Repurposing metformin as a potential anticancer agent using in silico technique.

BACKGROUND: The focus on repurposing readily available, well-known drugs for new, creative uses has grown recently. One such medication is metformin, a drug commonly used to manage diabetes, which shows a favorable correlation between its use and lower cancer morbidity and death. Numerous investigations and clinical trials have been conducted to evaluate the possible application of metformin as an anticancer medication in light of this conclusion. OBJECTIVE: This study used 'pathway/gene-set analysis' Gene2drug, a resource for Gene Ontology (GO), and DepMap to determine whether metformin would be potentially advantageous for treating cancer. METHODS: A total of 1826 tumor cell lines were analyzed using the Drug Sensitivity (Primary Purposing Primary Screening) 19Q4 Tool. RESULTS: 9 genes from 402 genes, SGPL1, CXCR6, ATXN2L, LAMP3, RTN3, BTN2A1, FOXM1, NQO1, and L1TD1 in 1826 cancer cell line showed statistical sensitivity to metformin. CONCLUSION: This in-silico study showed the sensitivity of specific cancer cell lines to metformin. Therefore, holding promises for metformin and tumor-targeted treatment strategies. It is recommended, however, to conduct further research into its potential effectiveness and mechanism of action.

Cancer Stem Cells and Their Therapeutic Usage.

Cancer stem cells (CSC) have unique characteristics which include self-renewal, multi-directional differentiation capacity, quiescence/dormancy, and tumor-forming capability. These characteristics are referred to as the "stemness" properties. Tumor microenvironment contributes to CSC survival, function, and remaining them in an undifferentiated state. CSCs can form malignant tumors with heterogeneous phenotypes mediated by the tumor microenvironment. Therefore, the crosstalk between CSCs and tumor microenvironment can modulate tumor heterogeneity. CSCs play a crucial role in several biological processes, epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. In this chapter, we focused characteristics of cancer stem cells, reprogramming strategies cells into CSCs, and then we highlighted the contribution of CSCs to therapy resistance and cancer relapse and their potential of therapeutic targeting of CSCs.

Epigenetic Alteration in Colorectal Cancer: A Biomarker for Diagnostic and Therapeutic Application.

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. A crucial process that initiates and progresses CRC is various epigenetic and genetic changes occurring in colon epithelial cells. Recently, huge progress has been made to understand cancer epigenetics, especially regarding DNA methylation changes, histone modifications, dysregulation of miRNAs and noncoding RNAs. In the "epigenome" of colon cancer, abnormal methylation of genes that cause gene alterations or expression of miRNA has been reported in nearly all CRC; these findings can be encountered in the average CRC methylome. Epigenetic changes, known as driving events, are assumed to play a dominant part in CRC. Furthermore, as epigenetic changes in CRC become properly understood, these changes are being established as clinical biomarkers for therapeutic and diagnostic purposes. Progression in this area indicates that epigenetic changes will often be utilized in the future to prevent and treat CRC.

Targeted massively parallel sequencing in the management of cytogenetically normal lymphoid malignancies.

The variations in clinical and biological background of lymphoid malignancies trigger researchers to try to find out novel therapeutic targets. A typical treatment includes multiagent chemotherapy and/or targeted therapy in the light of driver mutations. Next generation sequencing (NGS) plays a pivotal role during the identification of genetic alterations in lymphoid malignancies. A total of 52 patients [30 men (58%) and 22 women (42%)] having normal cytogenetic and FISH results were enrolled in this study. Usage of NGS based targeted sequencing could confirm or support a particularly preferred diagnosis (41/52, 78%) or make a differential diagnosis in cases of interference. Notably, in 11 out of these 52 cases (21%), the initial suspect diagnosis was not supported by the NGS result and thereby had to be reconsidered. In this study, we highlight the importance of targeted NGS panel testing for diagnosis, prognosis and treatment decision in highly selected instances of lymphoid malignancies and lymphoproliferative disorders in which histopathology and more conventional molecular analyses remain inconclusive.

3-Hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-6H-benzo[c]chromen-6-one act as on-off selective fluorescent sensors for Iron (III) under in vitro and ex vivo conditions.

