A Novel Epigenetic Strategy to Concurrently Block Immune Checkpoints PD-1/PD-L1 and CD155/TIGIT in Hepatocellular Carcinoma.

Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.

In Silico and In Vitro Mapping of Receptor-Type Protein Tyrosine Phosphatase Receptor Type D in Health and Disease: Implications for Asprosin Signalling in Endometrial Cancer and Neuroblastoma.

BACKGROUND: Protein Tyrosine Phosphatase Receptor Type D (PTPRD) is involved in the regulation of cell growth, differentiation, and oncogenic transformation, as well as in brain development. PTPRD also mediates the effects of asprosin, which is a glucogenic hormone/adipokine derived following the cleavage of the C-terminal of fibrillin 1. Since the asprosin circulating levels are elevated in certain cancers, research is now focused on the potential role of this adipokine and its receptors in cancer. As such, in this study, we investigated the expression of PTPRD in endometrial cancer (EC) and the placenta, as well as in glioblastoma (GBM). METHODS: An array of in silico tools, in vitro models, tissue microarrays (TMAs), and liquid biopsies were employed to determine the gene and protein expression of PTPRD in healthy tissues/organs and in patients with EC and GBM. RESULTS: PTPRD exhibits high expression in the occipital lobe, parietal lobe, globus pallidus, ventral thalamus, and white matter, whereas in the human placenta, it is primarily localised around the tertiary villi. PTPRD is significantly upregulated at the mRNA and protein levels in patients with EC and GBM compared to healthy controls. In patients with EC, PTPRD is significantly downregulated with obesity, whilst it is also expressed in the peripheral leukocytes. The EC TMAs revealed abundant PTPRD expression in both low- and high-grade tumours. Asprosin treatment upregulated the expression of PTPRD only in syncytialised placental cells. CONCLUSIONS: Our data indicate that PTPRD may have potential as a biomarker for malignancies such as EC and GBM, further implicating asprosin as a potential metabolic regulator in these cancers. Future studies are needed to explore the potential molecular mechanisms/signalling pathways that link PTPRD and asprosin in cancer.

Analysis of SIGLEC12 expression, immunomodulation and prognostic value in renal cancer using multiomic databases.

Siglecs belong to a family of immune regulatory receptors predominantly found on hematopoietic cells. They interact with Sia, resulting in the activation or inhibition of the immune response. Previous reports have suggested that the SIGLEC12 gene, which encodes the Siglec-XII protein, is expressed in the epithelial tissues and upregulated in carcinomas. However, studies deciphering the role of Siglec-XII in renal cancer (RC) are still unavailable, and here we provide insights on this question. We conducted expression analysis using the Human Protein Atlas and UALCAN databases. The impact of SIGLEC12 on RC prognosis was determined using the KM plotter, and an assessment of immune infiltration with SIGLEC12 was performed using the TIMER database. GSEA was conducted to identify the pathways affected by SIGLEC12. Finally, using GeneMania, we identified Siglec-XII interacting proteins. Our findings indicated that macrophages express SIGLEC12 in the kidney. Furthermore, we hypothesize that Siglec-XII expression might be involved in the increase of primary RC, but this effect may not be dependent on the age of the patient. In the tumour microenvironment, oncogenic pathways appeared to be upregulated by SIGLEC12. Similarly, our analysis suggested that SIGLEC12-related kidney renal papillary cell carcinomas may be more suitable for targeted immunotherapy, such as CTLA-4 and PD-1/PD-L1 inhibitors. These preliminary results suggested that high expression of SIGLEC12 is associated with poor prognosis for RC. Future studies to assess its clinical utility are necessitated.

Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology.

The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.

A Snapshot of Photoresponsive Liposomes in Cancer Chemotherapy and Immunotherapy: Opportunities and Challenges.

To provide precise medical regimens, photonics technologies have been involved in the field of nanomedicine. Phototriggered liposomes have been cast as promising nanosystems that achieve controlled release of payloads in several pathological conditions such as cancer, autoimmune, and infectious diseases. In contrast to the conventional liposomes, this photoresponsive element greatly improves therapeutic efficacy and reduces the adverse effects of gene/drug therapy during treatment. Recently, cancer immunotherpay has been one of the hot topics in the field of oncology due to the great success and therapeutic benefits that were well-recognized by the patients. However, several side effects have been encountered due to the unmonitored augmentation of the immune system. This Review highlights the most recent advancements in the development of photoresponsive liposome nanosystems in the field of oncology, with a specific emphasis on challenges and opportunities in the field of cancer immunotherapy.

