The epigenetics orchestra of Notch signaling: a symphony for cancer therapy.

The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.

PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.

First Report of Association Between Rare α-Thalassemia Mutation (HBA1: c.298A>T) and Hb Fontainebleau (HBA2: c.64G>C).

α-Thalassemia is one of the most common monogenic diseases worldwide. The combination of alpha-chain variants with thalassemia mutations may lead to clinical and hematological characteristics, which is of importance for genetic counseling. The present study describes for the first time a rare α1-globin nonsense mutation, codon 99 (HBA1: c.298A>T) associated with a α2-chain variant Hb Fontainebleau (HBA2: c.64G>C) in a family from northern Iran. The case is a 23-year-old man with hypochromic microcytic anemia that requested for prenatal diagnosis. The combination of α1-globin mutation and Hb Fontainebleau can cause clinical and hematologic features of thalassemia. This combination also highlights the important heterogeneity of alpha thalassemia in this part of the world.

Krüppel-Like Factor 1 Gene Mutations in Thalassemia Patients from North Iran: Report of a New Mutation Associated with ß-Thalassemia Intermedia.

Thalassemia is a hereditary disease with an autosomal recessive inheritance pattern resulting in reduced production of globin chains. Mutations in modifier genes can cause or affect thalassemia. Krüppel-like factor 1 (KLF1) is a modifier gene that was investigated in this study. Thirty-five Iranian ß-thalassemia (ß-thal) minor patients with hematological symptoms including Hb A2 3.0%, mean corpuscular volume (MCV) <75.0 fL, mean corpuscular hemoglobin (Hb) (MCH) <25.0 pg, and two ß-thal intermedia (ß-TI) patients in 50 subjects who carried no mutations on the HBB and HBA2 or HBA1 genes were investigated for all exons of the KLF1 gene by polymerase chain reaction (PCR) and sequencing methods. Of the 35 patients with a ß-thal minor phenotype, one patient was heterozygous for the c.544T>C mutation in exon 2 of KLF1 and HBB: c.380T>G variant, Hb Dhonburi [also known as Hb Neapolis or codon 126 (T>G)]. The c.340T>C mutation was also found in exon 2 of the KLF1 gene with an allele frequency of 16.6% in the studied ß-thal carriers. The two ß-TI patients were homozygous for a new mutation c.942delA in exon 3 of KLF1. Mutations in modifier genes can cause or affect thalassemia. Therefore, exact investigation of globin genes and modifiers such as KLF1 is necessary in areas where globin gene disorders are most prevalent to understand the reason of clinical and hematological symptoms of thalassemia and facilitate newborn screening or prenatal diagnosis (PND) programs.

Finding a very rare mutation in non-Caucasian LCAT patients from Southwest Asia for the first time.

INTRODUCTION: Lecithin cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder occurred by different mutations in the LCAT gene that cause two extremely rare syndromes including familial LCAT deficiency (FLD) and fish-eye disease (FED). Unlike FED in FLD renal failure is the most important defect due to deposition of abnormal lipoproteins in the renal stroma. In this study, FLD patients from the North of Iran were investigated for mutations in the LCAT gene. MATERIALS AND METHODS: Eight patients with corneal opacification and renal defect were analyzed for mutations in the LCAT gene by PCR sequencing. RESULTS: Sequencing analysis revealed a missense pathogenic variation c.301 G>A in exon 2 of LCAT gene in all patients changing the amino acid aspartate to asparagine at the conserved position of amino acid 101 of LCAT protein. CONCLUSION: In this study, a very rare variation was reported for the first time in this part of the world. Investigation of a larger number of LCAT patients in different parts of Iran can provide availability of mutations panel that is useful for phenotype prediction and also prenatal diagnosis programming in families with a previous history of the disease.

Genetic Identification of Orientobilharzia turkestanicum from Sheep Isolates in Iran.

BACKGROUND: Adult worms of Orientobilharzia turkestanicum live in the portal veins, or intestinal veins of cattle, sheep, goat and many other mammals causing orientobilharziasis. Orientobilharziasis causes significant economic losses to livestock industry of Iran. However, there is limited information about genotypes of O. turkestanicum in Iran. METHODS: In this study, 30 isolates of O. turkestanicum obtained from sheep were characterized by sequencing mitochondrial cytochrome c oxidase subunit 1 (cox1) and nicotinamide adenine dinucleotide dehydrogenase subunit 1 (nad1) gene. The mitochondrial cox1 and nad1 DNA were amplified by polymerase chain reaction (PCR) and then sequenced and compared with O. turkestanicum and that of other members of the Schistosomatidae available in Gen-Bank(™). RESULTS: Phylogenetic relationships between them were re-constructed using the maximum parsimony method. Phylogenetic analyses done in present study placed O. turkestanicum within the Schistosoma genus, and indicates that O. turkestanicum was phylogenetically closer to the African schistosome group than to the Asian schistosome group. CONCLUSION: Comparison of nad1 and cox1 sequences of O. turkestanicum obtained in this study with corresponding sequences available in Genbank(™) revealed some sequence variations and provided evidence for presence of microvarients in Iran.

