The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation

<p>Abstract</p> <p>Background</p> <p>The neural transcription factor SOX11 has been described as a prognostic marker in epithelial ovarian cancers (EOC), however its role in individual histological subtypes and tumour grade requires further clarification. Furthermore, methylation-dependent silencing of SOX11 has been reported for B cell lymphomas and indicates that epigenetic drugs may be used to re-express this tumour suppressor, but information on SOX11 promoter methylation in EOC is still lacking.</p> <p>Methods</p> <p>SOX11 expression and clinicopathological data was compared using χ²test in a cohort of 154 cases of primary invasive EOC. Kaplan-Meier analysis and the log rank test were applied to evaluate ovarian cancer-specific survival (OCSS) and overall survival (OS) in strata, according to SOX11 expression. Also, the methylation status of the SOX11 promoter was determined by sodium bisulfite sequencing and methylation specific PCR (MSP). Furthermore, the effect of ectopic overexpression of SOX11 on proliferation was studied through [3H]-thymidine incorporation.</p> <p>Results</p> <p>SOX11 expression was associated with an improved survival of patients with high grade EOC, although not independent of stage. Further analyses of EOC cell lines showed that SOX11 mRNA and protein were expressed in two of five cell lines, correlating with promoter methylation status. Demethylation was successfully performed using 5'-Aza-2'deoxycytidine (5-Aza-dC) resulting in SOX11 mRNA and protein expression in a previously negative EOC cell line. Furthermore, overexpression of SOX11 in EOC cell lines confirmed the growth regulatory role of SOX11.</p> <p>Conclusions</p> <p>SOX11 is a functionally associated protein in EOC with prognostic value for high-grade tumours. Re-expression of SOX11 in EOC indicates a potential use of epigenetic drugs to affect cellular growth in SOX11-negative tumours.</p

Cathepsins B, L and cystatin C in cyst fluid of ovarian tumors

Contains fulltext : 88032.pdf (publisher's version ) (Closed access)INTRODUCTION: In cancer, an extracellular and membrane bound localization of cathepsins contribute to the invasion of tumor cells at the basement membrane. METHODS: This is the first study that explored levels of cathepsins B (CatB), L (CatL) and their inhibitor cystatin C (CysC) in the cystic fluid (CF) of ovarian tumors (n = 110). RESULTS: CF contained considerable amounts of CatB, CatL and CysC. Remarkable differences in CatB and CatL and CysC CF levels were found between different histopathological tumor subtypes. Levels of CatB and CysC were significantly higher in CF of malignant serous tumors compared to those found in benign serous tumors (p = 0.010 and p = 0.001 respectively), whereas levels of CatL were significantly higher in CF of malignant mucinous tumors compared to those found in benign mucinous tumors (p = 0.035). CatB and CysC showed a strong correlation in the group of patients with malignant serous tumors (p < 0.001; R = 0.921) suggesting that the increase in CatB might be balanced by a corresponding increase in CysC. CONCLUSION: Further studies are warranted to investigate cathepsins as possible prognostic biomarkers for the aggressiveness of ovarian cancer.1 mei 201

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival (P<0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability (P<0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instablity status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR+ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, P<0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, P<0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR+ vs 17 out of 45 CLR− CRCs, P=0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P=0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation

Understanding missed opportunities for more timely diagnosis of cancer in symptomatic patients after presentation.

The diagnosis of cancer is a complex, multi-step process. In this paper, we highlight factors involved in missed opportunities to diagnose cancer more promptly in symptomatic patients and discuss responsible mechanisms and potential strategies to shorten intervals from presentation to diagnosis. Missed opportunities are instances in which post-hoc judgement indicates that alternative decisions or actions could have led to more timely diagnosis. They can occur in any of the three phases of the diagnostic process (initial diagnostic assessment; diagnostic test performance and interpretation; and diagnostic follow-up and coordination) and can involve patient, doctor/care team, and health-care system factors, often in combination. In this perspective article, we consider epidemiological 'signals' suggestive of missed opportunities and draw on evidence from retrospective case reviews of cancer patient cohorts to summarise factors that contribute to missed opportunities. Multi-disciplinary research targeting such factors is important to shorten diagnostic intervals post presentation. Insights from the fields of organisational and cognitive psychology, human factors science and informatics can be extremely valuable in this emerging research agenda. We provide a conceptual foundation for the development of future interventions to minimise the occurrence of missed opportunities in cancer diagnosis, enriching current approaches that chiefly focus on clinical decision support or on widening access to investigations.We acknowledge the helpful and incisive comments by Dr Rikke Sand Andersen (Aarhus University, Denmark) in conceptualising this piece and in drafts of the manuscript. The work is independent research supported by different funding schemes. GL was supported by a Post-Doctoral Fellowship by the National Institute for Health Research (PDF-2011-04-047) until the end of 2014 and by a Cancer Research UK Clinician Scientist Fellowship award (A18180) from 2015. HS is supported by the VA Health Services Research and Development Service (CRE 12-033; Presidential Early Career Award for Scientists and Engineers USA 14-274), the VA National Center for Patient Safety, the Agency for Health Care Research and Quality (R01HS022087) and in part by the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413). PV was supported by CaP, funded by The Danish Cancer Society and the Novo Nordisk Foundation.This is the final version of the article. It first appeared at http://dx.doi.org/10.1038/bjc.2015.4