Post-Operative Thoracic Epidural Analgesia and Incidence of Major Complications according to Specific Safety Standardized Documentation: A Large Retrospective Dual Center Experience.

(1) Background: Thoracic epidural analgesia is considered the gold standard in post-operative pain management following thoracic surgery. This study was designed to explore the safety of thoracic epidural analgesia and to quantify the incidence of its post-operative complications and side effects in patients undergoing thoracotomy for major surgery, such as resection of lung malignancies and lung transplantation. (2) Methods: This is a retrospective, dual-center observational study including patients that underwent major thoracic surgery including lung transplantation and received concurrent placement of thoracic epidural catheters for post-operative analgesia. An electronic system of referral and documentation of complications was used, and information was retrieved from our electronic critical care charting system. (3) Results: In total, 1145 patients were included in the study. None of the patients suffered any major complication, including hematoma, abscess, or permanent nerve damage. (4) Conclusions: the present study showed that in experienced centers, post-operative epidural analgesia in patients with thoracotomy is a safe technique, manifesting minimal, none-serious complications.

Novel Siglec-15-Sia axis inhibitor leads to colorectal cancer cell death by targeting miR-6715b-3p and oncogenes.

Siglecs are well known immunotherapeutic targets in cancer. Current checkpoint inhibitors have exhibited limited efficacy, prompting a need for novel therapeutics for targets such as Siglec-15. Presently, small molecule inhibitors targeting Siglec-15 are not explored alongside characterised regulatory mechanisms involving microRNAs in CRC progression. Therefore, a small molecule inhibitor to target Siglec-15 was elucidated in vitro and microRNA mediated inhibitor effects were investigated. Our research findings demonstrated that the SHG-8 molecule exerted significant cytotoxicity on cell viability, migration, and colony formation, with an IC50 value of approximately 20µM. SHG-8 exposure induced late apoptosis in vitro in SW480 CRC cells. Notably, miR-6715b-3p was the most upregulated miRNA in high-throughput sequencing, which was also validated via RT-qPCR. MiR-6715b-3p may regulate PTTG1IP, a potential oncogene which was validated via RT-qPCR and in silico analysis. Additionally, molecular docking studies revealed SHG-8 interactions with the Siglec-15 binding pocket with the binding affinity of -5.4 kcal/mol, highlighting its role as a small molecule inhibitor. Importantly, Siglec-15 and PD-L1 are expressed on mutually exclusive cancer cell populations, suggesting the potential for combination therapies with PD-L1 antagonists.

Box-Behnken design of thermo-responsive nano-liposomes loaded with a platinum(iv) anticancer complex: evaluation of cytotoxicity and apoptotic pathways in triple negative breast cancer cells.