Mutation and new polymorphisms insight in introns 11 to 14a of CFTR gene of northern Iranian cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). The type and distribution of mutations vary widely between different countries and ethnic groups. We therefore aimed to perform a comprehensive analysis of the CFTR gene in northern Iranian CF patients. METHODS: Forty northern Iranian CF patients were analyzed for mutations in introns 11 to 14a of their CFTR genes, using sequencing and reverse dot blot methods. Five normal subjects were also analyzed as normal control. RESULTS: One mutation and seven polymorphisms were identified. Of the eighty alleles studied, c.2043delG in exon 13 represented 12.5% of mutant alleles and was associated with two distinct haplotypes. rs1042077T>G, rs4148712delAT, rs4148711T>A and rs3808183 T>C with frequencies varying between 29.2% and 6.9% for the least common allele, as well as three new polymorphisms c.1680-224C>A (11.1%), c.2491-275T>G (14.1%) and c.2491-274C>G (35.9%) were detected. CONCLUSION: These findings suggest a founder effect for c.2043delG in the Middle East and will assist in genetic counseling, prenatal diagnosis and future screening of CF in Iran.

CFTR haplotypes in northern Iranian population.

BACKGROUND: Cystic fibrosis (CF) is a multiorganic autosomal recessive disorder, caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). CF is highly heterogeneous in Iranian population and molecular diagnosis based on direct identification of mutations is not completely efficient. The use of polymorphic intragenic markers not only can facilitate phenotype prediction in prenatal diagnosis by gene tracking, but also can lead to the demonstration of possible associations between haplotypes and specific mutations. METHODS: 60 CF patients and 53 fertile normal subjects originating from North of Iran were analyzed for F508del mutation and c.1210-12T(5_9), c.1408A>G and c.744-33GATT(6_8) polymorphisms. RESULTS: c.1210-12T[7] is the most prevalent allele in normal individuals and CF non-F508del patients with 87.7%and 86.7% frequencies respectively. c.1408A>G survey showed that frequency of allele G and A is nearly equal in both non-F508del CF patients and normal individuals. c.744-33GATT(6_8) study showed that 7 repeat is the most prevalent allele in normal individuals and non-F508del CF patients with 80.2% and 82.1% frequencies respectively. The [c.1408A; c.1210-12T[9]; c.744-33GATT[6]] haplotype was only associated with mutant alleles including F508del. CONCLUSIONS: The allelic distribution and heterozygosity results suggest that c.1408A>G, c.1210-12T(5_9) and c.744-33GATT(6_8) can contribute to carrier detection and prenatal diagnosis of CF in Iranian families with previous history of the disease.

Poly thymidine polymorphism and cystic fibrosis in a non-Caucasian population.

BACKGROUND: Cystic fibrosis is a monogenic recessive disorder found predominantly in Caucasian population. This disease arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In this study we consider poly T polymorphism c.1210-12T[5], c.1210-12T[7], c.1210-12T[9] (T{5}, T{7}, T{9}) in the intron 8 of CFTR gene in normal individuals and cystic fibrosis patients in the north of Iran. MATERIAL AND METHODS: 40 CF patients and 40 normal individuals were screened for poly T polymorphism in intron 8 of CFTR gene using Reverse Dot Blot method which was also used to detect p.Phe508del among CF patients. RESULTS: T{7} allele is the most prevalent in both normal and CF patients. Its abundance is approximately 75%. T{9} and T{5} represent approximately 20% and 5% of alleles respectively. T{7}/T{7} genotype is the most present in both normal and CF patients with 72.5% and 60% prevalence respectively. p.Phe508del was present in 13 CFTR alleles belonging to 7 patients with either homozygote T{9}/ T{9}, T{7}/ T{7} or compound heterozygote T{7}/ T{9} genotypes. CONCLUSION: Contrary to the Caucasians, T{7} allele is more frequent in Northern Iranian CF patients. The presence of p.Phe508del and T{7} allele in the same framework is reported for the first time in this part of the world. Further investigations of other populations will help to understand whether p.Phe508del arose by selection pressure in this part of the world or was imported from European countries. The abundance of T{5}, T{7}, T{9} alleles indicates that this polymorphism can be used as one of the informative markers for detection of normal and mutant alleles in prenatal diagnosis or carrier assessment in families with previous history of the disease in regions with high degree of CFTR mutation heterogeneity.