Identification of the Relationship Between DNA Methylation of Circadian Rhythm Genes and Obesity.

In children, teenagers, and young adults, environmental factors and genetic modifications have contributed to the development of obesity. There is a close relationship between obesity and circadian rhythm. To understand the role of CLOCK and BMAL1 in obesity, we analyzed the methylation status of CLOCK and BMAL1 in obese and control subjects. In this paper, we analyzed the methylation status of the CLOCK and BMAL1 genes by using MS-HRM in a total of 55 obese and 54 control subjects. In our study, we demonstrated that the level of fasting glucose and the level of HDL-cholesterol were associated with CLOCK methylation in obesity. We also showed a significant association between BMAL1 gene methylation and waist and hip circumference in obese subjects. This is the first study that shows the methylation of BMAL1 is associated with the obese phenotype. However, we could not show a direct association between CLOCK methylation and the obese phenotype. In this paper, a novel epigenetic interaction between circadian clock genes and obesity was demonstrated.

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.

Customised targeted massively parallel sequencing enables more precise diagnosis of patients with epilepsy.

BACKGROUND: Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy. AIM: To show the importance of genes in the next-generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease. METHODS: This was a single-centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel. RESULTS: In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2). CONCLUSIONS: NGS-based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy.

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.

Genetic and epigenetic perspective of microbiota.

The gut microbiota has an extremely important role within the body and it is necessary for the regulation of the metabolism of the host and also for the development of metabolic diseases such as obesity. Here, we show several different factors leading to obesity such as epigenetic changes and how they result in differences to occur in the gut microbiota, along with gut dysbiosis which is caused by disturbances in the microbiota homeostasis. Several studies have been explained in this paper, providing evidence in how these findings can actually decrease the susceptibility of obesity, whether it be by changing an individual's diet pattern or observing the epigenetic changes which are taking place. KEY POINTS: • The microbiota depends on an individual's diet, lifestyle, environment, genetics and epigenetic profile. • Changes of the gut microbiota can increase obesity susceptibility. • Non-coding RNA has an important role in the metabolic homeostasis in check so if a disturbance occurs it can lead to resistance to obesity.

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.

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.

The Use of Scaffolds in Cartilage Regeneration.

Scaffolds are important tools in tissue engineering and play a unique role in tissue regeneration and repair of damaged tissues. A variety of natural, synthetic, and composite scaffold types can be used in cartilage tissue engineering. The limited capability of cartilage to repair itself has always been a problem during recovery from damage. The success of cartilage regeneration is dependent on a couple of factors, but the basic properties of scaffolds are biocompatibility, degradability under physiological conditions, and structural support for cell attachment. In this review, we summarize the use of different scaffold types in cartilage regeneration.

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 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.

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.

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.

Hypoxia Is the Driving Force Behind GBM and Could Be a New Tool in GBM Treatment.

Glioblastoma (GBM) can be divided into two distinct disease entities according to the genetic and the epigenetic background of the tumor. Tumor location is associated with high variability in its genetic abnormalities. The treatment procedures for these tumors are often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcomes of these tumors have encouraged researchers to find new markers associated with prognosis and treatment planning. In the present communication, we discuss hypoxia as a new therapeutic target of glioblastoma multiforme and the molecular and phenotypic effects of hypoxia on cancer cells. We focus on the inhibition of the signaling pathways, which is associated with the hypoxia-mediated maintenance of glioblastoma stem cells and the knockdown of the hypoxia-inducible factor 1-alpha (HIFlα). This discussion may contribute to the development of new specifically targeted treatments. Furthermore, we highlight the idea that hypoxia-inducible factors (HIFs) could be attractive molecular targets for GBM therapeutics.

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.

A New Perspective of COVID-19 Infection: An Epigenetics Point of View.

Coronavirus disease 2019 (COVID-2019) started in Wuhan, China, in December 2019. Angiotensin-converting enzyme 2 (ACE2) receptor was one of the most important genes related to the entrance of the virus to the host. Until now, several variations have been identified in ACE2 and related transmembrane protease serine 2. Epigenetic modifications not only play an important role during the maintenance of genome and cellular homoeostasis but also for the etiopathophysiology of the virus infection. Studies showed methylation of ACE2 was changed to depend on host and age of the host during the viral infection. In this study, we provided an epigenetics point of view to the coronavirus infection. We highlight the importance of epigenetic modifications during viral replication and infection and their interaction with COVID-19 susceptibility and host viral response.

Epigenetic Approach to PTSD: In the Aspects of Rat Models.

Posttraumatic stress disorder (PTSD) is a stress-related mental disorder and develops after exposure to life-threatening traumatic experiences. The risk factors of PTSD included genetic factors; alterations in hypothalamic-pituitary-adrenal (HPA) axis; neurotrophic, serotonergic, dopaminergic, and catecholaminergic systems; and a variety of environmental factors, such as war, accident, natural disaster, pandemic, physical, or sexual abuse, that cause stress or trauma in individuals. To be able to understand the molecular background of PTSD, rodent animal models are widely used by researchers. When looking for a solution for PTSD, it is important to consider preexisting genetic risk factors and physiological, molecular, and biochemical processes caused by trauma that may cause susceptibility to this disorder. In studies, it is reported that epigenetic mechanisms play important roles in the biological response affected by environmental factors, as well as the task of programming cell identity. In this article, we provided an overview of the role of epigenetic modifications in understanding the biology of PTSD. We also summarized the data from animal studies and their importance during the investigation of PTSD. This study shed light on the epigenetic background of stress and PTSD.

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.

Investigation of Genetic Alterations in Congenital Heart Diseases in Prenatal Period.

The prenatal diagnosis of congenital heart disease (CHD) is important because of mortality risk. The onset of CHD varies, and depending on the malformation type, the risk of aneuploidy is changed. To identify possible genetic alterations in CHD, G-banding, chromosomal microarray or if needed DNA mutation analysis and direct sequence analysis should be planned. In present study, to identify genetic alterations, cell culture, karyotype analysis, and single nucleotide polymorphism, array analyses were conducted on a total 950 samples. Interventional prenatal genetic examination was performed on 23 (2, 4%, 23/950) fetal CHD cases. Chromosomal abnormalities were detected in 5 out of 23 cases (21, 7%). Detected chromosomal abnormalities were 10q23.2 deletion, trisomy 18, 8p22.3-p23.2 deletion, 8q21.3-q24.3 duplication, 11q24.2q24.5 (9 Mb) deletion, and 8p22p12 (16.8 Mb) deletion. Our study highlights the importance of genetic testing in CHD.

Genetic and Epigenetic Alterations in Autism Spectrum Disorder.

It is extremely important to understand the causes of autism spectrum disorder (ASD) which is a neurodevelopmental disease. Treatment and lifelong support of autism are also important to improve the patient's life quality. In this article, several findings were explained to understand the possible causes of ASD. We draw, outline, and describe ASD and its relation with the epigenetic mechanisms. Here, we discuss, several different factors leading to ASD such as environmental, epigenetic, and genetic factors.