Herein, thermo-responsive liposomes (TLs) loaded with Asp (Asp/TLs) were produced by self-assembling DPPC, DSPE-PEG2000, and cholesterol. The preparation variables were optimized using the Box-Behnken design (BBD). The optimized Asp/TLs exhibited an average particle size of 114.05 ± 1.56 nm, PDI of 0.15 ± 0.015, zeta potential of -15.24 ± 0.65 mV, and entrapment efficiency (EE%) of 84.08 ± 2.75%. In addition, under physiological conditions, Asp/TLs showed spherical shape, outstanding stability and thermo-triggered the release of Asp at 38 °C, reaching the maximum Asp release at 40 °C. The MTT assay showed that the optimal Asp/TLs exhibited the highest cytotoxic activity upon exposure to mild hyperthermia (40 °C) against the invasive triple-negative breast cancer cell line (MDA-MB-231) when compared to other preparations. The IC50 of Asp/TLs (40 °C) was estimated at 0.9 µg mL-1, while that of free Asp (40 °C) was 3.83 µg mL-1. As such, the optimal Asp/TLs were shown to increase the cytotoxic activity of Asp by 4-fold upon exposure to mild hyperthermia. The IC50 values of Asp and Asp/TLs without exposure to 40 °C were 6.6 µg mL-1 and 186 µg mL-1, respectively. This indicated that Asp was released only when placed at 40 °C. The apoptosis assay revealed that Asp/TLs (40 °C) caused a remarkable increase in the percentage of cell population among both the late apoptosis and necrosis quartiles, as well as a significant decline in the viable cell quartile (P ≤ 0.001) when compared to Asp (40 °C). Asp/TLs (40 °C) and Asp (40 °C) could stimulate the intrinsic apoptosis pathway by upregulating the apoptotic genes Bak and Bax, while downregulating the anti-apoptotic genes, BCL-xL and BCL-2. The free Asp (40 °C) increased the gene expression of Bak and Bax by 4.4- and 5.2-folds, while reducing the expression of BCL-xL and BCL-2 by 50% and 73%, respectively. The optimal Asp TLs (40 °C) manifested more potent effects as demonstrated by the upregulation of Bak, Bax, and P53 by 5.6-, 7.2-, and 1.3-folds, as well as the downregulation of BCL-xL and BCL-2 by 70% and 85%, respectively. As such, the optimal Asp TLs (40 °C) treatment displayed the most potent cytotoxic profile and induced both apoptosis and necrosis in MDA-MB-231.

Oral Delivery of Psoralidin by Mucoadhesive Surface-Modified Bilosomes Showed Boosted Apoptotic and Necrotic Effects against Breast and Lung Cancer Cells.

This study aims to design and optimize chitosan-coated bilosomal formulations loaded with psoralidin (Ps-CS/BLs) with improved physicochemical properties, oral bioavailability, and boosted apoptotic and necrotic effects. In this regard, uncoated bilosomes loaded with Ps (Ps/BLs) were nanoformulated using the thin-film hydration technique using different molar ratios of phosphatidylcholine (PC), cholesterol (Ch), Span 60 (S60), and sodium deoxycholate (SDC) (1:0.4:0.2:0.125, 1:0.4:0.2:0.25, and 1:0.4:0.2:0.5, respectively). The best-optimized formulation with respect to size, PDI, zeta potential, and EE% was selected and then coated with chitosan at two different concentrations (0.125 and 0.25 w/v%), forming Ps-CS/BLs. The optimized Ps/BLs and Ps-CS/BLs showed a spherical shape and relatively homogenous size with negligible apparent agglomerations. Additionally, it was demonstrated that coating Ps/BLs with chitosan has significantly increased the particle size from 123.16 ± 6.90 in the case of Ps/BLs to 183.90 ± 15.93 nm in the case of Ps-CS/BLs. In addition, Ps-CS/BLs exhibited higher zeta potential (+30.78 ± 1.44 mV) as compared to Ps/BLs (-18.59 ± 2.13 mV). Furthermore, Ps-CS/BL showed enhanced entrapment efficiency (EE%) of 92.15 ± 7.20% as compared to Ps/BLs (68.90 ± 5.95%). Moreover, Ps-CS/BLs exhibited a more sustained release behavior of Ps compared to Ps/BLs over 48 h, and both formulations were best obeying the Higuchi diffusion model. More importantly, Ps-CS/BLs displayed the highest mucoadhesive efficiency% (74.89 ± 3.5%) as compared to Ps/BLs (26.78 ± 2.9%), indicating the ability of the designed nanoformulation to improve oral bioavailability and extend the residence time inside the gastrointestinal tract upon oral administration. Moreover, upon evaluating the apoptotic and necrotic effects of free Ps and Ps-CS/BLs on human breast cancer cell lines (MCF-7) and human lung adenocarcinoma cell lines (A549), there was a dramatic increase in the percentages of the apoptotic and necrotic cell compared to the control and free Ps. Our findings suggest the possible oral use of Ps-CS/BLs in hampering breast and lung cancers.

Deciphering the Role of microRNA Mediated Regulation of Coronin 1C in Glioblastoma Development and Metastasis.

