miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer

AbstractIntroductionRadiotherapy in combination with medical castration is the standard treatment for high-risk prostate cancer. Some relapses may be explained by the presence of radioresistant clones arising from hypoxic microenvironment. Since microRNAs (miR) are increased upon hypoxia, the aim of this study was to see whether miR-210 is a potential marker for hypoxia and/or a therapeutic target in prostate cancer.MethodsHuman LNCaP, DU145 or PC3 prostate cancer cells were exposed to normoxia or hypoxia for several hours. Gene expression of miR-210, miR-373 and several hypoxia markers were analyzed by Taqman and SYBR green qRT-PCR, respectively. Clonogenic survival after LNA miR-210 inhibitor (78nM) and concomitant irradiation were evaluated.ResultsDuring anoxia, CAIX and VEGF expressions were dramatically increased. miR-210 expression increased during anoxia exposure, while basal miR-373 expression was low and remained stable upon anoxia. LNA miR-210 inhibitor decreased anoxic miR-210 expression by 90% and clonogenic survival under anoxia (p=0.01). However, no enhanced effect was observed when miR-210 inhibitor was combined with irradiation.ConclusionmiR-210 could be an interesting marker of chronic hypoxia irrespective of the androgen dependency and should, therefore, be tested as a prognostic marker in high risk prostate cancer patients

Extinction and the Dimming of KIC 8462852

To test alternative hypotheses for the behavior of KIC 8462852, we obtained measurements of the star over a wide wavelength range from the UV to the mid-infrared from October 2015 through December 2016, using Swift, Spitzer and at AstroLAB IRIS. The star faded in a manner similar to the long-term fading seen in Kepler data about 1400 days previously. The dimming rate for the entire period reported is 22.1 +\- 9.7 milli-mag/yr in the Swift wavebands, with amounts of 21.0 +\- 4.5 mmag in the groundbased B measurements, 14.0 +\- 4.5 mmag in V, and 13.0 +\- 4.5 in R, and a rate of 5.0 +\- 1.2 mmag/yr averaged over the two warm Spitzer bands. Although the dimming is small, it is seen at >= 3 sigma by three different observatories operating from the UV to the IR. The presence of long-term secular dimming means that previous SED models of the star based on photometric measurements taken years apart may not be accurate. We find that stellar models with T_{eff} = 7000 - 7100 K and A_V ~ 0.73 best fit the Swift data from UV to optical. These models also show no excess in the near-simultaneous Spitzer photometry at 3.6 and 4.5 microns, although a longer wavelength excess from a substantial debris disk is still possible (e.g., as around Fomalhaut). The wavelength dependence of the fading favors a relatively neutral color (i.e., R_V >= 5, but not flat across all the bands) compared with the extinction law for the general ISM (R_V = 3.1), suggesting that the dimming arises from circumstellar material.Comment: accepted by the Astrophysical Journal; acknowledgements revised 9/1/201

Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis

Hypoxia is a characteristic of many solid tumors and an adverse prognostic factor for treatment outcome. Hypoxia increases the expression of carbonic anhydrase IX, an enzyme that is predominantly found on tumor cells and is involved in maintaining the cellular pH balance. Many clinical studies investigated the prognostic value of carbonic anhydrase IX expression, but most have been inconclusive, partly due to small numbers of patients included. The present meta-analysis was therefore performed utilizing the results of all clinical studies to determine the prognostic value of carbonic anhydrase IX expression in solid tumors. Renal cell carcinoma was excluded from this meta-analysis due to an alternative mechanism of upregulation. 958 papers were identified from a literature search performed in Pubmed and Embase. These papers were independently evaluated by two reviewers and 147 studies were included in the analysis. The meta-analysis revealed strong significant associations between CAIX expression and all endpoints: overall survival (HR=1.76, 95%CI 1.58 – 1.98), disease-free survival (HR=1.87, 95%CI 1.62 – 2.16), locoregional control (HR=1.54, 95%CI 1.22 – 1.93), disease-specific survival (HR=1.78, 95%CI 1.41 – 2.25), metastasis-free survival (HR=1.82, 95%CI 1.33 – 2.50), and progression-free survival (HR=1.58, 95%CI 1.27 – 1.96). Subgroup analyses revealed similar associations in the majority of tumor sites and types. In conclusion, these results show that patients having tumors with high carbonic anhydrase IX expression have higher risk of locoregional failure, disease progression, and higher risk to develop metastases, independent of tumor type or site. The results of this meta-analysis further support the development of a clinical test to determine patient prognosis based on CAIX expression and may have important implications for the development of new treatment strategies

An impact model to understand and improve work-life balance in early-career researchers in radiation oncology.