Regarding the abundant use of metals for different purposes, it becomes more critical from various scientific and technological perspectives to discover novel agents as selective probes for the detection of specific metals. In our previous studies, we have shown that aqueous solutions of natural urolithins (i.e., hydroxyl-substituted benzo[c]chromen-6-one derivatives) are selective Iron (III) sensors in fluorescence assays. In this study, we have extrapolated these findings to another coumarine compound (i.e., 3-Hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one) and compared the selective metal binding properties with Urolithin B (i.e., 3-Hydroxy-6H-benzo[c]chromen-6-one). Following the synthesis and structure identification studies, the fluorometric studies pointed out that the lactam group in the structure still persists to be the important scaffold for maintaining selective on-off sensor capacity that renders the compound a selective Iron (III) binding probe. Moreover, for the first time, fluorescence cellular imaging studies concomitant to cytotoxicity assays with the title compounds were also performed and the results displayed the cell-penetrative, safe, and fluorescent detectable characteristics of the compounds in neuroblastoma and glioblastoma cells through servings as intracellular Iron (III) on-off sensors.

The Importance of Targeted Next-Generation Sequencing Usage in Cytogenetically Normal Myeloid Malignancies.

Advanced diagnostic methods give an advantage for the identification of abnormalities in myeloid malignancies. Various researchers have shown the potential importance of genetic tests before the disease's onset and in remission. Large testing panels prevent false-negative results in myeloid malignancies. However, the critical question is how the results of conventional cytogenetic and molecular cytogenetic techniques can be merged with NGS technologies. In this paper, we drew an algorithm for the evaluation of myeloid malignancies. To evaluate genetic abnormalities, we performed cytogenetics, molecular cytogenetics, and NGS testing in myeloid malignancies. In this study, we analyzed 100 patients admitted to the Medical Genetics Laboratory with different myeloid malignancies. We highlighted the possible diagnostic algorithm for cytogenetically normal cases. We applied NGS 141 gene panel for cytogenetically normal patients, and we detected two or more pathogenic variations in 61 out of 100 patients (61%). NGS's pathogenic variation detection rate varies in disease groups: they were present in 85% of A.M.L. and 23% of M.D.S. Here, we identified 24 novel variations out of total pathogenic variations in myeloid malignancies. A total of 18 novel variations were identified in A.M.L., and 6 novel variations were identified in M.D.S. Despite long turnaround times, conventional techniques are still a golden standard for myeloid malignancies but sometimes cryptic gene fusions or complex abnormalities cannot be easily identified by conventional techniques. In these conditions, advanced technologies like NGS are highly recommended.

A Pilot Study of Identification Genetic Background of Craniosynostosis Cases.

ABSTRACT: The early fusion of the cranial sutures was described as a craniosynostosis. The early diagnosis and management of craniosynostosis is very important. Environmental factors and genetic abnormalities plays a key role during the development of craniosynostosis. Syndromic craniosynostosis cases are related with autosomal dominant disorders but nearly half of the affected cases carry a new mutation. In this study, in order to identify the genetic etiology of craniosynostosis the authors analyzed 20 craniosynostosis patients by using conventional karyotype, aCGH, sanger sequencing, next generation sequencing (NGS) and Multiplex ligation-dependent probe amplification (MLPA) techniques. The authors identified mutations on FGFR2 and FGFR3 genes which were associated with Muenke syndrome, Crouzon syndrome and skeletal dysplasia syndromes. NGS applied all of the cases and 7 clinical variations in 5 different gene were detected in %20 of cases. In addition to these abnormalities; del(11)(q14.1q22.2), del(17)(q21.31), dup(22)(q13.31) and t(2;16)(q37;p13) have been identified in our cohort which are not previously detected in craniosynostosis cases. Our study demonstrates the importance of detailed genetic analysis for the diagnosis, progression and management of the craniosynostosis.

Cancer Treatment: An Epigenetic View.

Cancer can be identified as an uncontrolled growth and reproduction of cell. Accumulation of genetic aberrations (mutations of oncogenes and tumor-suppressor genes and epigenetic modifications) is one of the characteristics of cancer cell. Increasing number of studies highlighted importance of the epigenetic alterations in cancer treatment and prognosis. Now, cancer epigenetics have a huge importance for developing novel biomarkers and therapeutic target for cancer. In this review, we will provide a summary of the major epigenetic changes involved in cancer and preclinical results of epigenetic therapeutics.

RANK/RANKL/OPG pathway is an important for the epigenetic regulation of obesity.

