Suppressive effect of secretory phospholipase A2 inhibitory peptide on interleukin-1β-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice

Introduction  

Secretory phospholipase A₂ (sPLA₂) and matrix metalloproteinase (MMP) inhibitors are potent modulators of inflammation with therapeutic potential, but have limited efficacy in rheumatoid arthritis (RA). The objective of this study was to understand the inhibitory mechanism of phospholipase inhibitor from python (PIP)-18 peptide in cultured synovial fibroblasts (SF), and to evaluate its therapeutic potential in a human tumor necrosis factor (hTNF)-driven transgenic mouse (Tg197) model of arthritis.     

Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study

Background

The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.

Methods

Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.

Results

PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69–0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.

Conclusions

The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.     

Associations of Quality of Life with Service Satisfaction in Psychotic Patients: A Meta-Analysis

Background

Quality of life (QoL) has gained increasing attention as a desired outcome of psychosocial treatments targeting psychotic patients. Yet, the relationship between the patients’ satisfaction with services and QoL has not been clearly established, perhaps due to the multidimensionality of the QoL concept and the variability in its assessment.

Aim

This is the first systematic meta-analysis of all available evidence assessing the relationship between QoL and service satisfaction. Methods: In all, 19 studies reporting data of 21 independent samples (N = 5,337) were included in the present meta-analysis. In moderator analyses, effects of age, sex, diagnoses (schizophrenia vs. other psychoses), treatment context (inpatients vs. outpatients), study design (cross-sectional vs. longitudinal), and QoL domain (subjective vs. health-related) were examined.

Results

Analyses revealed a highly significant medium-sized effect (r = .30, p < .001) for the associations of QoL and service satisfaction. Effect sizes were significantly stronger for subjective than health-related quality of life (r = .35 vs. r = .14, respectively). Moreover, associations with subjective QoL remained largely robust when accounting for moderating variables, although there was a trend of stronger associations for outpatients compared to inpatients. In contrast, effect sizes for health-related QoL were small and only observable for samples with longitudinal designs.

Conclusion

Associations between QoL and service satisfaction appear to be robust but are differentiated in regard to QoL domain. Our findings suggest that agents responsible for service design and implementation need to take the patients’ perception of the service adequacy for achieving QoL enhancement into account.     

Mass Transport Properties of the Rabbit Aortic Wall

Uptake of circulating macromolecules by the arterial wall may be a critical step in atherogenesis. Here we investigate the age-related changes in patterns of uptake that occur in the rabbit. In immature aortas, uptake was elevated in a triangle downstream of branch ostia, a region prone to disease in immature rabbits and children. By 16-22 months, uptake was high lateral to ostia, as is lesion prevalence in mature rabbits and young adults. In older rabbits there was a more upstream pattern, similar to the disease distribution in older people. These variations were predominantly caused by the branches themselves, rather than reflecting larger patterns within which the branches happened to be situated (as may occur with patterns of haemodynamic wall shear stress). The narrow streaks of high uptake reported in some previous studies were shown to be post mortem artefacts. Finally, heparin (which interferes with the NO pathway) had no effect on the difference in uptake between regions upstream and downstream of branches in immature rabbits but reversed the difference in older rabbits, as does inhibiting NO synthesis directly. Nevertheless, examination of uptake all around the branch showed that changes occurred at both ages and that they were quite subtle, potentially explaining why inhibiting NO has only minor effects on lesion patterns in mature rabbits and contradicting the earlier conclusion that mechanotransduction pathways change with age. We suggest that recently-established changes in the patterns of haemodynamic forces themselves are more likely to account for the age-dependence of uptake patterns.     

Let-7, Mir-98 and Mir-181 as Biomarkers for Cancer and Schizophrenia

Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders. The expression pattern of a variety of different microRNAs was investigated in patients (N = 6) suffering from schizophrenia termed control, patients with a solid tumor (N = 10) and patients with both schizophrenia and tumor (N = 8). miRNA profiling was performed on whole blood samples using the miRCURY LNA microRNA Array technology (6th & 7th generation). A subset of 3 microRNAs showed a statistically significant differential expression between the control and the study groups. Specifically, significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumorand schizophrenia) was observed (p<0.05). The results of the present study showed that let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia, although a larger sample size is required to validate these results. Nevertheless, further studies are warranted in order to highlight a possible role of these and other micro-RNAs in the molecular pathways of schizophrenia.     