Purpose The COVID-19 pandemic had a substantial effect on mental health and work productivity of early-career researchers working in Radiation Oncology (RO). However, the underlying mechanisms of these effects are unclear. The aim of the current qualitative study was therefore to achieve a better understanding of how these effects arose and could be managed in the future. Methods This study was conducted jointly by RO and qualitative health researchers. Data was collected in four online Focus Groups with 6-11 RO researchers (total N = 31) working in Europe. The transcripts were analysed through a qualitative cross-impact analysis. Results Causal relations were identified between seventeen variables that depict the impact of disrupted working conditions. Mental health and work productivity were indeed the most important affected variables, but relations between variables towards these impacts were complex. Relations could either be positive or negative and direct or indirect, leading to a cascade of interrelated events which are highly personal and could change over time. We developed the model 'impact of disrupted working conditions' depicting the identified variables and their relations, to allow more individual assessment and personalised solutions. Conclusion The impacts of disrupted working conditions on RO researchers varied due to the complexity of interrelated variables. Consequently, collective actions are not sufficient, and a more personal approach is needed. Our impact model is recommended to help guide conversations and reflections with the aim of improving work/life balance. The participants showed high levels of personal responsibility towards their own mental health and work productivity. Although being an individual issue, a collective responsibility in developing such approaches is key due to the dependency on organizational variables

An impact model to understand and improve work-life balance in early-career researchers in radiation oncology

Purpose: The COVID-19 pandemic had a substantial effect on mental health and work productivity of early-career researchers working in Radiation Oncology (RO). However, the underlying mechanisms of these effects are unclear. The aim of the current qualitative study was therefore to achieve a better understanding of how these effects arose and could be managed in the future.Methods: This study was conducted jointly by RO and qualitative health researchers. Data was collected in four online Focus Groups with 6-11 RO researchers (total N = 31) working in Europe. The transcripts were analysed through a qualitative cross-impact analysis.Results: Causal relations were identified between seventeen variables that depict the impact of disrupted working conditions. Mental health and work productivity were indeed the most important affected variables, but relations between variables towards these impacts were complex. Relations could either be positive or negative and direct or indirect, leading to a cascade of interrelated events which are highly personal and could change over time. We developed the model 'impact of disrupted working conditions' depicting the identified variables and their re-lations, to allow more individual assessment and personalised solutions.Conclusion: The impacts of disrupted working conditions on RO researchers varied due to the complexity of interrelated variables. Consequently, collective actions are not sufficient, and a more personal approach is needed. Our impact model is recommended to help guide conversations and reflections with the aim of improving work/life balance. The participants showed high levels of personal responsibility towards their own mental health and work productivity. Although being an individual issue, a collective responsibility in devel-oping such approaches is key due to the dependency on organizational variables

A novel data management platform to improve image-guided precision preclinical biological research

Objective: Preclinical biological research is mandatory for developing new drugs to investigate the toxicity and efficacy of the drug. In this paper, the focus is on radiobiological research as an example of advanced preclinical biological research. In radiobiology, recent technological advances have produced novel research platforms which can precisely irradiate targets in animals and use advanced onboard image-guidance, mimicking the clinical radiotherapy environment. These platforms greatly facilitate complex research combining several agents simultaneously (in our example, radiation and non-radiation agents). Since these modern platform can produce a large amount of wide-ranging data, one of the main impediments in preclinical research platforms is a proper data management system for preclinical studies. Methods: A preclinical data management system, inspired by current radiotherapy clinical data management systems was designed. The system was designed with InterSystems technology, i.e. a programmable Enterprise Service Bus solution. New DICOM animal imaging standards are used such as DICOM suppl. 187 for storing small animal acquisition context and the DICOM second generation course model. Results: A small animal big data warehouse environment for research is designed to work with modern image-guided precision research platforms. Its modular design includes (1) a study workflow manager, (2) a data manager, and (3) a storage manager. The system provides interfaces to, e.g. preclinical treatment planning systems and data analysis plug-ins, and guides the user efficiently through the many steps involved in preclinical research. The system manages various data source locations, and arranges access to the data centrally. Conclusion: A novel preclinical data management system can be designed to improve preclinical workflow, facilitate data exchange between researchers, and support translation to clinical trials. Advances in knowledge: A preclinical data management system such as the one proposed here would greatly benefit preparation, execution and analysis of biological experiments, and will eventually facilitate translation to clinical trials