Glioblastoma multiforme (GBM) is a highly heterogenic and malignant brain tumour with a median survival of 15 months. The initial identification of primary glioblastomas is often challenging. Coronin 1C (CORO1C) is a key player in actin rearrangement and cofilin dynamics, as well as enhancing the processes of neurite overgrowth and migration of brain tumour cells. Different bioinformatic databases were accessed to measure CORO1C expression at the mRNA and protein level in normal and malignant brains. CORO1C expression was observed in brain regions which have retained high synaptic plasticity and myelination properties. CORO1C was also expressed mainly within the hippocampus formation, including the Cornu Ammonis (CA) fields: CA1-CA4. Higher expression was also noticed in paediatric GBM in comparison to their adult counterparts. Pediatric cell populations were observed to have an increased log2 expression of CORO1C. Furthermore, 62 miRNAs were found to target the CORO1C gene. Of these, hsa-miR-34a-5p, hsa-miR-512-3p, hsa-miR-136-5p, hsa-miR-206, hsa-miR-128-3p, and hsa-miR-21-5p have shown to act as tumour suppressors or oncomiRs in different neoplasms, including GBM. The elevated expression of CORO1C in high grade metastatic brain malignancies, including GBM, suggests that this protein could have a clinical utility as a biomarker linked to an unfavorable outcome.

Circular RNAs: New layer of complexity evading breast cancer heterogeneity.

Advances in high-throughput sequencing techniques and bioinformatic analysis have refuted the "junk" RNA hypothesis that was claimed against non-coding RNAs (ncRNAs). Circular RNAs (circRNAs); a class of single-stranded covalently closed loop RNA molecules have recently emerged as stable epigenetic regulators. Although the exact regulatory role of circRNAs is still to be clarified, it has been proven that circRNAs could exert their functions by interacting with other ncRNAs or proteins in their own physiologically authentic environment, regulating multiple cellular signaling pathways and other classes of ncRNAs. CircRNAs have also been reported to exhibit a tissue-specific expression and have been associated with the malignant transformation process of several hematological and solid malignancies. Along this line of reasoning, this review aims to highlight the importance of circRNAs in Breast Cancer (BC), which is ranked as the most prevalent malignancy among females. Notwithstanding the substantial efforts to develop a suitable anticancer therapeutic regimen against the heterogenous BC, inter- and intra-tumoral heterogeneity have resulted in an arduous challenge for drug development research, which in turn necessitates the investigation of other markers to be therapeutically targeted. Herein, the potential of circRNAs as possible diagnostic and prognostic biomarkers have been highlighted together with their possible application as novel therapeutic targets.

Molecular Engines, Therapeutic Targets, and Challenges in Pediatric Brain Tumors: A Special Emphasis on Hydrogen Sulfide and RNA-Based Nano-Delivery.

Pediatric primary brain tumors represent a real challenge in the oncology arena. Besides the psychosocial burden, brain tumors are considered one of the most difficult-to-treat malignancies due to their sophisticated cellular and molecular pathophysiology. Notwithstanding the advances in research and the substantial efforts to develop a suitable therapy, a full understanding of the molecular pathways involved in primary brain tumors is still demanded. On the other hand, the physiological nature of the blood-brain barrier (BBB) limits the efficiency of many available treatments, including molecular therapeutic approaches. Hydrogen Sulfide (H2S), as a member of the gasotransmitters family, and its synthesizing machinery have represented promising molecular targets for plentiful cancer types. However, its role in primary brain tumors, generally, and pediatric types, particularly, is barely investigated. In this review, the authors shed the light on the novel role of hydrogen sulfide (H2S) as a prominent player in pediatric brain tumor pathophysiology and its potential as a therapeutic avenue for brain tumors. In addition, the review also focuses on the challenges and opportunities of several molecular targeting approaches and proposes promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumor patients.

Chemokines and chemokine receptors in colorectal cancer; multifarious roles and clinical impact.

