DNA methylation, histone modifications, and miRNAs affect ovarian cancer (OC) progression and therapy response.
Identification of epigenetically downregulated miRNAs in drug-resistant OC cell lines ...with a possible role in drug resistance and/or drug-induced mesenchymal-like phenotype.
MiRNA profiling was performed on parental and carboplatin-resistant OC cells, MES-OV and MES-OV CBP. RT-qPCR validation, epigenetic modulation and other CBP-resistant OC cell lines were used to select miRNAs of interest. The integration of miRNA-predicted target genes and differentially expressed genes (DEGs), pathway and functional analysis were used for forecasting their biological role. Data mining was performed to determine their possible prognostic and predictive values.
MiRNA profiling revealed 48 downregulated miRNAs in OC cells whose drug sensitivity and metastatic potential were impacted by epigenetic modulators. Of the fourteen selected, nine were validated as changed, and seven of these restored their expression upon treatment with epigenetic inhibitors. Only three had similar expression patterns in other OC cell lines. MiRNA-mRNA integrative analysis resulted in 56 target DEGs. Pathway analysis revealed that these genes are involved in cell adhesion, migration, and invasion. The functional analysis confirmed the role of miR-103a–3p, miR-17–5p and miR-107 in cell invasion, while data mining showed their prognostic and predictive values. Only miR-103a–3p was epigenetically regulated at the constitutive level.
High throughput miRNA and cDNA profiling coupled with pathway analysis and data mining delivered evidence for miRNAs which can be epigenetically regulated in drug-resistant, mesenchymal-like OC cells as possible markers to combat therapy-induced short overall survival and tumor metastatic potential.
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•Microarray analysis identifies 77 differentially expressed miRNAs in drug resistant EOC cells.•Epigenetic modulators impact cells’ drug response and metastatic capacity.•Downregulated miR-103a, 17 and 107 are shared feature of several resistant EOC cell lines and has a prognostic value.•MiRNA-mRNA integrative analysis reveals signaling pathways involved in metastasis.•Epigenetically regulated miR-103a is involved in metastasis but not drug response.
In the last decade, gaming has become one of the activities that many school-aged children have been using daily. As such, gaming has been having a bad effect on children’s physical activity but, at ...the same time, it has helped them in the process of learning English. The goal of the study was: 1) to establish a correlation between the frequency of gaming with motor abilities and grades in English; 2) to establish a correlation between motor abilities and English. Thirty-four 7th- graders (m=19, f=15; age 13.24±0.55) of a primary school in Split participated in the study. The subjects were tested in 3 motor and 1 functional ability test. Grades in English were collected. The participants also filled out the questionnaire on the frequency and manner of gaming. The questionnaire is reliable. There is no statistically significant correlation between the frequency of gaming and better grades in English. Girls game less than boys (MWU Test), have better grades in English, and achieve less in certain motor abilities (MWU Test trunk lifting; 6-min running). The findings suggest that by gaming we do not improve our knowledge of English but that gaming is statistically negatively correlated with motor abilities.
Abstract
Objective
Desmoplastic small round cell tumor (DSRCT) is a rare intraabdominal neoplasm that grows along serosal surfaces and is primarily found in young men. To date, only 16 cases of ...ovarian DSRCT have been previously reported in women in the English literature, and no large population-based studies on this topic exist.
Case Report
We report the case of a 19-year-old virgo with unremarkable past medical history, initially presented with abdominal fullness. After being treated with the optimal treatment modality (primary and secondary surgical debulking, unique chemotherapy, protocol and adjuvant radiotherapy), the patient has remained without tumor disease for 40 months.
Conclusion
Although the best therapy for patients with DSRCT has yet to be determined, combining complete surgical resection, adjuvant chemotherapy, and radiotherapy is required to prolong survival and to achieve proper quality of life.
Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer ...metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
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•mTORC2 is required for the growth of GBM cells in glucose•mTORC2 controls glycolytic metabolism by regulating the cellular level c-Myc•mTORC2 signaling acetylates FoxO1 and FoxO3 to upregulate c-Myc•mTORC2, acetylated FoxO, and c-Myc axis confer shorter survival in patients
This paper presents a novel approach for an Intrusion Detection System (IDS) based on one kind of asymmetric optimization which use any three already well-known IDS algorithms and Triple Modular ...Redundancy (TMR) algorithm together. Namely, a variable threshold which indicates an attack on an observed and protected network is determined by using all three values obtained with three known IDS algorithms i.e., on previously recorded data by making a decision by majority. For these algorithms authors used algorithm of k-nearest neighbors, cumulative sum algorithm, and algorithm of exponentially weighted moving average. Using a proposed method we can get a threshold that is more precisely determined than in the case of any method individual. Practically, using TMR we obtain a dynamically threshold adjustment of IDS software, which reduces the existence of false alarms and undetected attacks, so the efficiency of such IDS software is notably higher and can get better results. Today, Denial of Service attacks (DoS) are one of the most present type of attacks and the reason for the special attention paid to them in this paper. In addition, the authors of the proposed method for IDS software used a known CIC-DDoS2019 dataset, which contains various data recordings of such attacks. Obtained results with the proposed solution showed better characteristics than each individual used algorithm in this solution. IDS software with the proposed method worked precisely and timely, which means alarms were triggered properly and efficiently.
The research presented in this paper aims at creating a bilingual (sr-en), easily searchable, hypertext, born-digital, corpus-based terminological database of raw material terminology for dictionary ...production. The approach is based on linking dictionaries related to the raw material domain, both digitally born and printed, into a lexicon structure, aligning terminology from different dictionaries as much as possible. This paper presents the main features of this approach, data used for compilation of the terminological database, the procedure by which it has been generated and a mobile application for its use. Available (terminological) resources will be presented—paper dictionaries and digital resources related to the raw material domain, as well as general lexica morphological dictionaries. Resource preparation started with dictionary (retro)digitisation and corpora enlargement, followed by adding new Serbian terms to general lexica dictionaries, as well as adding bilingual terms. Dictionary development is relying on corpus analysis, details of which are also presented. Usage examples, collocations and concordances play an important role in raw material terminology, and have also been included in this research. Some important related issues discussed are collocation extraction methods, the use of domain labels, lexical and semantic relations, definitions and subentries.
Cellular Src (c-Src) integrates a large number of signal transduction pathways regulating cell division, migration, and other aspects of cell physiology. Mutations of Src kinase have not been ...described in human prostate cancer, but evidence for increased levels of expression accompanying cancer progression has been reported. We analyzed overexpression of c-Src in naïve mouse prostate epithelium and observed no change in tubule formation frequency or histologic structure. However, when enhanced c-Src expression is coupled with enhanced expression of androgen receptor (AR), it results in a strong activation of Src kinase activity accompanied by activation of the MAPK pathway, and enhanced AR activity. Similar to the pathology induced by constitutively active c-Src(Y529F), the tubules progress to frank carcinoma with invasion and display markers of epithelial-to-mesenchymal transition. These combined results suggest that nonmutated Src kinase may play a more important role in the genesis and progression of prostate cancer than previously appreciated and that epigenetic changes that enhance the level of AR may select for enhanced expression of c-Src with accompanying activation and a strong drive to malignant progression.
Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We ...characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
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•EGFRvIII regulates hnRNPA1 splicing factor expression in glioblastoma•HnRNPA1 promotes splicing of the Myc interacting protein Max to generate Delta Max•Delta Max promotes Myc-dependent glycolysis and tumor growth in vivo•HnRNPA1 and glycolytic gene expression correlate with poor patient survival
Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that ...activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.
The aim of the study was to investigate the activity of slow-release non-protein nitrogen compound with the enzymatic activity (SENPN) and to compare it with the activity of slow-releasing ...non-protein nitrogen compound (SNPN) in beef cattle feeding. The following indicators were monitored: body weight (BW), average weight gain (AWG), feed conversion ratio (FCR), trunk weight at slaughter (TWS) and dressing percentage (DP). Beef cattle were divided into two groups of uniform body weights; control group (CG) and experimental group (EG). The feed ration of the CG contained SNPN, while the feed ration of the EG contained SENPN. During the trial, three weights were performed to measure BW. The trial consisted of two parts: (i) the first part of the trial refers to the period between the first and second weighing, in which the feed ration of the EG contained 4.81% less starch per kg of dry matter (DM) compared to the feed ration of the CG, and (ii) the second part of the trial was conducted in the period between the second and third weighing, in which the feed ration contained equal starch levels. After the third weighing, the beef cattle were transported to the slaughterhouse, where they were sacrificed, and subsequently the values of TWS and DP were measured. There were no statistically significant differences found for each of the measured parameters. In conclusion, the usage of SENPN positively affects the utilisation of nutrients in the mixture, e.g. feed ration.
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