Ezrin expression combined with MSI status in prognostication of stage II colorectal cancer

Currently used factors predicting disease recurrence in stage II colorectal cancer patients are not optimal for risk stratification. Thus, new biomarkers are needed. In this study the applicability of ezrin protein expression together with MSI status and BRAF mutation status were tested in predicting disease outcome in stage II colorectal cancer. The study population consisted of 173 stage II colorectal cancer patients. Paraffin-embedded cancer tissue material from surgical specimens was used to construct tissue microarrays (TMAs) with next-generation technique. The TMA-slides were subjected to following immunohistochemical stainings: MLH1, MSH2, MSH6, PMS2, ezrin and anti-BRAF V600E antibody. The staining results were correlated with clinicopathological variables and survival. In categorical analysis, high ezrin protein expression correlated with poor disease-specific survival (p = 0.038). In univariate analysis patients having microsatellite instabile / low ezrin expression tumors had a significantly longer disease-specific survival than patients having microsatellite stable / high ezrin expression tumors (p = 0.007). In multivariate survival analysis, the presence of BRAF mutation was associated to poor overall survival (p = 0.028, HR 3.29, 95% CI1.14-9.54). High ezrin protein expression in patients with microsatellite stable tumors was linked to poor disease-specific survival (p = 0.01, HR 5.68, 95% CI 1.53-21.12). Ezrin protein expression is a promising biomarker in estimating the outcome of stage II colorectal cancer patients. When combined with microsatellite status its ability in predicting disease outcome is further improved.Peer reviewe

Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease

Tulehdukselliset suolistosairaudet (IBD) Crohnin tauti (CD) ja haavainen paksusuolentulehdus (UC) ovat maailmanlaajuisesti lisääntyviä sairauksia, joihin liittyy muuntunut suoliston mikrobisto. Infliksimabi (IFX) on TNF-alfan estäjä, jota käytetään IBD:n hoidossa, vaikkakin kolmas osa potilaista voi jäädä ilman hoitovastetta tai menettää sen. Luotettavia testejä hoitovasteen ennustamiseksi ei ole vielä saatavilla. Tutkimuksemme tavoitteena oli selvittää potilaiden ulosteen bakteerit, sienet ja hiivat infliksimabihoidon aikana sekä etsiä hoitovastetta ennustavia mittareita IBD potilailta. Tutkimuksessamme 72 IBD-potilasta (25 CD ja 47 UC) aloitti infliksimabihoidon ja heitä seurattiin vuoden ajan hoidon aloituksesta tai hoidon keskeytykseen saakka. Potilaiden ulostenäytteistä määritettiin sekvensointia hyödyntäen erikseen suoliston bakteerit (16S rRNA geenistä) sekä hiivat ja sienet (ITS1 geenin alueesta). Mikrobiston profiilit määritettiin ennen hoidon aloitusta, 2, 6, 12 viikkoa sekä 1 vuosi hoidon aloituksen jälkeen. IFX hoidon vaste määritettiin kolonoskopialla ja kliinisesti 12 viikon hoidon jälkeen. Tutkimuksessa havaittiin, että potilaiden ulosteen bakteerit sekä sienet ja hiivat erosivat merkittävästi toisistaan infliksimabihoitovasteen mukaan jo ennen hoidon aloitusta. Potilailla, jotka eivät saaneet vastetta hoidosta, oli vähemmän lyhytketjuisia rasvahappoja tuottavia bakteereja erityisesti Clostridia-luokasta sekä enemmän tulehdusta aiheuttavia bakteereja ja sieniä mm. Candida-suvusta. Tämä tulos testattiin bakteerien osalta myös ennustetestillä (ROC), joka erotti toisistaan ne potilaat, jotka saivat hyvän vasteen ja ne, jotka eivät saaneet vastetta (area under the curve > 0.8). Tulosten perusteella ulosteen bakteerit ja hiivat voisivat sopia ennustaviksi mittareiksi IBD-potilaiden infliksimabihoidon vasteen ennustamiseen.Peer reviewe

ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer reviewe

Puut tarjoumina paikkasuhteen muotoutumiseen - viitekehys lasten luontosuhteen tukemiseen