Obesity is a complex disorder that is influenced by genetic and environmental factors. DNA methylation is an epigenetic mechanism that is involved in development of obesity and its metabolic complications. The aim of this study was to investigate the association between the RANKL and c-Fos gene methylation on obesity with body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), plasma leptin, adiponectin and resistin levels. The study included 68 obese and 46 non-obese subjects. Anthropometric parameters, including body weight, body mass index, waist circumference, and waist-hip ratio, were assessed. Serum glucose, triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), plasma leptin, adiponectin and resistin levels were measured. Methylation status of RANKL and c-Fos gen were evaluated by MS-HRM. Statistically significant differences were observed between obese patients and the controls with respect to RANKL and c-Fos gene methylation status (p < 0.001). Also, statistically significant importance was observed RANKL gene methylation and increased level of leptin in obese subjects (p = 0.0081). At the same time, statistically significant association between methylation of c-Fos and increased level of adiponectin was observed in obese patients (p = 0.03) On the other hand, decreased level of resistin was observed where the c-Fos was unmetyladed in controls (p = 0.01). We conclude that methylation of RANKL and c-Fos genes have significant influences on obesity and adipokine levels. Based on literature this was the first study which shows the interactions between RANKL and c-Fos methylation and obesity.

Importance of m N6-methyladenosine (m6A) RNA modification in cancer.

RNA methylation, which was identified back in 1970s, has gained remarkable interest in recent years as it was shown to be a reversible modification involved in many cellular processes like mRNA and miRNA processing, mRNA localisation, translation suppression, or activation. These, in turn, affect important bioprocesses such as tissue development, sex determination, and DNA damage response. Important group of proteins are responsible for adding, recognizing, and removing the methyl group to and from the RNA molecules, which are referred as writers, readers, and erasers, respectively. If any of the processes is not strictly controlled, this can cause abnormalities in gene expression, which result in diseases including cancers such as lung, pancreas, glioblastoma, and breast cancer. Mechanisms of RNA methylation and its role in various cancer types and diagnostic methods for RNA methylation are discussed in this article.

Receptor tyrosine kinase-Ras-PI 3 kinase-Akt signaling network in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most malignant form of the brain tumors and shows different genetic and epigenetic abnormalities. Gene amplification, genetic instability, disruption of apoptotic pathways, deregulated oncogene expression, invasive phenotypical changes, abnormal angiogenesis, and epigenetic changes have all been described in GBMs. These abnormalities indicate that a number of different signaling pathways are deregulated in GBM. Increasing number of studies provide a better understanding of the tumor biology, genetic, and epigenetic background of the GBM. Also, current research provides us useful approaches in designing novel therapies for GBM. In this review, we summarize the receptor tyrosine kinase-Ras-PI 3 kinase-Akt signaling network, focusing on the potential molecular targets for anti-signaling molecular therapies in this pathway.

The Interactions between Bone Remodelling, Estrogen Hormone and EPH Family Genes.

Osteoporosis is a major health issue, especially in older women. The absence of estrogen is the main cause of menopausal osteoporosis. Estrogen and androgen hormones play major roles during the growth and development of the skeletal system, including preservation of bone structure. Estrogen plays an important role in the balance between the bone formation of osteoblasts and osteoclasts, which are associated with bone resorption. Several pathways have been shown to regulate bone formation and degradation. Estrogen and Ephrin-Eph pathways are among the most important molecular mechanisms that regulate bone reconstruction. Many different genes are involved in these pathways, and in some cases, these pathways may work together for the bone reconstruction and resorption. In this review, we evaluate the relationship between estrogen, RANKL, and EphirinB2, and we highlight the direct relation between osteoporosis and estrogen hormone. The identification of direct or indirect pathways of bone formation and degradation in pre- and postmenopausal women could be an important tool for the development of therapeutic strategies in postmenopausal women.

Role of Mesenchymal Stem Cells in Cancer Development and Their Use in Cancer Therapy.

Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal stem cells (MSCs) play an important role in tissue homeostasis - supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great therapeutic potential in cancer therapy, as well as stem cell exosome and/or microvesicle-mediated tissue regeneration. In this review, the use of hMSCs in stem cell-mediated cancer therapy is discussed.

The Impacts of miRNAs in Glioblastoma Progression.

miRNAs are short noncoding RNA sequences that cause translational repression or mRNA degradation. A growing number of studies have sought new biomarkers in GBM that will be important in disease progression and prognosis and as potential therapeutic targets. miRNA-profiling studies in glioblastoma patients have found that aberrant miRNA expression can be used as a target to develop new biomarkers for disease detection and for determining prognosis or therapeutic response. In evaluating the tumor or its therapeutic response, genetic abnormalities such as mutations, epigenetic abnormalities, and aberrant miRNA expressions can be useful markers. This review summarizes the known miRNAs according their therapeutic importance and their use as disease progression biomarkers.

