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This study aimed to discover whether parents of children with disabilities report higher levels of depression, anxiety and stress compared to parents of typical children, but also whether having a child with special needs influences the parent's job. By applying the DASS and PSS questionnaires, we concluded that these parents are more stressed, depressed and anxious, but also that they give up their jobs to take care of the disabled child.

BRAFV600E mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280–90. ©2018 AACR.

Table S1: Top 20 pathways identified by IPA containing genes significantly upregulated between poor and good prognostic BRAFMT stage II/III CRC in GSE39582; Table S2: Top 20 pathways identified by IPA containing genes significantly downregulated between poor and good prognostic BRAFMT stage II/III CRC in GSE39582; Table S3: Top 20 pathways identified by IPA containing genes differentially expressed between poor (disease free survival 5 years) in E-MTAB-863 and E-MTAB-864; Table S4: Results of siRNA screen in BRAFMT CRC.

Supplementary materials and methods

Integration of multi-omics data can provide a more complex view of the biological system consisting of different interconnected molecular components. We present a new comprehensive R/Bioconductor-package, IntOMICS, which implements a Bayesian framework for multi-omics data integration. IntOMICS adopts a Markov Chain Monte Carlo sampling scheme to systematically analyze gene expression, copy number variation, DNA methylation, and biological prior knowledge to infer regulatory networks. The unique feature of IntOMICS is an empirical biological knowledge estimation from the available experimental data, which complements the missing biological prior knowledge. IntOMICS has the potential to be a powerful resource for exploratory systems biology.

The paper explores the possibility of employing an Entity – Attribute – Value (EAV) database in relation with the historical sources and the digital tools in use for prosopographical research of the mid- and upper social strata in Transylvania, from early modernity to the interwar period. The massive digitization projects and the emergence of several historical databases, both taking place mainly during the last decade and still on-going, have provided the scholars of Transylvania with a wealth of information, but the development of proper tools for extracting and structuring it has hardly started. By transferring the digitized narratives from the primary sources into a structured database, which allows automated verification, linkage and comparisons, and approaching the data as “factoids”, and not as given historical facts, historians should be able to improve the selection of the prosopographical samples in view of further analyses, keep track of conflicting information provided by different sources, and revisit any piece of data when required. In view of the above, the paper illustrates the application of digital prosopography on one of the historical databases focusing on the upper social layers of Transylvania during late modernity: “Historical Data Grinder”.

This study aimed to explore the possible moderating role of emotional regulation in the relationship between problem-solving ability, visuomotor precision and visuospatial integration on the one hand and school results on the other in pupils with ADHD. A total of 241 pupils with ADHD (study group) and 207 children without ADHD (control group) were included in our research. Specific tests for the evaluation of the problem-solving ability, visuomotor precision, visuospatial integration, and emotional regulation were applied. The results showed that emotional regulation is a significant moderator of the relationship between school results and problem-solving ability, visuomotor precision, visuospatial integration, and working memory. There are statistically significant differences depending on emotional regulation, visuomotor precision, visuospatial integration, problem-solving ability and working memory in terms of school results of students with ADHD compared to children without this diagnosis. These results can be used in the development of intervention programs.

People with disabilities are prone to health problems and face discrimination and stigma and these problems were exacerbated during the COVID-19 epidemic. People with disabilities have an increased risk of contracting COVID-19 for several reasons, including due to difficulties in using basic protection measures and the need to comply with the requirements set for social distancing, and the risk of death due to COVID is estimated for persons with disabilities as being approximately double that of persons without disabilities. The society's response to the COVID-19 pandemic should also include disability as concern, protection of the rights and needs of people with disabilities, as provided for in the Convention on the Rights of Persons with Disabilities and in the 2030 Agenda for Sustainability and Development.

"The study provides the documentation for the first public version of the database Digital Framework for the History of the Austrian Military Border in Transylvania by means of a detailed description and user manual. It includes: a short overview of the historical context of the establishment of the Austrian military border in this province, references to the international and Romanian state of the art, the detailing of primary sources issued by the military environment and starting from which the database was built and the main principles of construction and operation of the latter. The information in the database is extracted from the records of the military and administrative personnel of the Transylvanian border regiments between 1763 and 1850, including monthly staff records, information on salaries, enrollments, transfers, desertions, medical certificates, etc. The lists of conduct of the officers should also be mentioned, each of them including a detailed physical and psychological description of the respective person. The database serves two aims. On the one hand, to boost the use of and access to documents generated by the Austrian military and with this to bring the Romanian historical writing on the military border in Transylvania closer to the primary sources. On the other hand, to complement, for the territory of the former military border, the vital registration data provided by parish registers with social history data that can improve life course reconstruction and analysis. Keywords: Historical databases, Austrian Military Border, Transylvania, Habsburg Monarchy, Military history "

Many studies correlate changes in human gut microbiome with the onset of various diseases, mostly by 16S rRNA gene sequencing. Setting up the optimal sampling and DNA isolation procedures is crucial for robustness and reproducibility of the results. We performed a systematic comparison of several sampling and DNA isolation kits, quantified their effect on bacterial gDNA quality and the bacterial composition estimates at all taxonomic levels. Sixteen volunteers tested three sampling kits. All samples were consequently processed by two DNA isolation kits. We found that the choice of both stool sampling and DNA isolation kits have an effect on bacterial composition with respect to Gram-positivity, however the isolation kit had a stronger effect than the sampling kit. The proportion of bacteria affected by isolation and sampling kits was larger at higher taxa levels compared to lower taxa levels. The PowerLyzer PowerSoil DNA Isolation Kit outperformed the QIAamp DNA Stool Mini Kit mainly due to better lysis of Gram-positive bacteria while keeping the values of all the other assessed parameters within a reasonable range. The presented effects need to be taken into account when comparing results across multiple studies or computing ratios between Gram-positive and Gram-negative bacteria.