Progression of Osteosarcoma from a Non-Metastatic to a Metastatic Phenotype Is Causally Associated with Activation of an Autocrine and Paracrine uPA Axis

Pulmonary metastasis is the major untreatable complication of osteosarcoma (OS) resulting in 10–20% long-term survival. The factors and pathways regulating these processes remain unclear, yet their identification is crucial in order to find new therapeutic targets. In this study we used a multi-omics approach to identify molecules in metastatic and non-metastatic OS cells that may contribute to OS metastasis, followed by validation in vitro and in vivo. We found elevated levels of the urokinase plasminogen activator (uPA) and of the uPA receptor (uPAR) exclusively in metastatic OS cells. uPA was secreted in soluble form and as part of the protein cargo of OS-secreted extracellular vesicles, including exosomes. In addition, in the tumour microenvironment, uPA was expressed and secreted by bone marrow cells (BMC), and OS- and BMC-derived uPA significantly and specifically stimulated migration of metastatic OS cells via uPA-dependent signaling pathways. Silencing of uPAR in metastatic OS cells abrogated the migratory response to uPA in vitro and decreased metastasis in vivo. Finally, a novel small-molecule inhibitor of uPA significantly (P = 0.0004) inhibited metastasis in an orthotopic mouse model of OS. Thus, we show for the first time that malignant conversion of OS cells to a metastatic phenotype is defined by activation of the uPA/uPAR axis in both an autocrine and paracrine fashion. Furthermore, metastasis is driven by changes in OS cells as well as in the microenvironment. Finally, our data show that pharmacological inhibition of the uPA/uPAR axis with a novel small-molecule inhibitor can prevent the emergence of metastatic foci.     

Intrinsic Affective Network Is Impaired in Children with Attention-Deficit/Hyperactivity Disorder

Deficits in impulsivity and affect dysregulation are key features of attention-deficit/hyperactivity disorder (ADHD) besides impairing levels of hyperactivity and/or inattention. However, the neural substrates underlying these traits are relatively under-investigated. In this study, we use resting-state functional magnetic resonance imaging to test the hypothesis of diminished functional integration within the affective/limbic network (which includes the amygdala, hippocampus, subgenual cingulate cortex, orbitofrontal cortex and nucleus accumbens) of children with ADHD, which is associated with their behavioral measures of emotional control deficits. Resting state-fMRI data were obtained from 12 healthy control subjects and 15 children with ADHD, all who had a minimum one-month washout period for medications and supplements. Children with ADHD demonstrated less integrated affective network, evidenced by increased bilateral amygdalar and decreased left orbitofrontal connectivity within the affective network compared to healthy controls. The hyper-connectivity at the left amygdalar within the affective network was associated with increased aggressiveness and conduct problems, as well as decline in functioning in children with ADHD. Similar findings in affective network dysconnectivity were replicated in a subset of children with ADHD three months later. Our findings of divergent changes in amygdala and orbitofrontal intrinsic connectivity support the hypothesis of an impaired functional integration within the affective network in childhood ADHD. Larger prospective studies of the intrinsic affective network in ADHD are required, which may provide further insight on the biological mechanisms of emotional control deficits observed in ADHD.     

Subclinical atherosclerosis and impaired bone health in patients with primary Sjogren’s syndrome: prevalence,clinical and laboratory associations

IntroductionTo determine the prevalence and clinical/laboratory associations of subclinical atherosclerosis and impaired bone health in primary Sjogren’s syndrome (SS).Methods64 consecutive patients with primary SS, 77 with rheumatoid arthritis (RA) and 60 healthy controls (HC) οf similar age and sex distribution were enrolled. Demographics, clinical/laboratory features, classical risk factors for atherosclerosis and osteoporosis (OP) were recorded. Intima-medial thickness scores (IMT) and carotid/femoral (C/F) plaque formation, as well as bone mineral density (BMD) and fractures were evaluated. Determinants of IMT/BMD levels and the presence of plaque were assessed by univariate and multivariate models. Serum levels of the Wnt signaling mediators Dickkopf-related protein 1(DKK1) and sclerostin were determined in primary SS patients and HC.ResultsIncreased arterial wall thickening (IMT > 0.90 mm) and impaired bone health (defined as OP or osteopenia), were detected in approximately two-thirds of primary SS and RA patients, with a mean IMT value being significantly increased compared to HC. The presence of primary SS emerged as an independent risk factor for arterial wall thickening when traditional risk factors for cardiovascular disease (CVD) including age, sex, hypertension, smoking (pack/years), LDL and HDL levels were taken into account in a multivariate model [adjusted OR 95% (CI): 2.8 (1.04-7.54)]. In primary SS, age was revealed as independent predictor of increased IMT scores; age and lymphopenia as well as increased urine pH as independent determinants of C/F plaque formation and OP/osteopenia, respectively. An independent association of OP/osteopenia with plaque formation was observed when independent predictors for both variables were considered, with low DKK1 levels being associated with both plaque formation and lower BMD levels.ConclusionsComorbidities such as subclinical atherosclerosis and impaired bone health occur frequently in primary SS, in association with disease related features and traditional risk factors. Wnt signaling mediators are potentially involved in the pathogenesis of both entities.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0613-6) contains supplementary material, which is available to authorized users.