A Comprehensive Study of Disease-Causing Variants in PAH, QDPR, PTS, and PCD Genes in Iranian Patients with Hyperphenylalaninemia: A Systematic Review.

BACKGROUND: Hyperphenylalaninemia (HPA) is an autosomal recessive disorder that results from a deficiency in the phenylalanine hydroxylase enzyme (PAH) or from a flaw in the genes that are responsible for the biosynthesis or regeneration of the cofactor tetrahydrobiopterin (BH4), including GCH1, SR, QDPR, PTS, and PCD. Identification of disease-causing variants in these genes can help physicians and clinical geneticists in differential diagnosis, appropriate prescription drugs, and saving time and cost. This study attempted to identify these genes' most prevalent disease-causing variants in Iranian HPA patients. SUMMARY: This study was performed under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Before it started, the flow work and inclusion/exclusion criteria were published as a protocol in PROSPERO (CRD42021273705). We conducted a comprehensive search on December 10, 2022, on international online databases, including Web of Science, Scopus, EMBASE, Science Direct, PubMed/Medline, Google Scholar, SID, ISC, and Magiran search engine, to find pertinent publications. Some studies were chosen based on inclusion and exclusion criteria. Altogether, 1,243 Iranian patients from 13 articles were considered. In total, we identified 129 distinct disease-causing variants in PAH (20 novel variants), 29 in QDPR (17 novel variants), 15 in PTS (seven novel variants), and one novel variant in PCD. Twenty disease-causing variants for PAH, 18 for QDPR, and 8 for PTS are included in the genes' proposed genetic diagnostic panels. These panels include more than 75% of the documented disease-causing variants in the Iranian population. KEY MESSAGES: The findings of this research illustrated the spectrum of disease-causing variants in the PAH, QDPR, PTS, and PCD genes identified in Iranian HPA patients. Common disease-causing variants of these genes may be chosen as a preliminary diagnostic panel for early diagnosis and lowering therapy costs.

Association of Genotypes of ANGPTL3 with Vitamin D and Calcium Concentration in Cardiovascular Disease.

One of the leading causes of mortality worldwide is cardiovascular disease, which is influenced by some variables, including calcium and vitamin D. This study aimed to assess the relationship between Angiopoietin-Like 3 (ANGPTL3) gene polymorphisms with vitamin D and calcium levels in cardiovascular disease (CVD) patients. In this research, 1002 people participated. Participants' anthropometric parameters, and FBG, calcium, and vitamin D were assessed. Blood samples were used to extract DNA. Taqman®-based polymerase chain reaction (PCR) was used to conduct genetic analysis for the rs10789117 and rs17458195. Statistical analysis was applied to determine differences across subgroups and the relationship between polymorphisms and disease. Age, body mass index (BMI), fasting Blood Sugar (FBG), phenylalanine ammonia-lyase (PAL), and smoking history were significantly correlated with CVD. Vitamin D was statistically associated with rs10789117 and rs17458195 in non-CVD individuals. In the moderate group, individuals with the C allele in rs10789117 showed a tenfold increase in vitamin D deficiency compared to those with the A allele. However, in rs11207997, individuals with the T allele had 5 to 6 times higher vitamin D deficiency than those with the C allele in all groups. This research demonstrates the relationship between some ANGPTL3 gene polymorphisms and complement levels in CVD patients. It may be concluded that individuals carrying these variants would likely benefit from using vitamin D and calcium supplements to avoid CVD.

MicroRNAs as the critical regulators of epithelial mesenchymal transition in pancreatic tumor cells.

Pancreatic cancer (PC), as one of the main endocrine and digestive systems malignancies has the highest cancer related mortality in the world. Lack of the evident clinical symptoms and appropriate diagnostic markers in the early stages of tumor progression are the main reasons of the high mortality rate among PC patients. Therefore, it is necessary to investigate the molecular pathways involved in the PC progression, in order to introduce novel early diagnostic methods. Epithelial mesenchymal transition (EMT) is a critical cellular process associated with pancreatic tumor cells invasion and distant metastasis. MicroRNAs (miRNAs) are also important regulators of EMT process. In the present review, we discussed the role of miRNAs in regulation of EMT process during PC progression. It has been reported that the miRNAs mainly regulate the EMT process in pancreatic tumor cells through the regulation of EMT-specific transcription factors and several signaling pathways such as WNT, NOTCH, TGF-ß, JAK/STAT, and PI3K/AKT. Considering the high stability of miRNAs in body fluids and their role in regulation of EMT process, they can be introduced as the non-invasive diagnostic markers in the early stages of malignant pancreatic tumors. This review paves the way to introduce a non-invasive EMT based panel marker for the early tumor detection among PC patients.