Colorectal cancer (CRC) is considered the second cause of cancer death worldwide. The early diagnosis plays a key role in patient prognosis and subsequently overall survival. Similar to several types of cancer, colorectal cancer is also characterised by drug resistance and heterogeneity that contribute to its complexity -especially at advanced stages. However, despite the extensive research related to the identification of biomarkers associated to early diagnosis, accurate prognosis and the management of CRC patients, little progress has been made thus far. Therefore, the mortality rates, especially at advanced stages, remain high. A large family of chemoattractant cytokines called chemokines are known for their significant role in inflammation and immunity. Chemokines released by the different tumorous cells play a key role in increasing the complexity of the tumour's microenvironment. The current review investigates the role of chemokines and chemokine receptors in colorectal cancer and their potential as clinical molecular signatures that could be effectively used as a personalised therapeutic approach. We discussed how chemokine and chemokine receptors regulate the microenvironment and lead to heterogeneity in CRC. An important aspect of chemokines is their role in drug resistance which has been extensively discussed. This review also provides an overview of the current advances in the search for chemokines and chemokine receptors in CRC.

MYCN in Neuroblastoma: "Old Wine into New Wineskins".

MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) has been one of the most studied genes in neuroblastoma. It is known for its oncogenetic mechanisms, as well as its role in the prognosis of the disease and it is considered one of the prominent targets for neuroblastoma therapy. In the present work, we attempted to review the literature, on the relation between MYCN and neuroblastoma from all possible mechanistic sites. We have searched the literature for the role of MYCN in neuroblastoma based on the following topics: the references of MYCN in the literature, the gene's anatomy, along with its transcripts, the protein's anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification. MYCN plays a significant role in neuroblastoma biology. Its functions and properties range from the forming of G-quadraplexes, to the interaction with miRNAs, as well as the regulation of gene methylation and histone acetylation and deacetylation. Although MYCN is one of the most primary genes studied in neuroblastoma, there is still a lot to be learned. Our knowledge on the exact mechanisms of MYCN amplification, etiology and potential interventions is still limited. The knowledge on the molecular mechanisms of MYCN in neuroblastoma, could have potential prognostic and therapeutic advantages.

Differential and Common Signatures of miRNA Expression and Methylation in Childhood Central Nervous System Malignancies: An Experimental and Computational Approach.

Epigenetic modifications are considered of utmost significance for tumor ontogenesis and progression. Especially, it has been found that miRNA expression, as well as DNA methylation plays a significant role in central nervous system tumors during childhood. A total of 49 resected brain tumors from children were used for further analysis. DNA methylation was identified with methylation-specific MLPA and, in particular, for the tumor suppressor genes CASP8, RASSF1, MGMT, MSH6, GATA5, ATM1, TP53, and CADM1. miRNAs were identified with microarray screening, as well as selected samples, were tested for their mRNA expression levels. CASP8, RASSF1 were the most frequently methylated genes in all tumor samples. Simultaneous methylation of genes manifested significant results with respect to tumor staging, tumor type, and the differentiation of tumor and control samples. There was no significant dependence observed with the methylation of one gene promoter, rather with the simultaneous presence of all detected methylated genes' promoters. miRNA expression was found to be correlated to gene methylation. Epigenetic regulation appears to be of major importance in tumor progression and pathophysiology, making it an imperative field of study.

Co-Deregulated miRNA Signatures in Childhood Central Nervous System Tumors: In Search for Common Tumor miRNA-Related Mechanics.

Despite extensive experimentation on pediatric tumors of the central nervous system (CNS), related to both prognosis, diagnosis and treatment, the understanding of pathogenesis and etiology of the disease remains scarce. MicroRNAs are known to be involved in CNS tumor oncogenesis. We hypothesized that CNS tumors possess commonly deregulated miRNAs across different CNS tumor types. AIM: The current study aims to reveal the co-deregulated miRNAs across different types of pediatric CNS tumors. MATERIALS: A total of 439 CNS tumor samples were collected from both in-house microarray experiments as well as data available in public databases. Diagnoses included medulloblastoma, astrocytoma, ependydoma, cortical dysplasia, glioblastoma, ATRT, germinoma, teratoma, yoc sac tumors, ocular tumors and retinoblastoma. RESULTS: We found miRNAs that were globally up- or down-regulated in the majority of the CNS tumor samples. MiR-376B and miR-372 were co-upregulated, whereas miR-149, miR-214, miR-574, miR-595 and miR-765 among others, were co-downregulated across all CNS tumors. Receiver-operator curve analysis showed that miR-149, miR-214, miR-574, miR-595 and miR765 could distinguish between CNS tumors and normal brain tissue. CONCLUSIONS: Our approach could prove significant in the search for global miRNA targets for tumor diagnosis and therapy. To the best of our knowledge, there are no previous reports concerning the present approach.