RARß gene methylation is a candidate for primary glioblastoma treatment planning.

BACKGROUND: We screened RARß methylation in primary glioblastoma multiforme (GBM) and the results were evaluated based on the clinical data and treatment type. OBJECTIVE: The objective of this study was to find new areas for the usage of MS-HRM applications in the determination of methylation levels in primary GBM samples and it shows the association of RARß methylation with the clinical outcome. METHODS: In our study, tumor samples were collected during surgical resection by the Department of Neurosurgery. The clinical and radiologic data was carefully reviewed, compared, and evaluated with the histological results. The methylation status of RARß was determined by using MS-HRM. RESULTS: RARß gene methylation was detected in 24 out of 40 cases (60%), with different quantitative methylation levels. The mean survival time was 19 months form ethylated cases and 15 months for the non-methylated cases. The survival time of the patients who received treatment was 25 months and the survival time of the patients who received radiotherapy alone or where no treatment protocol applied was 15-20 months. Therefore, a significant difference in survival rates has been observed (P<0.05). This study indicates a potential prognostic value for GBM treatment planning. CONCLUSION: Our study is the first study to investigate RARß methylation in primary GBMs. We conclude that the RARß gene could be a new prognostic and predictive candidate marker to designate the treatment protocol for primary GBMs.

The Importance of Mutational Drivers in GBM.

Glioblastoma (GBM) is the most aggressive primary brain tumor, providing few effective therapeutic options, given the tumor heterogeneity and the accumulation of different genetic abnormalities that cause treatment failure. The many different genetic and epigenetic alterations present in GBM lead to modification of several major signaling pathways resulting in brain tumor growth, progression, and therapeutic resistance. Many functionally important mutations have been discovered, known as neutral passengers. IDH1/2, EZH2, and DNMT3A are the best known epigenetic modifiers in cancer. These mutations are important in determining disease prognosis such that the status of the MGMT gene is a direct target of chemotherapy. For these reasons, newly developed technologies are necessary to determine new candidate targets for targeted-therapy development in GBM. The determination of mutations will aid in this and in the discovery of combinations of targeted and conventional therapies to improve GBM treatment.

Human Mesenchymal Stem Cells in Cancer Therapy.

Human mesenchymal stem cells (hMSCs) have the ability to differentiate into several tissue types. Their use in cancer therapeutics or as therapeutic delivery vehicles has significant potential, particularly in their exosome/microvesicle-mediated tissue regeneration abilities. In this review, the potential use of hMSCs in cancer therapy is discussed.

Double faced role of human mesenchymal stem cells and their role challenges in cancer therapy.

Human mesenchymal stem cells (hMSCs) are multipotent non-hematopoietic precursor cells with the ability to differentiate into several tissue types. The use of hMSCs has gained significant importance in cancer therapies as well as a large number of degenerative disease therapies due to their homing abilities. However, these cells may undergo spontaneous transformation leading to them bypassing naturally built-in cell controls that could lead to senescence and carcinogenesis. Therefore, although MSCs have great potential for cancer therapy, they also risk the development of cancer, which provides them with double-faced characteristics for both cancer development and therapy. The potential use of hMSCs in therapeutics from the aspect of in vitro expansion of hMSCs and telomere dynamic is discussed.

Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma.

Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics.

Glioblastoma Multiforme: The Genetic Perspective of the Treatment Planning.

Glioblastoma multiforme (GBM) is divided into two distinct disease entities called primary and secondary GBM. The genetic and the epigenetic background of these tumors are highly variable. These tumors are not successfully treated because of their cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcomes of these tumors promote researchers to find new markers associated with prognosis and treatment planning. A better understanding of stem-like cells and the genetic and the epigenetic background of GBM are necessary for designing new effective treatments and developing novel molecular strategies to target tumor cells and glioblastoma stem cells. In this review, we discuss the new therapeutic targets. Focusing on inhibiting the signaling pathways, which are associated with hypoxia-mediated maintenance of glioblastoma stem cells or the knockdown of the hypoxia-inducible factor 1-alpha (HIF1α), may help to the develop new target-specific treatments.