Giving Moral Competence High Priority in Medical Education. New MCT-based Research Findings from the Polish Context

Nowadays, healthcare and medical education is qualified by test scores and competitiveness. This article considers its quality in terms of improving the moral competence of future healthcare providers. Objectives. Examining the relevance of moral competence in medico-clinical decision-making despite the paradigm shift and discussing the up-to-date findings on healthcare students (Polish sample). Design and method. N=115 participants were surveyed with a standard Moral Competence Test to examine how their moral competence development was affected by the learning environment and further important factors. Results. The sample allowed the identification of a regress in moral competence during students’ pre-clinical curriculum, and progress during their clinical curriculum. A gender-related bias, a segmentation effect, and a pronunciation effect were noticed. Explanations. Scholarly literature usually reports a linear decrease of medical students’ C-scores resulting from, e.g., competitive trends in education. We identified such trends in terms of gender-specific competitive tactics. Religious and ethical affiliations were discussed to explain the unexpected gender bias and the related segmentation and pronunciation effects. The findings can be regarded as predictive for similar developments in educational institutions regardless of cultural contexts as the sample examined in this article represents medical education in a country facing a transition from a non-competitive to competitive tertiary education model, and between presecular and monocultural to secular and pluralist social ethics

MicroRNAs as efficient biomarkers in high-grade gliomas

High-grade gliomas are the most aggressive and devastating brain neoplasms. Therefore much effort is put on understanding their background as well as development of new effective diagnostic and therapeutic methods. However, until now the genetic only approach has not provided a satisfactory answer. Recently, it has been shown that the epigenetic issue is important for high-grade gliomas’ development and progression. Out of many epigenetic mechanisms, as DNA methylation, histone methylation and acetylation, especially microRNAs showed to be deeply involved in the carcinogenesis process. MicroRNAs are short non-coding RNAs. They are new candidates for human disease biomarkers due to their simple identification. MicroRNAs are stable in tissue and body fluids, what makes them very prospective non-invasive, blood-based biomarkers. There is a lot of data showing that various profiles of serum microRNAs are linked to numerous neoplastic processes, indicating that microRNAs can be really a new class of biomarkers for human diseases

The degree of global DNA hypomethylation in peripheral blood correlates with that in matched tumor tissues in several neoplasia.

There are no good blood and serum biomarkers for detection, follow up, or prognosis of brain tumors. However, they are needed for more detailed tumor classification, better prognosis estimation and selection of an efficient therapeutic strategy. The aim of this study was to use the epigenetic changes in DNA of peripheral blood samples as a molecular marker to diagnose brain tumors as well as other diseases. We have applied a very precise thin-layer chromatography (TLC) analysis of the global amount of 5-methylcytosine (m(5)C) in DNA from brain tumors, colon and breast cancer tissues and peripheral blood samples of the same patients. The m(5)C level in tissue DNA from different brain tumor types, expressed as R coefficient, changes within the range of 0.2-1.6 and overlaps with R of that of blood samples. It negatively correlates with the WHO malignancy grade. The global DNA hypomethylation quantitative measure in blood, demonstrates a big potential for development of non-invasive applications for detection of a low and a high grade brain tumors. We have also used this approach to analyze patients with breast and colon cancers. In all these cases the m(5)C amount in DNA cancer tissue match with data of blood. This study is the first to demonstrate the potential role of global m(5)C content in blood DNA for early detection of brain tumors and others diseases. So, genomic DNA hypomethylation is a promising marker for prognosis of various neoplasms as well as other pathologies

mTOR Signaling and Potential Therapeutic Targeting in Meningioma

Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions.

Temozolomide (TMZ) is a drug of choice in glioblastoma treatment. Its therapeutic applications expand also beyond high grade gliomas. However, a significant number of recurrences and resistance to the drug is observed. The key factor in each chemotherapy is to achieve the therapeutic doses of a drug at the pathologic site. Nonetheless, the rate of temozolomide penetration from blood to cerebrospinal fluid is only 20-30%, and even smaller into brain intestinum. That makes a challenge for the therapeutic regimens to obtain effective drug concentrations with minimal toxicity and minor side effects. The aim of our research was to explore a novel epigenetic mechanism of temozolomide action in therapeutic conditions. We analyzed the epigenetic effects of TMZ influence on different glioblastoma cell lines in therapeutically achieved TMZ concentrations through total changes of the level of 5-methylcytosine in DNA, the main epigenetic marker. That was done with classical approach of radioactive nucleotide post-labelling and separation on thin-layer chromatography. In the range of therapeutically achieved temozolomide concentrations we observed total DNA hypomethylation. The significant hypermethylating effect was visible after reaching TMZ concentrations of 10-50 μM (depending on the cell line). Longer exposure time promoted DNA hypomethylation. The demethylated state of the glioblastoma cell lines was overcome by repeated TMZ applications, where dose-dependent increase in DNA 5-methylcytosine contents was observed. Those effects were not seen in non-cancerous cell line. The increase of DNA methylation resulting in global gene silencing and consecutive down regulation of gene expression after TMZ treatment may explain better glioblastoma patients' survival

The list of brain tumor types identified in 183 patients for whom DNA from brain tumor tissue and peripheral blood samples was isolated and analyzed for the content of m⁵C in DNA.

<p>Specific R coefficient was calculated as (m5dC/m5dC+dC+dT)×100 on the basis of analysis TLC plate exposed to Phosphoimager. Histopathological analysis revealed the WHO grade. Sex is also mentioned.</p

Effect of brain tumor tissue handling on content of m⁵C in DNA.

<p>The level of m⁵C content (R) in DNA isolated from resected meningioma tissue (WHO grade I) stored at −80°C (grey bar), formalin-fixed paraffin-embedded (FFPE) (empty bar) and exposed to room temperature for 3 h (black bar). Analysis was done for 5 samples in each conditions. Standard deviations for R is shown.</p

Comparison of m⁵C content in DNA in tissue and blood with malignancy of brain tumors.

<p><b>A</b>. Pearson r correlation (0.9; p<0.0001) of genomic m⁵C contents of DNA from peripheral blood and from brain tumor tissues of the same subjects. <b>B</b>. Amounts of m⁵C in DNA (R) from blood and in tumor tissues of the same subjects with brain tumors (astrocytoma, anaplastic astrocytoma and glioblastoma) of different malignancy. Data on human brain metastasis and meningioma were also analyzed. Data were evaluated with ANOVA test.</p

Comparison of content of m⁵C in DNA from tissue and blood.

<p>5-methylcytosine content (R) in DNA from 183 patients with brain tumors: cancer tissues (upper panel) and blood (bottoms panel). The figure clearly shows that m⁵C content, expressed as R [ = (m5dC/m5dC+dC+dT)×100] coefficient, in DNA from tumor tissue matches the results from blood <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092599#pone.0092599-Barciszewska2" target="_blank">[25]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092599#pone.0092599-Barciszewska3" target="_blank">[26]</a>.</p