Systems Approaches in the Common Metabolomics in Acute Lymphoblastic Leukemia and Rhabdomyosarcoma Cells: A Computational Approach.

Acute lymphoblastic leukemia is the most common childhood malignancy. Rhabdomyosarcoma, on the other hand, is a rare type of malignancy which belongs to the primitive neuroectodermal family of tumors. The aim of the present study was to use computational methods in order to examine the similarities and differences of the two different tumors using two cell lines as a model, the T-cell acute lymphoblastic leukemia CCRF-CEM and rhabdomyosarcoma TE-671, and, in particular, similarities of the metabolic pathways utilized by two different cell types in vitro. Both cell lines were studied using microarray technology. Differential expression profile has revealed genes with similar expression, suggesting that there are common mechanisms between the two cell types, where some of these mechanisms are preserved from their ancestor embryonic cells. Expression of identified species was modeled using known functions, in order to find common patterns in metabolism-related mechanisms. Species expression manifested very interesting dynamics, and we were able to model the system with elliptical/helical functions. We discuss the results of our analysis in the context of the commonly occurring genes between the two cell lines and the respective participating pathways as far as extracellular signaling and cell cycle regulation/proliferation are concerned. In the present study, we have developed a methodology, which was able to unravel some of the underlying dynamics of the metabolism-related species of two different cell types. Such approaches could prove useful in understanding the mechanisms of tumor ontogenesis, progression, and proliferation.

Bioinformatics Analysis Reveals Ki-67 Specific microRNA Functions in Pediatric Embryonal Tumors.

Pediatric Central Nervous System (CNS) neoplasms are the second most prevalent tumors of childhood. CNS malignancies are considered as the most notorious type of tumors, due to their anatomic position manifesting an imminent threat to the patients' life. miRNAs are molecules that play a significant role in CNS tumor biology. At the same time diagnostic markers such as Ki-67 have played an important role in CNS tumor diagnosis. In a previous study we have identified several miRNAs, common to different subtypes of pediatric embryonal CNS malignancies as well as, we have identified miRNAs that manifest significant dynamics with respect to their expression and the neoplasmatic subtype. Among the previously reported miRNAs, several have manifested significant differences with respect to Ki-67 expression. Those miRNAs, were further analyzed bioinformatically and related functions were revealed, where some of them confirmed Ki-67 role as a proliferation marker but also predicted novel miRNAs functions in pediatric embryonal tumors.

Bioinformatics and Regression Analyses Manifest Tumor-Specific miRNA Expression Dynamics in Pediatric Embryonal Malignancies.

Pediatric Central Nervous System (CNS) neoplasms are the second most prevalent tumors of childhood. Further on, prognosis of this type of neoplasms still remain poor and the comprehension of the etiology and pathogenesis of the disease still remains scarce. Several reports have identified microRNAs as significant molecules in the development of central nervous system tumors and propose that they might compose key molecules underlying oncogenesis. In a previous study we have identified several miRNAs, common to different subtypes of pediatric embryonal CNS malignancies as well as, we have identified miRNAs that manifest significant dynamics with respect to their expression and the neoplasmatic subtype. Overall, 19 tumor cases from children diagnosed with embryonal brain tumors were investigated. As controls, children who suffered a sudden death underwent autopsy and were not present with any brain malignancy were used (13 samples of varying localization). Our experimental approach included microarrays covering 1211 miRNAs, which appeared to manifest tumor-specific dynamics. In conclusion, it appeared that certain miRNAs are neoplasm specific and in particular, their expression manifests linear dynamics. Thus, the investigation of miRNA expression in pediatric embryonal brain tumors might contribute towards the discovery of tumor-specific miRNA signatures, which could potentially afford the identification of gene-specific biomarkers related to diagnosis, prognosis and patient targeted therapy, as well as help us understand oncogenetic dynamics.