An Update on the Application of CRISPR Technology in Clinical Practice.

The CRISPR/Cas system, an innovative gene-editing tool, is emerging as a promising technique for genome modifications. This straightforward technique was created based on the prokaryotic adaptive immune defense mechanism and employed in the studies on human diseases that proved enormous therapeutic potential. A genetically unique patient mutation in the process of gene therapy can be corrected by the CRISPR method to treat diseases that traditional methods were unable to cure. However, introduction of CRISPR/Cas9 into the clinic will be challenging because we still need to improve the technology's effectiveness, precision, and applications. In this review, we first describe the function and applications of the CRISPR-Cas9 system. We next delineate how this technology could be utilized for gene therapy of various human disorders, including cancer and infectious diseases and highlight the promising examples in the field. Finally, we document current challenges and the potential solutions to overcome these obstacles for the effective use of CRISPR-Cas9 in clinical practice.

Genetic evaluation of hyperphenylalaninemia patients with tetrahydrobiopterin deficiency in Iranian population: Identification of four novel disease-causing variants.

BACKGROUND: Hyperphenylalaninemia (HPA) is the most common inborn error of amino acid metabolism worldwide. At least 2% of HPA cases are caused by a deficiency in tetrahydrobiopterin (BH4) metabolism. Genes such as QDPR and PTS are essential in the BH4 metabolism. This study aims to identify disease-causing variants in HPA patients, which may be helpful in genetic counseling and prenatal diagnosis. METHODS: A total of 10 HPA patients were enrolled in this study. The coding and adjacent intronic regions of PTS and QDPR genes were examined using Sanger sequencing. Protein modeling was also performed for novel identified variants. RESULTS: Ten patients and a total of 20 alleles were studied, which led to the identification of 10 different variants. All variants identified in PTS and QDPR were missense, except for the c.383_407del variant in the QDPR. Also, three novel variants were identified in the QDPR, including c.79G>T, c.383_407del and c.488G>A, and a novel variant, c.65C>G, in the PTS. CONCLUSIONS: Despite the genetic similarities in the disease-causing variants, differences were observed in the Asian and European populations with our populations; As a result, similar but more extensive studies are needed to investigate the distribution of disease-causing variants in genes involved in non-PKU hyperphenylalaninemia.

Inconsistency in the expression pattern of a five-lncRNA signature as a potential diagnostic biomarker for gastric cancer patients in bioinformatics and in vitro.

Objectives: Due to diagnosis of gastric cancer in advanced stages as well as its poor prognosis, finding biomarkers is essential. In this study, using the TCGA RNAseq data of gastric cancer patients, we evaluated the diagnostic value of lncRNAs that had differential expression. Materials and Methods: We evaluated P-value, FDR, and log fold change for whole transcripts. Next, by comparison of the RNAseq gene names with the total known lncRNA names, we identified differential expressed lncRNAs. Following this, specificity and sensitivity for lncRNAs coming from the previous step were calculated. For more confirmation, we predicted target genes and performed GO and KEGG signaling pathway analysis. In the end, we examined reliability and consistency of expression of this signature in three gastric cancer cell lines and one of them in twenty tumors and tumor-adjacent normal tissue samples using qRT-PCR. Results: Five lncRNAs had proper sensitivity and specificity and had target genes involved in cancer-related signaling pathways; however, they showed different expression patterns in TCGA data and in vitro. Conclusion: The results of our study demonstrated that the five-lncRNAs PART1, UCA1, DIRC3, HOTAIR, and HOXA11AS require more investigation to be confirmed as diagnostic biomarkers in gastric cancer.

A novel mutation in the cathepsin C (CTSC) gene in Iranian family with Papillon-Lefevre syndrome.

OBJECTIVES: In this study, we analyzed the whole exomes of CTSC gene in a family with history of PLS. MATERIALS AND METHODS: Genomic DNA was extracted from peripheral blood and genotype analysis was performed. The mutated protein sequence was used to find the best possible tertiary structure for homology modeling. The homology modeling of the novel mutation was then performed using the online Swiss-Prot server. The results were also analyzed for to verify its validity. RESULTS: The analysis of CTSC gene elucidated a novel insertion GAC. The novel mutation was proved by analyzing 50 healthy control volunteers. Modeling of the novel found mutation in CTSC gene revealed structural defects that may have caused the functional abnormalities. CONCLUSIONS: The structural analysis of the mutated protein model identifies changes in the stereo-chemical and the energy level of the mutated protein. Since this protein play a role in the activation of granule serine proteases from cytotoxic T lymphocytes, natural killer cells, mast cells, such structural defects may lead to its malfunction causing dysfunctioning of immune defense mechanisms.

Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. CONCLUSIONS: Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.