The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

The potential use of online tools for scientific collaboration by biology researchers

Purpose - The purpose of this paper is to discover the research practices of biology researchers and to assess the suitability of the OJAX++ Virtual Research Environment (VRE) for these researchers. Design/methodology/approach â Usability testing was used to evaluate the usability of OJAX++ in relation to biology researchers. Interviews with biology researchers in a large Irish university were conducted to investigate their research information behaviour, to establish user requirements in their discipline and to evaluate the feasibility of using OJAX++ in their research. Findings - The results show that biology researchers used online tools extensively in their research but do not use social networking tools. E-mail and phone conversations are the preferred methods of collaborating with colleagues. The biology researchers found that OJAX++ was easy to use, intuitive and professionally presented but in its present format, OJAX++ does not fit in with current research practices as they do not use Web 2.0 tools that facilitate tagging. A list of requirements of a VRE for biology researchers is presented. Originality/value - The findings of the study will assist developers of VREs and other web tools to better understand how researchers, in particular biologists, collaborate during the research process and what they require from online research tools. This study gives an important insight into the information behaviour of life science researchers

Connecting population functionality with distribution model predictions to support freshwater and marine management of diadromous fish species

Diadromous fish species have a complex life cycle during which they migrate between marine and freshwater habitats. They experience multiple human-induced pressures in both environments, likely exacerbated by climate change, leading to dramatic population declines across their distribution ranges. Currently Species Distribution Models (SDMs) have been applied separately in both their continental and marine habitats to improve our understanding of their lifecycles and help with species management. Integrating the freshwater-sea continuum into the decisions would now be a step further in improving their management. With this objective, we developed a decision tree that links marine and freshwater SDM outputs with current observations of population functionality and suggested management guidance options for the viability of these species. Potential effects of climate change were included through future SDM projections to guide integrative and long-term management. Several criteria were proposed to assess the SDM validity considering the main sources of SDM uncertainties and local expert knowledge on habitat and population status. The framework was applied to approximately one hundred catchments from southern Portugal to southern Scandinavia for four diadromous species. At the European level, management guidance options differed between the two anadromous and two catadromous species. Platichthys flesus and Chelon ramada European populations seemed in better state than those of Alosa alosa and A. fallax. Finally, with the help of national diadromous species experts, we focused on four catchments distributed along the European latitudinal gradient to test the proposed methodology and demonstrate local management challenges in terms of freshwater-sea continuity

Constructing the Irish Presidency : the Early Incumbents, 1938-1973

Eamon de Valera's 1937 constitution created the office of President. Initially viewed with suspicion and interpreted by some as a step towards dictatorship, the presidency gradually came to be seen as a remote office and place of retirement for elder statesmen. The age profile of the three presidents examined in this article and their collective time in office initially appear to confirm such observations. Theirs tended to be a quiet office with days filled entertaining or dealing with correspondence. However, the first three presidents should not be considered as passive. Their willingness to exercise their discretionary powers was an important part of ensuring that the office functioned properly and effectively. It was also during these early years that the protocols and procedures of the office were decided. Though less remarkable than the later, more active presidents, the first three office holders played an important role in ensuring the smooth emergence of the presidencyPeer reviewe

Report of the Joint EIFAAC/ICES/GFCM Working Group on Eels (WGEEL)