RANK, RANKL and osteoprotegerin in bone biology and disease

Upon the discovery of RANK, RANKL and OPG in the late 1990s, their importance in the maintenance of the skeletal structure and their dramatic role in bone disease were largely unexpected. In recent years the understanding of these proteins, in particular their regulation, has greatly increased. This review aims to bring the interested reader up to date with the latest news and views on the mechanisms controlling bone resorption in normal and pathological conditions

RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases

The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational modification process by encoding molecular mimics of E3 ubiquitin ligases, eukaryotic enzymes that catalyze the final step in the ubiquitylation cascade. Here, we show that the Legionella pneumophila effector protein RavN belongs to a growing class of bacterial proteins that mimic host cell E3 ligases to exploit the ubiquitylation pathway. The E3 ligase activity of RavN was located within its N-terminal region and was dependent upon interaction with a defined subset of E2 ubiquitin-conjugating enzymes. The crystal structure of the N-terminal region of RavN revealed a U-box-like motif that was only remotely similar to other U-box domains, indicating that RavN is an E3 ligase relic that has undergone significant evolutionary alteration. Substitution of residues within the predicted E2 binding interface rendered RavN inactive, indicating that, despite significant structural changes, the mode of E2 recognition has remained conserved. Using hidden Markov model-based secondary structure analyses, we identified and experimentally validated four additional L. pneumophila effectors that were not previously recognized to possess E3 ligase activity, including Lpg2452/SdcB, a new paralog of SidC. Our study provides strong evidence that L. pneumophila is dedicating a considerable fraction of its effector arsenal to the manipulation of the host ubiquitylation pathway.Funding: This work was funded by the Intramural Research Program of the National Institutes of Health (to MPM)(Project Number: 1ZIAHD008893-07) and by the Spanish Ministry of Economy and Competitiveness Grant (to AH)(BFU2014-59759-R) and the Severo Ochoa Excellence Accreditation (to AH)(SEV-2016-0644). This study made use of the Diamond Light Source beamline I04 (Oxfordshire, UK) and ALBA synchrotron beamline BL13-XALOC, funded in part by the Horizon 2020 programme of the European Union, iNEXT (H2020 Grant # 653706). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Changes in the geographical distribution of plant species and climatic variables on the West Cornwall peninsula (South West UK)

Recent climate change has had a major impact on biodiversity and has altered the geographical distribution of vascular plant species. This trend is visible globally; however, more local and regional scale research is needed to improve understanding of the patterns of change and to develop appropriate conservation strategies that can minimise cultural, health, and economic losses at finer scales. Here we describe a method to manually geo-reference botanical records from a historical herbarium to track changes in the geographical distributions of plant species in West Cornwall (South West England) using both historical (pre-1900) and contemporary (post-1900) distribution records. We also assess the use of Ellenberg and climate indicator values as markers of responses to climate and environmental change. Using these techniques we detect a loss in 19 plant species, with 6 species losing more than 50% of their previous range. Statistical analysis showed that Ellenberg (light, moisture, nitrogen) and climate indicator values (mean January temperature, mean July temperature and mean precipitation) could be used as environmental change indicators. Significantly higher percentages of area lost were detected in species with lower January temperatures, July temperatures, light, and nitrogen values, as well as higher annual precipitation and moisture values. This study highlights the importance of historical records in examining the changes in plant species’ geographical distributions. We present a method for manual geo-referencing of such records, and demonstrate how using Ellenberg and climate indicator values as environmental and climate change indicators can contribute towards directing appropriate conservation strategies