.