The Joint EIFAAC/ICES/GFCM Working group on eels (WGEEL) met in a split meeting from 4–8 September (online) and 25 September–02 October 2023 (hybrid meeting) in Helsinki, Finland, to provide the scientific basis for the ICES advice on fishing opportunities and conservation aspects for the European eel and address requests from EIFAAC and GFCM.WGEEL assessed the state of the European eel and its fisheries, collated and analysed biometric data, reviewed the implementation of the WKFEA (Workshop on the future of eel advice) roadmap, examined available recruitment data from coastal and marine habitats, reported on any updates to the scientific basis of the advice, new and emerging threats or opportunities, including developments in the Mediterranean region.After high levels in the late 1970s, the recruitment declined dramatically in the 1980s and remains low. Compared to 1960–1979, the recruitment in the “North Sea” was 0.4% in 2023 (provisional) and 0.7 % in 2022 (final). In the “Elsewhere Europe” index series was 8.8 % in 2023 (provisional) and 11.3% in 2022 (final). For the yellow eel data series, recruitment for 2022 was 9% (final). Time-series from 1980 to 2023 show that glass eel recruitment remains at a very low level, with an historical minimum value in the North Sea.Silver eel time series have been analysed to identify patterns in abundance trends. These analyses are exploratory and have enabled us to test certain statistical methods and their limitations for analysing temporal series on silver eels. Although they give us an initial idea of trends in silver eel abundance, their results should be treated with caution. In fact, several problems have been identified and these points need to be improved in order to be able to interpret the results. The trend of reported commercial landings shows a long-term continuing decline, from a level of around 10,000 t in the 1960s, reported commercial landings have now dropped to 2028 (glass eel + yellow eel + silver eel) in 2022. The commercial glass eel fishery in 2022 was 60.1 t and 53.6 t in 2023. Reported landings from yellow and silver eel commercial fisheries (Y, S, YS) add up to 2914 t in 2021 and 2437 t in 2022. Spain was the only country allowing a recreational catch of glass eel, with landings estimated at 0.72 t in 2022 and 1.32 t in 2023. Reported recreational landings for yellow and silver eel combined were 240 t for 2021 (11 countries reporting) and 249 t for 2022.Progress with regards to the ‘road map’ developed within WKFEA was evaluated. The returns from the three questionnaires distributed by WKSMEEL to WGEEL members were summarised. In relation to the progress of the WKFEA roadmap, item 1; the inclusion of biological data is advanced with biometry data included in the annual data call. Item 2 relates to the reconstruction of the landings data and a workshop will take place in December 2023. Items 3 and 4 are also in progress, the Spatial database and Model for Eel (WKSMEEL) workshop was held in June 2023 with a follow up workshop planned for October 2023. A questionnaire for 3 topics (electrofishing, hydrographic network, and river obstructions &amp; hydropower) was circulated to WGEEL members in August 2023. Of the 21 countries who responded, a large majority carry out electrofishing, have available hydrographic networks and hold some information of obstructions to migration. However, it was recognised that considerable effort and resources will be required before the available data could be collated

MyD88 expression and survival (Kaplan-Meier curves: median survival time shown in months).

<p>MyD88 positive tumours (n = 12) had significantly reduced progression-free survival (A) and overall survival (B) (p = 0.018 and p = 0.008, respectively).</p

TLR4/MyD88 and progression-free survival (Kaplan-Meier curves; median survival shown in months).

<p>TLR4 (A) or MyD88 (B) negative cases had significantly better PFS (15 & 18 months longer; p<0.05).</p

The effect of silencing MyD88 and TLR4 mRNA on the chemoresponsive properties of SKOV-3 cells.

<p>SKOV-3 cells were left untransfected (Unt), transfected with negative control siRNA (siNeg), MyD88 targeting siRNA (siMyD88) or TLR4 targeting siRNA (siTLR4). The transfected cells were incubated for 72 hrs before either harvesting for mRNA analysis (A), for protein analysis (B) or treatment with paclitaxel (C). (A) MyD88 and TLR4 mRNA expression levels were evaluated by TaqMan RT-PCR. MyD88 and TLR4 mRNA expression was normalised to that of an endogenous control, B2M, and calibrated to that of untreated cells to establish the relative percentage of mRNA expression (n = 3, mean +SD). (B) MyD88 and TLR4 mRNA expression levels were evaluated by western blot analysis. GAPDH was used as a loading control. (C) Transfected cells were either left untreated, treated with DMSO (vehicle control) or 3.5 nM of paclitaxel (IC25). 48 hrs post treatment, cell viability was assessed by means of the CCK-8 assay. % cell viability rate was calculated by comparing the absorbance values for the vehicle control to the corresponding paclitaxel treated samples. Results are expressed as mean +SD, n = 3; *p<0.05, **p<0.01 (un-paired Student's t-test).</p