This study, informed by phenomenology and ethnography, explores urban children’s relationship with trees in a garden camp context: what are trees for urban children? Studying Finnish 7- to 12-year-old children, the research employed triangulation: participant and non-participant observation methods with mixed data collection over the course of three years. Engaging in grounded theory analysis after an intermission, the study unites the theoretical constructs of affordance and connectedness to place. Based on empirical observations, this study provides a theoretical framework to clarify the phased process of how urban children’s connectedness to place is evolving. Exploitation of tree affordances during place-based play reflected connectedness to place; utilization of trees became more versatile over time. The results showed trees to be intriguing and multifaceted, satisfying many of the children’s private and social needs. Trees provided the materials, space and often purpose and contents for the actual play that could not have thrived without them. In addition, children learned to manage possible tree-related risks mainly from experience and through scaffolding with peers. Recommendations for supporting beneficial nature contact emphasize allowing child-directed, place-based play time and planning biodiverse, low-maintenance spaces with a wide variety of trees that will invite children to use green spaces according to their needs.This study, informed by phenomenology and ethnography, explores urban children’s relationship with trees in a garden camp context: what are trees for urban children? Studying Finnish 7- to 12-year-old children, the research employed triangulation: participant and non-participant observation methods with mixed data collection over the course of three years. Engaging in grounded theory analysis after an intermission, the study unites the theoretical constructs of affordance and connectedness to place. Based on empirical observations, this study provides a theoretical framework to clarify the phased process of how urban children’s connectedness to place is evolving. Exploitation of tree affordances during place-based play reflected connectedness to place; utilization of trees became more versatile over time. The results showed trees to be intriguing and multifaceted, satisfying many of the children’s private and social needs. Trees provided the materials, space and often purpose and contents for the actual play that could not have thrived without them. In addition, children learned to manage possible tree-related risks mainly from experience and through scaffolding with peers. Recommendations for supporting beneficial nature contact emphasize allowing child-directed, place-based play time and planning biodiverse, low-maintenance spaces with a wide variety of trees that will invite children to use green spaces according to their needs.Peer reviewe

REG4 Is Highly Expressed in Mucinous Ovarian Cancer : A Potential Novel Serum Biomarker

Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non-neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer.Peer reviewe

Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension

Background: It remains unclear whether patients with positive surgical margins or extracapsular extension benefit from adjuvant radiotherapy following radical prostatectomy. Objective: To compare the effectiveness and tolerability of adjuvant radiotherapy following radical prostatectomy. Design, setting, and participants: This was a randomised, open-label, parallel-group trial. A total of 250 patients were enrolled between April 2004 and October 2012 in eight Finnish hospitals, with pT2 with positive margins or pT3a, pN0, M0 cancer without seminal vesicle invasion. Intervention: A total of 126 patients received adjuvant radiotherapy at 66.6 Gy. Outcome measurements and statistical analysis: The primary endpoint was biochemical recurrence-free survival, which we analysed using the Kaplan-Meier method and Cox proportional hazard regression. Overall survival, cancer-specific survival, local recurrence, and adverse events were secondary endpoints. Results and limitations: The median follow-up time for patients who were alive when the follow-up ended was 9.3 yr in the adjuvant group and 8.6 yr in the observation group. The 10-yr survival for biochemical recurrence was 82% in the adjuvant group and 61% in the observation group (hazard ratio [HR] 0.26 [95% confidence interval {CI} 0.14-0.48], p <0.001), and for overall survival 92% and 87%, respectively (HR 0.69 [95% CI 0.29-1.60], p = 0.4). Two and four metastatic cancers occurred, respectively. Out of the 43 patients with biochemical recurrence in the observation group, 37 patients received salvage radiotherapy. In the adjuvant group, 56% experienced grade 3 adverse events, versus 40% in the observation group (p = 0.016). Only one grade 4 adverse event occurred (adjuvant group). A limitation of this study was the number of patients. Conclusions: Adjuvant radiotherapy following radical prostatectomy is generally well tolerated and prolongs biochemical recurrence-free survival compared with radical prostatectomy alone in patients with positive margins or extracapsular extension. Patient summary: Radiotherapy given immediately after prostate cancer surgery prolongs prostate-specific antigen progression-free survival, but causes more adverse events, when compared with surgery alone. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewe

A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

Peer reviewe

Acute effects of visits to urban green environments on cardiovascular physiology in women: A field experiment

Background: Epidemiological studies have reported positive associations between the amount of green space in the living environment and mental and cardiovascular human health. In a search for effect mechanisms, field studies have found short-term visits to green environments to be associated with psychological stress relief. Less evidence is available on the effect of visits on cardiovascular physiology. Objectives: To evaluate whether visits to urban green environments, in comparison to visits to a built-up environment, lead to beneficial short-term changes in indicators of cardiovascular health. Methods: Thirty-six adult female volunteers visited three different types of urban environments: an urban forest, an urban park, and a built-up city centre, in Helsinki, Finland. The visits consisted of 15 min of sedentary viewing, and 30 min of walking. During the visits, blood pressure and heart rate were measured, and electrocardiogram recorded for the determination of indicators of heart rate variability. In addition, levels of respirable ambient particles and environmental noise were monitored. Results: Visits to the green environments were associated with lower blood pressure (viewing period only), lower heart rate, and higher indices of heart rate variability [standard deviation of normal-to-normal intervals (SDNN), high frequency power] than visits to the city centre. In the green environments, heart rate decreased and SDNN increased during the visit. Associations between environment and indicators of cardiovascular health weakened slightly after inclusion of particulate air pollution and noise in the models. Conclusions: Visits to urban green environments are associated with beneficial short-term changes in cardiovascular risk factors. This can be explained by psychological stress relief with contribution from reduced air pollution and noise exposure during the visits. Future research should evaluate the amount of exposure to green environments needed for longer-term benefits for cardiovascular health.201

The clinicopathological variables of the patient population included in the MSI, BRAF and Ezrin analyses (n = 173).

<p>NA = not available, R0 = microscopically radical surgery, R1 macroscopically radical surgery, R2 macroscopically non-radical surgery.</p