The dysfunction of the DNA mismatch repair system results in microsatellite instability (MSI). MSI plays a central role in the development of multiple human cancers. In colon cancer, despite being associated with resistance to 5-fluorouracil treatment, MSI is a favourable prognostic marker. In gastric and endometrial cancers, its prognostic value is not so well established. Nevertheless, recognising the MSI tumours may be important for predicting the therapeutic effect of immune checkpoint inhibitors. Several gene expression signatures were trained on microarray data sets to understand the regulatory mechanisms underlying microsatellite instability in colorectal cancer. A wealth of expression data already exists in the form of microarray data sets. However, the RNA-seq has become a routine for transcriptome analysis. A new MSI gene expression signature presented here is the first to be valid across two different platforms, microarrays and RNA-seq. In the case of colon cancer, its estimated performance was (i) AUC = 0.94, 95% CI = (0.90 – 0.97) on RNA-seq and (ii) AUC = 0.95, 95% CI = (0.92 – 0.97) on microarray. The 25-gene expression signature was also validated in two independent microarray colon cancer data sets. Despite being derived from colorectal cancer, the signature maintained good performance on RNA-seq and microarray gastric cancer data sets (AUC = 0.90, 95% CI = (0.85 – 0.94) and AUC = 0.83, 95% CI = (0.69 – 0.97), respectively). Furthermore, this classifier retained high concordance even when classifying RNA-seq endometrial cancers (AUC = 0.71, 95% CI = (0.62 – 0.81). These results indicate that the new signature was able to remove the platform-specific differences while preserving the underlying biological differences between MSI/MSS phenotypes in colon cancer samples.

Digital tools have enhanced the possibilities of historical prosopographic researches, bringing to light facts and connections unnoticed before. Showcasing two very different databases – in structure, timeframe and employed sources – we will try to highlight how structured data can prove useful and revealing for the proposography of the people living in all historical periods and area. In order to make our point, we will first present the two databases form architectural and technical points of view, then we will focus on case studies extracted from each of them. We will try to highlight the extra historical knowledge brought forth by the employment of digital tools and technologies and how these means actually increase our insightfulness when facing the sources.

BackgroundLong-term dysbiosis of the gut microbiome has a significant impact on the development, progression and the aggressiveness of colorectal cancer (CRC) and may explain part of the observed heterogeneity of the disease from phenotypic, prognostic and response to treatment perspectives. Although the shifts in gut microbiome in the normal-adenoma-carcinoma sequence have been described, the landscape of microbiome within CRC and its associations with clinical variables remain under-explored. ResultsWe performed 16S rRNA gene sequencing of paired tumour tissue, adjacent visually-normal mucosa and stool swabs of N=186 patients with stage 0-IV CRC to describe the tumour microbiome and its association with clinical variable and to derive tumour microbial subtypes.We identified new genera never previously associated with CRC tumour mucosa (Flavonifractor, Haemophilus, Howardella, Pseudomonas, Sutterella, Treponema 2) or CRC (Actinobacillus, Aggregatibacter, Bergeyella, Phocaeiola, Defluviitaleaceae UCG-011, Massilia, Tyzzerella 4). The bacteria residing on tumour-mucosa were dominated by genera belonging to (potential) oral pathogens. Based on tumour microbial profiles, we stratified CRC patients into three subtypes. The subtypes were significantly associated with prognostic factors such as tumor grade, primary tumour sidedness and TNM staging, with one subtype enriched in tumours with poor prognosis. Further, we inspected the associations of microbiome with clinical variables in a subtype-agnostic setting. The primary tumour-associated clinical variables predominantly correlated with tumour mucosal microbiome, while the presence of local and distant metastases was mostly associated with the stool microbiome.ConclusionsUnderstanding the interactions of the bacteria residing on tumour mucosa within different CRC tumour microbiome subtypes will help to better understand the underlying biological background of the heterogeneity of this disease. Indeed, the tumour microbiome is a possible source of additional integrative markers of CRC patients’ survival and prognosis. We found that CRC microbiome is strongly correlated with clinical variables, but these associations are dependent on the microbial environment (tumour mucosa, normal mucosa, stool). Our study thus identifies limitations of the usage of microbiome composition as marker of CRC progression, suggesting the need of combining several sampling sites (e.g. stool and tumour swabs).

Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon cancer samples from the PETACC-3 study, which randomized the patients to Fluorouracil/leucovorin (5FUL) +/&minus, irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Patients were divided into one group with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (&ldquo, resistant&rdquo, ) (n = 216) and another group including all other combinations of these two genes (&ldquo, sensitive&rdquo, ) (n = 364). The rationale for the cut-offs were based on the distribution of expression levels in the PETACC-3 Stage II set of patients, where ABCG2 was unimodal and TOP1 was bimodal with a high expression level mode in the top quarter of the patients. Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Significant differences were found for both RFS (Hazard ratio (HR): 0.63 (0.44&ndash, 0.92), p = 0.016) and OS (HR: 0.60 (0.39&ndash, 0.93), p = 0.02) between the two biomarker groups when the patients received FOLFIRI (5FUL+irinotecan). Considering only the Microsatellite Stable (MSS) and Microsatellite Instability-Low (MSI-L) patients (n = 470), the differences were even more pronounced. In contrast, no significant differences were observed between the groups when patients received 5FUL alone. This study shows that the combination of ABCG2 and TOP1 gene expression significantly divided the Stage III colon cancer patients into two groups regarding benefit from adjuvant treatment with FOLFIRI but not 5FUL.